WO2026015877A1

WO2026015877A1 - Fluid biomarker

Info

Publication number: WO2026015877A1
Application number: PCT/US2025/037415
Authority: WO
Inventors: Kristin WILDSMITH; Viswanath Devanarayan; Pallavi SACHDEV; Kanta HORIE
Original assignee: Eisai R&D Management Co Ltd
Current assignee: Eisai R&D Management Co Ltd
Priority date: 2024-07-12
Filing date: 2025-07-11
Publication date: 2026-01-15
Anticipated expiration: 2027-01-12

Abstract

Disclosed herein are methods of diagnosing, selecting, monitoring, and treating subjects having, suspected of having, or at risk for developing Alzheimer's disease (AD).

Description

FLUID BIOMARKER

RELATED APPLICATIONS

[1] This Application claims the benefit of and priority to US Provisional Patent Application Nos. 63/670,673, filed July 12, 2024, and 63/763,784, filed February 26, 2025.

SEQUENCE LISTING

[2] The instant application contains a Sequence Listing which has been submitted electronically in ST.26 XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on July 9, 2025, is named "08061_0070-00304_SL.xml" and is 34,440 bytes in size.

FIELD

[3] Described herein are methods for diagnosing, selecting patients for treatment, monitoring, and treating Alzheimer’s disease (AD) in a subject, relating to measurements of various peptides from the microtubule-binding region of tau containing the residue 243 (MTBR-tau243), based on determining levels of the peptides in biofluid samples from a subject. MTBR-tau243 levels may be used for different aspects of treating AD, such as selecting a subject for treatment, treating AD and symptoms associated with AD, monitoring and/or adjusting the treatment, and determining maintenance dosing regimens for subjects.

BACKGROUND

[4] Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder of uncertain etiology and the most common form of dementia among older people. In 2006, there were 26.6 million cases of AD in the world (range: 11.4-59.4 million) (Brookmeyer, R., et al.. Forecasting the global burden of Alzheimer’s Disease. Alzheimer Dement. 2007; 3: 186-91), while there were more than 5 million people in the United States reportedly living with AD (Alzheimer’s Association, Alzheimer’s Association report, 2010 Alzheimer’s disease facts and figures. Alzheimer Dement. 2010;6: 158-94). By the year 2050, the worldwide prevalence of AD is predicted to grow to 106.8 million (range: 47.2-221.2 million), while in the United States alone the prevalence is estimated to be 11 to 16 million. (Brookmeyer, supra, and 2010 Alzheimer’s disease facts and figures, supra).

[5] The disease generally involves a global decline of cognitive function that progresses slowly and leaves end-stage subjects bedridden. AD subjects typically survive for only 3 to 10 years after symptom onset, although extremes of 2 and 20 years are known. (Hebert, L.E., et aL, Alzheimer disease in the U.S. population: prevalence estimates using the 2000 census. Arch Neurol. 2003; 60: 1119-1122.) AD is the seventh leading cause of all deaths in the United States and the fifth leading cause of death in Americans older than the age of 65 years, despite the fact that mortality due to AD is greatly underestimated because death certificates rarely attribute the cause of death to AD. (Alzheimer’s Association.

Alzheimer’s Association report. 2010 Alzheimer’s disease facts and figures. Alzheimer Dement. 2010; 6: 158-94.)

[6] AD represents a significant economic burden across industrialized countries with a substantial impact on healthcare systems and the public purse as well as on subjects and their families. In the United States alone, total payments for 2010 were estimated at $172 billion, including $123 billion for Medicare and Medicaid.

[7] Histologically, the disease is characterized by the presence of extracellular neuritic plaques, which primarily consist of amyloid beta (AP), as well as the presence of intracellular tangles, which primarily consist of aggregated, insoluble tau species. Both Ap and tau exists in various conformational states - Ap in monomers, oligomers, protofibrils, and insoluble fibrils and tau in neurofibrillary tangles (NFTs) in neuronal somata, neuropil threads (NTs) in neuronal dendrites, and also neuritic plaques (NPs). These pathological forms of Ap and tau accumulate in the brain of AD patients and are believed to interact, for example, with Ap acting as a molecular trigger for events leading to tau aggregation, or possibly in a synergistic manner in which pathological forms of Ap and tau enhance the function of one another (Busche and Hyman, Nature Neuroscience, 2020: 23, 1183-1193). Ap plaques may be present decades before any cognitive symptoms are detected, while tau accumulation, starting in the medial temporal lobe after around 60 years of age, spreads to limbic and association areas in concert with the emergence of clinical symptoms.

[8] Details of the exact mechanistic relationship between onset of Alzheimer’s disease, Ap, and tau are poorly understood. However, as key components of AD pathology, both Ap and tau have been targeted as treatments are developed for AD. Currently, anti-Ap antibodies and anti-tau antibodies are undergoing clinical studies as potential therapeutic agents for Alzheimer’s disease.

[9] Despite the recent development of treatments for AD, including those targeting Ap and tau, there remains a need for better monitoring of treatments, including non-invasive assays to evaluate treatment efficacy and to calibrate treatment regimens in subjects. Currently, disease monitoring is largely dependent upon assays such as positron emission tomography (PET), in which amyloid plaques or tau tangles are bound to radiotracers and imaged. However, PET is an expensive procedure that requires complex equipment and expert analysis, and the process can increase the risk of complications to the subject.

[10] There remains a need in the art for minimally invasive methods of diagnosing AD in subjects, determining the stage of AD and prognosis, selecting subjects for treatment, and monitoring efficacy of treatments for AD. Methods based on biomarkers found in biofluids such as cerebrospinal fluid (CSF) and blood offer promise, particularly where biomarkers track with progression of AD, as well as changes in amyloid and/or tau pathology which are mediated by treatments. However, a need remains to identify improved markers, including those that can correlate with effects on amyloid and tau in the brain.

SUMMARY

[11] An aspect of the present disclosure relates to a method of treating a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the MTBR- tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and/or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., comparable to a MTBR-tau243 concentration in an individual who has AD, optionally wherein the anti- Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[12] In some embodiments, the method further comprises in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; and in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a p-tau217 concentration in a control sample, or if the p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample.

[13] In some embodiments, the method further comprises c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is elevated as compared to the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration is comparable to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject.

[14] In some embodiments, the method further comprises c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is less than the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject, wherein the further therapeutically effective dose of the anti-Ap protofibril antibody is administered according to a maintenance dosing regimen.

[15] An aspect of the present disclosure relates to a method of selecting a subject having, suspected of having, or at risk for developing AD for a treatment with an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for treatment if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., compared to a MTBR-tau243 concentration in an individual who has AD, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[16] In some embodiments, the method further comprises in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; in step b), selecting the subject for treatment if the p-tau217 concentration is elevated compared to a p- tau217 concentration in the control sample or if the p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample.

[17] An aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD) and/or if the first MTBR-tau243 concentration is comparable to a positive control sample, e.g., compared to a MTBR-tau243 concentration in an individual who has AD; and c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, wherein a decrease in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration, and/or a rate of increase from the first MTBR-tau243 concentration to the first MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[18] In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample from the subject; in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration is elevated compared to a p-tau217 concentration in the control sample or if the first p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample; and in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample, wherein a decrease in the second p-tau217 concentration as compared to the first p- tau217 concentration or a decrease in the rate of increase from the first p-tau217 concentration to the second p-tau217 concentration as compared to the rate of increase in the positive control indicates a reduction in tau tangles. [19] An aspect of the present disclosure relates to a method of preventing or treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody; b) comparing the MTBR-tau243 concentration to a control sample, e.g., a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD) and/or comparing the MTBR- tau243 concentration to a positive control, e.g., a MTBR-tau243 concentration in an individual who has AD; and c) adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody if the MTBR-tau243 concentration differs from the control sample or if the MTBR-tau243 concentration differs from the positive control sample, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[20] In some embodiments, the method further comprises in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; in step b), comparing the p-tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the control sample and/or comparing the p-tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample; and in step c), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody, if the p-tau217 concentration and the MTBR-tau243 concentration in the sample differ from the control sample or if the p-tau217 concentration and the MTBR-tau243 concentration in the sample differ from the p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample.

[21] In some embodiments, the control is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status. [22] In some embodiments, wherein the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

[23] An aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second MTBR-tau243 concentration as compared to first MTBR- tau243 concentration is an indicator of treatment efficacy, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[24] In some embodiments, a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates an effective treatment.

[25] In some embodiments, a lack of a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control, indicates a non-effective treatment.

[26] In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p- tau217 concentration is an indicator of treatment efficacy.

[27] In some embodiments, a decrease from the first p-tau217 concentration to the second p-tau217 concentration, or reduction in a rate of increase from the first p-tau217 concentration to the second p-tau217 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first p-tau217 to a second tau217 concentration in an individual who has AD and is not treated, indicates an effective treatment.

[28] In some embodiments, a lack of a decrease from the first p-tau217 concentration to the second p-tau217 concentration and from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in a rate of increase between the first and second p-tau217 concentrations and MTBR-tau243 concentrations, as compared to rates in a placebo control, indicates a non-effective treatment.

[29] An aspect of the present disclosure relates to a method of detecting a decrease in a brain Ap level in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain Ap level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[30] In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p- tau217 concentration indicates a decrease of the brain Ap level in the subject.

[31] An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau level in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease in the second MTBR-tau243 concentration and the first MTBR-tau243 concentration, or a reduction in a rate of increase between the first and second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain tau level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[32] In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change from the first p-tau217 concentration to the second p-tau217 concentration indicates a decrease of the brain tau level in the subject.

[33] In some embodiments, a decrease in a brain tau level is a reduction in tau tangles.

[34] In some embodiments, the treatment with the anti-Ap protofibril antibody comprises administration of a therapeutically effective dose of the anti-Ap protofibril antibody according to an initiation dosing regimen, optionally after which the subject is switched to a maintenance dosing regimen.

[35] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject is at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD.

[36] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of p-tau217 and a further measurement of MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject are at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD.

[37] In some embodiments, the subject is switched to a maintenance dosing regimen when at least one of: a decrease in amyloid or tau positron emission tomography (PET); an increase in cerebrospinal fluid level of Ap42 and/or AP42/40 ratio; a decrease in cerebrospinal fluid level of total tau, cerebrospinal fluid level of neurogranin, and/or cerebrospinal fluid level of neurofilament light peptide (NfL); and a change in blood biomarkers as measured in the serum or plasma (e.g. increased levels of Ap42 and/or AP42/40 ratio; decreased plasma levels of plasma total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np- tau205, p-tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light (NfL)) is detected in a sample from the subject as compared to a control disease sample, e.g., a sample from an individual who has AD.

[38] In some embodiments, the subject is switched to a maintenance dosing regimen when a decrease in tau PET SUVr is measured in the subject as compared to control sample, e.g., a sample from an individual who has AD.

[39] In some embodiments, the subject is switched to a maintenance dosing regimen when a low tau PET level as measured by PET SUVr is detected in the subject, e.g., a tau PET SUVr of about 1.1, preferably about 1.06, as measured with a MK6240 PET scan, e.g., of whole cortical gray matter.

[40] In some embodiments, the maintenance dosing regimen comprises administering a maintenance dose that maintains a tau PET SUVr level at or below 1.06.

[41] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen at least 6 months (e.g., 6 months, or 12 months, or 18 months, or 24 months, or 36 months) after the start of the initiation dosing regimen.

[42] In some embodiments, the maintenance dosing regimen differs from the initiation dosing regimen in the size of dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody. [43] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject.

[44] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 2 weeks.

[45] In some embodiments, the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks, preferably as an intravenous administration at 10 mg/kg relative to the weight of the subject.

[46] In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg.

[47] In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[48] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

[49] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[50] In some embodiments, at least one of the initiation dosing regimen and the maintenance dosing regimen further comprises administration of a therapeutically effective dose of an anti-tau antibody, e.g., E2814, sequentially or simultaneously with administration of the anti-Ap protofibril antibody.

[51] In some embodiments, the anti-tau antibody is E2814.

[52] In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose once every 4 weeks.

[53] In some embodiments, the method comprises intravenous administration of E2814 at a therapeutically effective dose between 500-4500 mg (e.g., (e.g., 1500, 3000, 4500 mg).

[54] In some embodiments, the anti-tau antibody is administered prior to the first administration of the anti-Ap protofibril antibody, optionally wherein the subject has pre- AD (e.g., is asymptomatic for AD). [55] In some embodiments, the anti-Ap antibody is administered prior to the first administration of the anti-tau antibody, optionally wherein the subject has AD (e.g., early AD).

[56] In some embodiments, the MTBR-tau243 concentration is quantified by LC/MS.

[57] In some embodiments, the biofluid sample is CSF.

[58] In some embodiments, the biofluid sample is blood.

[59] In some embodiments, the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment.

[60] In some embodiments, the change and/or difference in the measurement is selected from: a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), c) decreased cerebrospinal fluid levels of ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, neurogranin, and/or neurofilament light chain (NfL), and d) decreased blood serum or plasma levels of a ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL).

[61] In some embodiments, the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology during and/or after treatment.

[62] In some embodiments, the change and/or difference in the measurement is selected from: a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), c) increased cerebrospinal fluid levels of ratio of Api-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, neurogranin, and/or neurofilament light chain (NfL), and d) increased blood serum or plasma levels of a ratio of Api-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL).

[63] In some embodiments, the decreased amyloid in the brain is an adjusted mean change from baseline in amyloid PET SUVr of at least about 0.10, or 0.15, or 0.20.

[64] In some embodiments, the treatment a) delays clinical decline as determined by ADCOMS; b) delays clinical decline as determined by ADAS MCI-ADL; c) delays clinical decline as determined by modified iADRS; d) delays clinical decline as measured by a CDR- SB; or e) delays clinical decline as measured by an ADAS-Cog.

[65] In some embodiments, the method further comprises monitoring for ARIA, e.g., ARIA-E and/or ARIA-H, e g., as observed by MRI.

[66] In some embodiments, the subject has a genetic mutation for a dominantly inherited

Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP.

[67] In some embodiments, the subject has a mutation in APP.

[68] In some embodiments, the subject has a family history of Alzheimer’s disease, e.g., a history of a family member being diagnosed with Alzheimer’s disease before the age of 60.

[69] In some embodiments, the subject is ApoE4-positive.

[70] In some embodiments, the subject is 65 to 80 years old.

[71] In some embodiments, the subject is 55 to 64 years old and has at least one risk factor chosen from: (i) a first degree relative diagnosed with dementia onset before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing prior to said administration.

[72] In some embodiments, the subject is amyloid positive.

[73] In some embodiments, the subject is amyloid positive based on a PET assessment, a CSF assessment of AP(l-42), a CSF assessment of total tau, a CSF assessment of phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), a CSF assessment of the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, MRI, retinal amyloid accumulation, and/or a blood biomarker assessment (e.g. a plasma Api-42/1- 40 ratio, plasma total tau, plasma phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), and/or the plasma ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231)).

[74] In some embodiments, the subject has Alzheimer’s disease.

[75] In some embodiments, the subject has early Alzheimer’s disease. [76] In some embodiments, the subject has been diagnosed with a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and/or has been diagnosed as having mild Alzheimer’s disease dementia; b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging - Alzheimer’s Association (NIA-AA) core clinical criteria; c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last 1 year before treatment, e.g., as corroborated by an informant; e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.

[77] In some embodiments, the subject is suspected of having AD.

[78] In some embodiments, the subject is a subject at risk for developing AD.

[79] In some embodiments, the subject is at risk for developing AD has pre-Alzheimer’ s disease (pre- AD).

[80] In some embodiments, the subject does not have cognitive impairment.

[81] In some embodiments, the anti-Ap protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[82] In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[83] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

[84] In some embodiments, the anti-tau antibody is E2814.

[85] In some embodiments, the MTBR-tau243 is MTBR-tau243-254, MTBR-tau243-256, or MTBR-tau243-256 (deamidation on 255N).

[86] In some embodiments, the MTBR-tau243 is MTBR-tau243-254.

[87] In some embodiments, the MTBR-tau243 is MTBR-tau243-256.

[88] In some embodiments, the MTBR-tau243 MTBR-tau243-256 (deamidation on 255N).

[89] An aspect of the present disclosure relates to a method of treating or preventing Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration and/or the first MTBR-tau243 concentration are elevated compared to a first control sample, e.g., a sample from an individual who does not have AD;c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p- tau217 concentration and the second MTBR-tau243 concentration are elevated compared to the first p-tau217 concentration and the second MTBR-tau243 concentration, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[90] An aspect of the present disclosure relates to a method of treating or preventing Alzheimer’s disease (AD) in a subject having, suspected of having AD, or at risk for developing AD, comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., a p-tau217 concentration in an individual who does not have AD; c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., a MTBR-tau243 concentration in an individual who does not have AD; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[91] In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[92] In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 and the MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[93] An aspect of the present disclosure relates to a method of selecting a subject having, suspected of having, or at risk for developing AD for treatment with an anti-Ap protofibril antibody and an anti-tau antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the first p-tau217 concentration and/or the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[94] An aspect of the present disclosure relates to a method of selecting a subject having, suspected of having, or at risk for developing AD for a treatment with an anti-Ap protofibril antibody and an anti-tau antibody, comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[95] In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample; and in step b), selecting the subject for the first treatment with the anti-Ap protofibril antibody if the p- tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[96] In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step d), selecting the subject for a second treatment with the anti-tau antibody if the second p- tau217 concentration and the MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[97] An aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a first p-tau217 concentration and a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the first p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD; e) optionally obtaining a measurement of a third p-tau217 concentration and a third MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the third p-tau217 concentration as compared to the second p-tau217 concentration and in the third MTBR-tau243 concentration as compared to the second MTBR-tau243 concentration, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[98] An aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p- tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); e) obtaining a measurement of a second MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the second MTBR-tau243 concentration after the second treatment as compared to the MTBR-tau243 concentration after the first treatment, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[99] In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[100] In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[101] In some embodiments, the first control sample and/or the second control sample are obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

[102] In some embodiments, the second control sample is obtained from the subject after the first treatment and prior to the second treatment.

[103] An aspect of the present disclosure relates to a method of preventing or treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody; b) comparing the first p-tau217 concentration and the first MTBR-tau243 to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) adjusting the treatment regimen to further administer a therapeutically effective amount of an anti-tau antibody if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample, ptionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[104] In some embodiments, the method further comprises: d) obtaining a measurement of a third p-tau217 concentration and a third MTBR-tau243 concentration in a third biofluid sample, e.g., a CSF or blood sample, from the subject; e) comparing the third p-tau217 concentration and the third MTBR-tau243 concentration to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); and f), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody and/or the anti-tau antibody, if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample.

[105] In some embodiments, the control sample is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

[106] In some embodiments, the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

[107] An aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject having, suspected of having AD, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second p- tau217 concentration and a change in the second MTBR-tau243 concentration, as compared to the first p-tau217 concentration and the first MTBR-tau243 concentration, is an indicator of treatment efficacy, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[108] In some embodiments, a decrease or reduction in increase in the second p-tau217 concentration as compared to the first p-tau217 concentration and/or in the second MTBR- tau243 concentration as compared to the first MTBR-tau243 concentration indicates an effective treatment.

[109] In some embodiments, a lack of a decrease or lack of a reduction in increase in the second p-tau217 concentration as compared to the first p-tau217 concentration and/or in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration indicates a non-effective treatment.

[HO] An aspect of the present disclosure relates to a method of detecting a decrease in a brain Ap level in a subject having, suspected of having AD, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p- tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a decrease between the second p-tau217 concentration and the first p-tau217 concentration and a decrease between the second MTBR-tau243 concentration and the first MTBR-tau243 concentration indicates a decrease of a brain Ap level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[Hl] An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau level in a subject receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a decrease between the second p-tau217 concentration and the first p-tau217 concentration and a decrease between the second MTBR-tau243 concentration and the first MTBR-tau243 concentration, indicates a decrease of a brain tau level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[112] In some embodiments, a decrease in a brain tau level is a reduction in tau tangles.

[113] In some embodiments, the treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody is administered according to an initiation dosing regimen if the subject receives treatment with an anti -tau antibody.

[114] In some embodiments, the treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody is administered according to an initiation dosing regimen, optionally after which the subject is switched to a maintenance dosing regimen of the anti-Ap protofibril antibody.

[115] In some embodiments, the maintenance dosing regimen of the anti-Ap protofibril antibody is administered if a subject receives a treatment with an anti -tau antibody.

[116] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen of the anti-Ap protofibril antibody at least 6 months (e.g., 6 months, or 12 months, or 18 months, or 24 months, or 36 months) after the start of the initiation dosing regimen. [117] In some embodiments, wherein the maintenance dosing regimen differs from the initiation dosing regimen in the size of dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody.

[118] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject.

[119] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 2 weeks.

[120] In some embodiments, the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks, preferably as an intravenous administration at 10 mg/kg relative to the weight of the subject.

[121] In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg.

[122] In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[123] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

[124] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[125] In some embodiments, the second treatment comprises administration of a therapeutically effective dose of the anti-tau antibody E2814.

[126] In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose once every 4 weeks.

[127] In some embodiments, the method comprises intravenous administration of E2814 at a therapeutically effective dose between 500-4500 mg (e.g., (e.g., 500, 1000, 1500, 3000, or 4500 mg).

[128] In some embodiments, the MTBR-tau243 concentration is quantified by LC/MS.

[129] In some embodiments, the biofluid sample is CSF. [130] In some embodiments, the biofluid sample is blood.

[131] In some embodiments, the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment with the anti-Ap protofibril antibody.

[132] In some embodiments, the change and/or difference in the measurement is selected from: a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), c) decreased cerebrospinal fluid levels of ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, neurogranin, and/or neurofilament light chain (NfL), and d) decreased blood serum or plasma levels of a ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL).

[133] In some embodiments, the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology during and/or after treatment with the anti -tau antibody.

[134] In some embodiments, the change and/or difference in the measurement is selected from: a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), c) increased cerebrospinal fluid levels of ratio of Api-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, neurogranin, and/or neurofilament light chain (NfL), and d) increased blood serum or plasma levels of a ratio of Api-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL). [135] In some embodiments, the decreased amyloid in the brain is an adjusted mean change from baseline in amyloid PET SUVr of at least about 0.10, or 0.15, or 0.20.

[136] In some embodiments, the treatment a) delays clinical decline as determined by ADCOMS; b) delays clinical decline as determined by ADAS MCI-ADL; c) delays clinical decline as determined by modified iADRS; d) delays clinical decline as measured by a CDR- SB; or e) delays clinical decline as measured by an ADAS-Cog.

[137] In some embodiments, the method further comprises monitoring for ARIA, e.g., ARIA-E and/or ARIA-H, e g., as observed by MRI.

[138] In some embodiments, the subject has a genetic mutation for a dominantly inherited Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP.

[139] In some embodiments, the subject has a mutation in APP.

[140] In some embodiments, the subject has a family history of Alzheimer’s disease, e.g., a history of a family member being diagnosed with Alzheimer’s disease before the age of 60.

[141] In some embodiments, the subject is ApoE4-positive.

[142] In some embodiments, the subject is 65 to 80 years old.

[143] In some embodiments, the subject is 55 to 64 years old and has at least one risk factor chosen from: (i) a first degree relative diagnosed with dementia onset before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing prior to said administration.

[144] In some embodiments, the subject is amyloid positive.

[145] In some embodiments, the subject is amyloid positive based on a PET assessment, a CSF assessment of AP(l-42), a CSF assessment of total tau, a CSF assessment of phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), a CSF assessment of the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, MRI, retinal amyloid accumulation, and/or a blood biomarker assessment (e.g. a plasma Api-42/1- 40 ratio, plasma total tau, plasma phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), and/or the plasma ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231)).

[146] In some embodiments, the subject has Alzheimer’s disease.

[147] In some embodiments, the subject has early Alzheimer’s disease.

[148] In some embodiments, the subject has been diagnosed with a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and/or has been diagnosed as having mild Alzheimer’s disease dementia; b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging - Alzheimer’s Association (NIA-AA) core clinical criteria; c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last 1 year before treatment, e.g., as corroborated by an informant; e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.

[149] In some embodiments, the subject is suspected of having AD.

[150] In some embodiments, the subject is a subject at risk for developing AD.

[151] In some embodiments, the subject at risk for developing AD has pre- Alzheimer’ s disease (pre- AD).

[152] In some embodiments, the subject does not have cognitive impairment.

[153] In some embodiments, the anti-Ap protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[154] In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[155] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

[156] In some embodiments, the anti-tau antibody is E2814.

[157] In some embodiments, the MTBR-tau243 is MTBR-tau243-254, MTBR-tau243-256, or MTBR-tau243-256 (deamidation on 255N).

[158] In some embodiments, the MTBR-tau243 is MTBR-tau243-254.

[159] In some embodiments, the MTBR-tau243 is MTBR-tau243-256.

[160] In some embodiments, the MTBR-tau243 is MTBR-tau243-256 (deamidation on 255N).

BRIEF DESCRIPTION OF DRAWINGS

[161] Figure 1 shows effects of lecanemab on the rate of increase in CSF MTBR-tau243.

[162] Figure 2 shows effects of lecanemab on tau PET SUVr in 3 brain regions of interest. [163] Figure 3 shows an adjusted mean change from baseline (CFB) in CSF MTBR- tau243 over time, as determined in subjects who were categorized as having low tau PET levels or medium-high tau PET levels.

[164] Figure 4 show the result of a baseline correlation analysis of CSF MTBR-tau243, tau PET SUVr across brain regions of interest, and other fluid biomarkers assessed (CSF markers: ptaul81, total tau, neurogranin, NfL, Ap40 and Ap42; plasma markers: pTau217, pTaul81, AP42/40, NfL and GFAP).

[165] Figure 5 shows a correlation of CSF MTBR-tau243 with amyloid PET and tau PET SUVr.

[166] Figure 6 shows the association of brain amyloid and tau status with various biomarkers, indicated by the AUROC.

[167] Figure 7 shows the association of amyloid status (20 CL) with various biomarkers.

[168] Figure 8 shows the association of various biomarkers with tau progression.

DETAILED DESCRIPTION

[169] The presence of Ap and tau pathology in Alzheimer’s disease (AD) has led to the emergence of two hypotheses to explain the cause and progression of the disease. According to each hypothesis, one of the two pathologies emerges first and acts as a trigger for the other. For example, Ap aggregation may be observed before tau aggregation, and studies have identified molecular mechanisms by which Ap leads to aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). Conversely, tau tangles may be observed in the brains of patients with no Ap pathology, and tau pathology correlates more closely with AD severity and progression than Ap plaque load (Knox, StressMarq Biosciences Inc., 2022. stressmarq.com/amyloid-hvpothesis-vs-tau-hypothesis/). Depending on the hypothesis, either Ap or tau may be targeted to treat AD.

[170] The “amyloid hypothesis” of AD proposes that amyloid P (AP) peptides play a central role in the pathogenesis of AD. Specifically, it is hypothesized that neurodegeneration in AD may be caused by deposition of Ap plaques in brain tissue due to an imbalance between Ap production and Ap clearance, leading to formation of neurofibrillary tangles containing tau protein. Ap peptides generally exist in a dynamic continuum of conformational states such that species tend to progress from monomeric Ap, to soluble Ap assemblies that include a range of low molecular weight oligomers to higher molecular weight protofibrils, and finally to insoluble fibrils (plaques) which accumulate in extracellular spaces. Targeting these soluble and insoluble Ap tangles and plaques may provide therapeutic benefit.

[171] A number of immunotherapies have been developed with the intent to reduce the amount of insoluble Ap fibrils deposited in the brain, and/or, to reduce formation of tau tangles. However, a simple correlation between the quantity and progressive accumulation of insoluble amyloid plaques and the clinical course of AD has not been determined. While therapeutic strategies continue to focus on removal of insoluble amyloid plaques, an additional approach to therapy may include reducing the toxic Ap aggregates, such as protofibrils, that may contribute to the neuronal degeneration characteristic of AD. (See, e.g., Dodort, J.-C. and May, P., “Overview on rodent models of Alzheimer’s disease.” Curr. Protocols Neurosci. 2005; 9.22-1-9.22-6; Englund, H. et al., “Sensitive ELISA detection of amyloid-P protofibrils in biological samples.” J. Neurochem. 2007; 103:334-45; and Gotz, J. et al., “Transgenic animal models of Alzheimer’s disease and related disorders: histopathology, behavior and therapy.” Mol. Psychiat. 2004; 9:664-83.)

[172] In addition to Ap toxicity, tau protein pathology is a major hallmark of AD. Tau proteins belong to the family of microtubule-associated proteins (MAPs) that normally function to promote assembly and stability of microtubules. Changes in tau, such as hyperphosphorylation, affect its ability to bind microtubules and perform physiological functions, eventually leading to pathologies associated with AD. The “tau hypothesis” of AD proposes that accumulation of pathogenic misfolded tau proteins leads to the formation of neurofibrillary tangles (NFTs) inside neurons. NFTs correlate strongly with mitochrondial dysfunction, inflammation, synaptic loss, and neurodegeneration in affected neurons. In addition, pathological tau “seeds” of misfolded tau proteins, as well as fibrillar tau species, are believed to spread between neurons, possibly through direct anatomical connections, and across brain regions (Zhang et al., Front. Cell Dev. Biol., 2021, Sec. Molecular and Cellular Pathology, Volume 9). Evidence of tau spreading has been reported in animal studies, and circumstantial evidence has been found in post-mortem human brains from AD patients, analyses of tau PET signals in human brains at disease stages across the AD continuum, and simulations (Schoonhaven et al., Brain. 2023; 146(10): 4040-4054; Vogel et al., Nat Commun., 2020; 11, 2612). Brain regions where tau NFTs appear are affected by atrophy and hypometabolism, and the spatial distribution of tau NFTs over time tracks closely with clinical symptoms of AD (Koychev et al., Journal of Nuclear Medicine October 2020, 61 (10) 1413-1418). [173] Immunotherapies for targeting different forms of tau and reducing tau pathology have been developed. In clinical trials, various anti-tau antibodies have been used to target epitopes in each of the regions of tau (N-terminus, proline-rich domain, microtubule binding region, and C-terminus). Some antibodies are reported to facilitate tau clearance intracellularly, which may help to prevent tau toxicity mediated by oligomeric and soluble tau aggregates, while other antibodies are predicted to act on tau seeds extracellularly (Ji and Sigurdsson, Drugs. 2021; 81(10) 1135-1152). An exemplary anti-tau antibody, E2814, has been designed to target epitopes in the MTBR with the aim to prevent tau species from becoming seed competent (Roberts et al., Acta Neuropathol Commun. 2020; 8: 13) and WO2023079485A1, the contents of which are incorporated by reference herein.

[174] While immunotherapies for Ap and tau are an active area of research in both pre- clinical and clinical studies, the precise mechanisms by which any of these antibodies mediate their effects is not known. The relationship between Ap pathology, tau pathology, and clinical symptoms of AD is not clear. In one model, Ap pathology is upstream to tau in AD progression, and triggers or facilitates mechanisms leading to tau pathology, such as tau hyperphosphorylation and oligomerization (Hampel et al., Mol Psychiatry. 2021; 26, 5481— 5503; Zhang et al., Int J Biol Sci. 2021; 17(9): 2181-2192). According to this model, it may be possible to use certain anti-Ap antibodies to inhibit amyloid-induced tau phosphorylation in the neuron where the Ap aggregates, e.g., particularly by inhibiting soluble forms of amyloid that may interact with tau. This amyloid removal could slow existing tau intracellular aggregation and secretion in the neuron and/or reduce or prevent formation of new tau seeds. However, existing tau seeds may still spread to neighboring neurons, facilitating tau spreading. Thus, the overall effect of an Ap antibody on tau NFT formation and AD symptoms is challenging to predict.

[175] Biomarkers for Ap pathology and tau pathology can help to track progress of AD and determine effects of therapeutic antibodies on the disease. Biomarkers may be any measurement obtained in an individual or from a sample obtained from an individual whose levels indicate the disease. In AD, exemplary biomarkers include PET biomarkers obtained from positron emission tomography (PET) imaging of radiotracers that bind to Ap plaques or tau aggregates and indicate the presence, localization, and density of the pathological structures. Data from PET biomarker imaging indicates that Ap may accumulate, sometimes for decades, without evidence of cognitive impairment, however, tracking of increased Ap accumulation and density in brain regions over time (e.g., by amyloid-PET) may be used to predict progression of cognitive impairment (Hampel et al., Mol Psychiatry. 2021; 26, 5481- 5503; Koychev et al., Journal of Nuclear Medicine October 2020, 61 (10) 1413-1418). In contrast, tau NFTs appear to correlate more closely with brain regions affected by atrophy and hypometabolism, and the spatial distribution of tau NFTs over time tracks closely with clinical symptoms of AD (Koychev et al., 2020, supra).

[176] Biomarkers may also be obtained from biofluids such as cerebrospinal fluid (CSF) or blood. Exemplary biomarkers which have been shown to reflect amyloid, tau pathology, and/or clinical symptoms of AD include but are not limited to Ap (Ap42, Ap40, ratio AP42/40), tau (total tau, phosphorylated tau, e.g., at sites 181, 205, 217, and 231, and the ratio of a phosphorylated tau species to its non-phosphorylated tau species), neurogranin, neurofilament light chain (NfL), and GFAP, which can be measured in CSF and/or blood (e.g., plasma) (Wang et al., Front Cell Neurosci. 2023; 17: 1279046). Notably, biomarkers such as tauPET, AP42/40, and p-taul81 have been shown to reflect not only changes which occur during AD, but also therapeutic effects mediated by the anti-Ap-protofibril antibody lecanemab (WO2023283650, WO2023149970, and WO2024118665, the contents of which are incorporated herein in their entirety).

[177] A further biomarker for tau is MTBR-tau243, which may be measured in CSF or blood, and which correlates closely with tau PET and clinical tests for dementia (Horie et al., Brain, 2021, 144(2): 515-527; Horie et al., Nature Medicine, 2023, 29: 1954-1963; Horie et al., The Journal of Prevention of Alzheimer’s Disease 2023,10: S36; Horie et al., Nature Medicine 2025, https://doi.org/10.1038/s41591-025-03617-7). One species of MTBR-tau243 is a peptide fragment of tau, spanning residues 243-254 in the microtubule-binding region of tau and is enriched in tau aggregates (also called “tryptic MTBR-tau243”). Another species of MTBR-tau243 is a peptide fragment of tau spanning residues 243-256 (also called “E- MTBR-tau243”). As used herein, “MTBR-tau243” encompasses both tryptic MTBR-tau243 and E-MTBR-tau243 unless context indicates otherwise. CSF MTBR-tau243 is more closely correlated with tau PET SUVR and MMSE scores than were other tau biomarkers, suggesting that MTBR-tau243 tracks more closely with tau pathology than with amyloid pathology, and may be a suitable biomarker for changes in aggregated tau pathology (Horie et al., 2023, supra).

[178] Surprisingly, however, certain forms of MTBR-tau243 have been demonstrated herein to track with changes mediated by an anti-Ap protofibril antibody. MTBR-tau243 levels in CSF showed a reduced rate of increase after treatment with lecanemab; the tryptic MTBR-tau243 species was measured in CSF after about 12 months and about 18 months of lecanemab treatment. These results were unexpected from prior studies. For example, subjects treated with the anti-Ap antibody gantenerumab, which binds to Ap fibrils, did not show a change in MTBR-tau243 even after 4 years of treatment ( Bateman et al., J Prev Alzheimers Dis. 2023;10(Suppl 1): S7; Barkhof et al., presentation at AD/PD 2023, available at https://medically.roche.com/global/en.html/home), although gantenerumab has been shown to reduce amyloid plaques and affect other measures of amyloid pathology (Bateman et al., N Engl J Med, 2023; 389(20): 1862-1876). Despite this, MTBR-tau243 has been shown herein to surprisingly be a proxy for the selection and monitoring of effectiveness of an anti-Ap protofibril antibody such as lecanemab.

[179] Without being bound by theory, binding of lecanemab to protofibrils may reduce the formation of new amyloid plaques and/or disrupt existing amyloid plaques, thereby reducing tau hyperphosphorylation and formation of new tau tangles. The reduction in tau tangles may be reflected in decreased MTBR-tau243 levels. In addition, MTBR-tau243 may be a pathological species that acts as a tau seed for extracellular tau propagation (Horie et al., 2021, supra), and decreased MTBR-tau243 levels after lecanemab treatment may reflect a reduction in formation of any or all tau seeds after lecanemab treatment. Accordingly, ongoing treatment with lecanemab, e.g., by maintenance dosing, may not only reduce formation and maintenance of amyloid plaques, but also downstream events related to tau seeding and/or formation of tau tangles.

[180] Described herein are methods and uses that link the biomarker MTBR-tau243 and immunotherapy for AD. In various embodiments, an anti-Ap protofibril antibody, such as lecanemab (also called BAN2401, see Tables 1-4), may be used to treat AD, e.g., by selecting a patient for treatment, treating, monitoring treatment, and making decisions regarding maintenance dosing, based on MTBR-tau243 levels in biofluid samples, e.g., CSF or blood.

Biomarkers for anti-Ap protofibril antibodies and anti-tan antibodies

[181] One aspect of the present disclosure relates to a biomarker which may be used at any step of treating a subject who has, is suspected of having, or is at risk of developing AD. In some embodiments, the biomarker may be used for selecting a subject for treatment with an anti-Ap protofibril antibody such as lecanemab, treating the subject with the anti-Ap protofibril antibody, reducing a brain Ap level by administering the anti-Ap protofibril antibody, reducing a brain tau level or slowing an increase in brain tau level by administering the anti-Ap protofibril antibody, monitoring efficacy of treatment with the anti-Ap protofibril antibody, and/or altering a treatment regimen that comprises administration of the anti-Ap protofibril antibody. Altering the treatment regimen may comprise adding an additional therapy, such as an anti-tau antibody (e.g., E2814). In some embodiments, the biomarker is a tau species. In some embodiments, the biomarker is an MTBR-tau243 species. In some embodiments, the biomarker is CSF MTBR-tau243 or blood (e.g., plasma) MTBR-tau243. In some embodiments, the MTBR-tau243 species is used in conjunction with one or more additional markers, such as p-tau217 or a ratio of p-tau217 to total tau217. In some embodiments, the additional marker is at least one of Ap42 and/or AP42/40 ratio; plasma total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light (NfL)..

MTBR-tau243 Peptides

[182] In some embodiments, the MTBR-tau243 species is a peptide fragment such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the biomarker is tryptic MTBR-tau243, e.g., in CSF or plasma. In some embodiments, the biomarker is E-MTBR-tau243, e.g., in CSF or plasma.

[183] In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma. As used herein, the terms “MTBR-tau243 species”, “MTBR-tau243” and “MTBR-tau243 peptide” are interchangeably used to refer to peptide fragments of the microtubule-binding region containing residue 243, unless context indicates otherwise, e.g. as in Example 4.

[184] In some embodiments, the tau isoform 2N4R comprises an N-terminus (amino acids 1-103), mid-domain (amino acids 104-243), MTBR (amino acids 244-268), and C- terminus (amino acids 369-441). Other tau isoforms vary in a predictable way the corresponding amino acids may be determined in other tau isoforms. In some embodiments, MTBR-tau refers to a tau peptide comprising at least two amino acids from the microtubule binding region (MTBR) of tau (e.g., amino acids 244-368 of the human tau isoform 2N4R, 441 amino acids in length). In some embodiments, a long form of MTBR (also called “long MTBR tau”) comprises at least two, e.g., all of the amino acids 259-441 of 2N4R. In some embodiments, a short form of MTBR (also called “short MTBR-tau”) comprises at least two, e.g., all of the amino acids 235-254 of 2N4R.

[185] In some embodiments, MTBR-tau243 fragments are purified from a biological samples (e.g., CSF and/or blood) and quantified using methods disclosed in WO2024044637, the contents of which are incorporated herein by reference in their entirety. For example, MTBR-tau243 may be purified from endogenously cleaved fragments of tau, which have been produced by an in vivo proteolytic cleavage event to identify E-MTBR-tau243. In some embodiments, purification of MTBR-tau243 comprises contacting a sample (e.g., CSF or blood) with one or more anti-tau antibodies in an immunodepletion step, followed by contacting the immunodepleted sample with an antibody that binds to a short MTBR-tau fragment, then washing the sample, digesting with a protease (e.g., trypsin) to mediate proteolytic cleavage, desalting, and analysis by liquid chromatography/mass spectrometry (LC-MS) to identify tryptic MTBR-tau243.

[186] In some embodiments, purification of MTBR-tau243 comprises a two-step process, in which a sample (e.g, CSF or blood) is contacted with one or more anti-tau antibodies (e.g., 3 or 4 anti-tau antibodies) in an immunodepletion step, followed by washing, digestion with a protease (e.g., trypsin), desalting, and analysis by LC-MS. In some embodiments, the remaining immunodepleted precipitate is immunoprecipitated with an antibody that binds to the short form of tau-MTBR, washed, and subjected to trypsin digestion, desalted, and analyzed by LC-MS.

[187] In some embodiments, purification of MTBR-tau243 comprises using a capture step for MTBR-tau species. In some embodiments, purification comprises a first and/or second immunodepletion step, or, optionally, no immunodepletion step. In some embodiments, the method comprises immunoprecipitation of the sample with an antibody to the short form of MTBR-tau, washing, digesting with a protease, desalting, and analyzing by LC-MS. In some embodiments, digestion with a protease comprises digestion with an endopeptidase such as a cysteine protease (Arg-C) that selectively cleaves at the C-terminal side of arginine residues. In some embodiments, the Arg-C is a highly selective Arg-C that primarily cleaves at the C-terminal side of Arg sites and does not substantially cleave Lys residues. An exemplary Arg-C is gingipain (Arg-C Ultra, a mass spec grade endoprotease, Promega, USA). Cleavage with such an Arg-C produces the MTBR-tau243-256 (E-MTBR- tau243) peptide, because of cleavage at the endogenous arginine at position 256. In some embodiments, digestion with a protease comprises digestion with trypsin, which cleaves at both lysine and arginine residues. Cleavage with trypsin produces the MTBR-tau243-254 peptides, because of cleavage of a lysine residues at position 254.

[188] In some embodiments, different MTBR-tau243 peptides are purified using the methods disclosed in WO2024044637. In some embodiments, trypsinized fragments of MTBR-tau243 comprise MTBR-tau243-254 (“tryptic MTBR-tau243). In some embodiments, non-trypsinized, endogenous fragments of MTBR-tau243 comprise MTBR-tau243-256 (also called “E-MTBR-tau243”). MTBR-tau243 fragments may be deamidated, for example, at position 255 in MTBR-tau243-256.

[189] In some embodiments, a level of a biomarker such as an MTBR-tau243 species (e.g., tryptic MTBR-tau243 and/or E-MTBR-tau243) in a biofluid sample obtained from a subject (“from a subject”) is compared to a level of the biomarker (e.g., MTBR-tau243 species) in a biofluid sample obtained from a control (“from a control” or from a “control sample”, e.g., a sample obtained from a control). In some embodiments, the control is a healthy individual. In some embodiments, the control is an individual who does not have AD. In some embodiments, the control is an individual who has signs or symptoms of AD, preclinical AD, prodromal AD, and/or early AD, but is at an earlier stage of disease progression than the subject. In some embodiments, the control is a sample from a subject with more advanced AD.

[190] In some embodiments, a level of a biomarker (e.g., a MTBR-tau243 species such as tryptic MTBR-tau243 and/or E-MTBR-tau243) in a biofluid sample obtained from a subject (“from a subject”) may be compared to a reference or threshold level of the biomarker (e.g., MTBR-tau243 species), reflecting a value obtained by using measurements of the biomarker (e.g., the MTBR-tau243 species) from a population of individuals who are at a known stage of disease or lack of disease, e.g., from an individual(s) who is healthy, does not have AD, and/or at an earlier stage of the disease than the subject. In some embodiments, the control is an individual who has amyloid-negative status, e.g., as indicated by biomarkers and/or amyloid PET. In some embodiments, the positive control is an individual who has tau- negative status, as indicated by biomarkers and/or tau PET. In some embodiments, the control is a reference/threshold level of a biomarker (e.g., MTBR-tau243 species) that has been determined by modeling. In some embodiments, the control sample is a previous measurement of a biomarker (e.g., a MTBR-tau243 species) in a biofluid sample from the subject who is receiving a treatment for AD. For example, the control sample may have been obtained from the subject prior to the treatment, or at an earlier time during the course of treatment, prior to performing the steps of the method. As used herein, the identity of the control will be apparent from the context of the embodiment.

[191] In some embodiments, a level of a biomarker (e.g., a MTBR-tau243 species such as tryptic MTBR-tau243 and/or E-MTBR-tau243) may be compared to a level of the biomarker in a biofluid sample from a positive control (also, “from a positive control sample”). As disclosed herein, a “positive control” (also “disease positive control”) refers to an individual who has AD, who is at a later stage of disease progression than the subject, and/or whose disease progresses without treatment while the subject receives treatment. In some embodiments, a positive control is an untreated AD subject or untreated control subject who is not being treated for AD. In some embodiments, a positive control has AD and is not treated with an anti-protofibril antibody. In some embodiments, a positive control has AD and is not treated with an anti-tau antibody. In some embodiments, the positive control is an individual with amyloid and/or tau pathology, e.g., as measured by biomarkers (e.g., AP42/40 ratio, p-tau species) and/or by amyloid PET and/or tau PET. In some embodiments, the positive control is an individual who has a known stage of AD and/or amyloid-positive status, e.g., as indicated by biomarkers, cognitive scores, and/or amyloid PET. In some embodiments, the positive control is an individual who has tau-positive status, as indicated by biomarkers and/or tau PET (e.g., low, intermediate, or high levels of tau PET). In some embodiments, a level of a biomarker (e.g., a MTBR-tau243 species such as tryptic MTBR- tau243 and/or E-MTBR-tau243) in a biofluid sample obtained from a subject may be compared to a reference or threshold level of the biomarker (e.g., MTBR-tau243 species), reflecting a value obtained by using measurements of the biomarker (e.g., the MTBR-tau243 species) from a population of individuals who have AD, who are at a later stage of the disease than the subject, and/or whose disease progresses without treatment while the subject receives treatment. In some embodiments, the control is a reference/threshold level of the biomarker (e.g., MTBR-tau243 species) that has been determined by modeling. In some embodiments, a measurement in a biofluid sample (e.g., CSF or blood) obtained from a subject may be comparable to a positive control, e.g., measurement from an individual who has AD. In some embodiments, a measurement obtained from subject sample is comparable to the positive control if it is equal, about equal, equivalent, about equivalent, similar, or has features in common such as quantity or rate of change after treatment, to the positive control. As used herein, the identity of the positive control will be apparent from the context of the embodiment.

[192] Without being bound by theory, the peptides MTBR-tau243-254 and MTBR- tau243-256 may show different dynamics during the course of AD and/or may show different responses to treatment with the anti-Ap protofibril antibody (e.g, lecanemab). For example, plasma MTBR-tau243, e.g., plasma E-MTBR-tau243, may show robust correlation with tau- PET in late Braak regions and may maintain diagnostic accuracy of tau-PET positivity in subjects who are AP-positive. Plasma E-MTBR-tau243 performance in predicting MMSE is similar to tau-PET, and may be better than p-tau217 in predicting subjects who are AP- positive, and thus may be used in selecting and monitoring patients for treatment with lecanemab, including decisions about when to add other therapies (e.g., E2814) to address build up of MTBR-tau243 and associated advancement in AD stage.

[193] In some embodiments, the MTBR-tau243 species is MTBR-tau243-254 (also called “tryptic MTBR-tau243”) or MTBR-tau243-256 (also called “E-MTBR-tau243”). In some embodiments, the MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR- tau243) is measured in CSF. In some embodiments, the MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR-tau243) is measured in blood, e.g., plasma.

[194] In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR- tau-243 or E-MTBR-tau243) in CSF and/or plasma of a subject is used to select a subject for treatment with an anti-Ap protofibril antibody (e.g., lecanemab). In some embodiments, a method of selecting a subject for a treatment with an anti-Ap protofibril antibody, comprises a) obtaining a measurement of a level of a MTBR-tau243 species in a biofluid sample (e.g., concentration of a MTBR-tau243 species in a biofluid sample), e.g., in a CSF or blood sample, from the subject; b) selecting the subject for treatment if the level of the MTBR- tau243 species is elevated compared to a control sample, e.g., compared to a level of the MTBR-tau243 species in a biofluid sample from an individual who does not have Alzheimer’s disease (AD). p-tau217 at early stages of AD progression

[195] In some embodiments, the biomarker p-tau217 (and/or the ratio of p-tau217 to non- p-tau217, also called the “p-tau217 ratio” or “ptau217R”) may also be assayed in addition to MTBR-tau243. CSF p-tau217 has been shown to correlate closely with amyloid PET in cohorts of subjects across certain stages of Alzheimer’s disease (AD) neuropathology (Barthelemy et al., Journal of Alzheimer’s Disease 85 (2022) 415-429, DOI 10.3233/JAD- 210677). Plasma p-tau217 has also been shown to accelerate in subjects with preclinical AD (amyloid-P-positive, cognitively unimpaired) or prodromal AD (amyloid-P-positive, with mild cognitive impairment) as compared to amyloid-P-negative counterparts (either cognitively unimpaired or with mild cognitive impairment), and to accelerate in subjects with mild cognitive impairment who later converted to AD dementia (Mattsson-Carlgren et al., Brain 2020: 143; 3234-3241, doi: 10.1093/brain/awaa286). Levels of p-tau217 (and/or the ratio of p-tau217) may be elevated in a subject sooner in the time course of disease for AD subjects than levels of MTBR-tau243. In addition, plasma p-tau217R measurements have been shown to improve plasma biomarker algorithms for identifying preclinical amyloid PET positivity (Rissman et al., Alzheimers Dement. 2023 Nov 6;20(2): 1214-1224. doi: 10.1002/alz.l3542). Thus, in some embodiments, p-tau217 and/or p-tau217R, measured in CSF and/or plasma, is used to stage subjects as being at early (e.g., preclinical or prodromal) stages of AD, as well as subjects who progress to AD. In some embodiments, staging is performed using a combination of p-tau217 and/or p-tau217R with an MTBR-243 species, e.g., as measured in CSF and/or plasma.

[196] In some embodiments, a level of the MTBR-tau243 species (e.g., tryptic MTBR- tau-243 or E-MTBR-tau243) in CSF and/or plasma of a subject is used in conjunction with a level of p-tau217 (or the level of a ratio of p-tau217/tau217) to select a subject for treatment with an anti-Ap protofibril antibody (e.g., lecanemab). In some embodiments, a method of selecting a subject for a treatment with an anti-Ap protofibril antibody, comprises a) obtaining a measurement of a level (e.g., concentration) of a MTBR-tau243 species and a level (e.g., concentration) of p-tau217 (or the level of a ratio of p-tau217/tau217) in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for treatment if the level of the MTBR-tau243 species and p-tau217 (or the level of a ratio of p- tau217/tau217) is elevated compared to a control sample, e.g., compared to levels in a biofluid sample from an individual who does not have Alzheimer’s disease (AD).

[197] In some embodiments, the level of p-tau217 and/or p-tau217R in the CSF and/or plasma of a subject is used to select the subject for treatment with an anti-Ap protofibril antibody (e.g., lecanemab). In some embodiments, a high level of p-tau217 and/or p-tau217R (e.g., including an increasing level of p-tau217 and/or p-tau271R measured over a period of time) and a low level of a MTBR-tau243 species (e.g., including little or no increase in the level of a MTBR-tau243 species measured over the same period of time) in the sample from the subject as compared to a control sample (e.g., a sample from the level of p-tau217 and/or p-tau217R and/or the MTBR-tau243 species in a biofluid sample from a subject who does not have AD) indicates an early Braak stage, e.g., stage I or stage II, of AD and/or tau progression. In some embodiments, a method of selecting a subject for a treatment with an anti-Ap protofibril antibody, comprises a) obtaining a measurement of a level of p-tau217 and/or p-tau217R in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for treatment if the level of p-tau217 and/or p-tau217R is elevated compared to a control sample, e.g., compared to a level of p-tau217 and/or p-tau217R in a biofluid sample from an individual who does not have Alzheimer’s disease (AD).

[198] In some embodiments, the subject with a high level of p-tau217 and/or p-tau217 (e.g., including an increasing level of p-tau217 and/or p-tau271R measured over a period of time in biofluid samples from the subject) and a low level of a MTBR-tau243 species (e.g., levels comparable to a healthy control, levels lower than a subject with more advanced AD, levels that show little or no increase measured over a period of time prior to commencing therapy) is administered the anti-Ap protofibril antibody. In some embodiments, the levels of p-tau217 and/or p-tau217R as well as the levels of MTBR-tau243 (tryptic MTBR-tau243 and/or E-MTBR-tau243 species) are monitored in biofluid samples from the subject over the course of treatment with lecanemab. In some embodiments, an increase in the level of either or both MTBR-tau243 species in CSF and/or plasma during treatment with lecanemab indicates tau progression, e.g., an increase in levels of pathogenic tau species such as tau tangles and/or spreading of pathogenic tau species across brain regions. In some embodiments, an increase in the level of either or both MTBR-tau243 species in CSF and/or plasma during treatment with lecanemab indicates tau progression, as confirmed by tau PET.

[199] In some embodiments, an increase in the level of either or both MTBR-tau243 species (tryptic MTBR-tau243 and/or E-MTBR-tau243 species) in CSF and/or plasma during treatment with lecanemab indicates AD progression, e.g., indicates that AD is advancing in severity. In some embodiments, when either or both MTBR-tau243 species increases in biofluid samples (e.g., CSF and/or plasma) obtained from the subject during lecanemab treatment as compared to levels of either or both MTBR-tau243 species in a biofluid sample from a control subject (e.g., a subject who does not have AD, a subject who has early AD, and/or the subject at baseline prior to treatment with the anti-Ap protofibril antibody), the subject is administered a further treatment, e.g., an anti-tau antibody such as E2814. In some embodiments, a subject is monitored for reduction in the MTBR-tau243 species in a biofluid sample (e.g., CSF and/or plasma) following treatment with an anti-tau antibody such as E2814. In some embodiments, a reduction in the level of the MTBR-tau243 species indicates effective treatment with the anti-tau antibody such as E2814. In some embodiments, a further dose of the anti-tau antibody such as E2814 is administered if an effective treatment is observed.

MTBR-tau243 and treatment with an anti-Ap protofibril antibody

[200] In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR- tau243 and/or E-MTBR-tau243) measured in biofluid samples from the subject is elevated relative to a healthy control prior to treatment with an anti-Ap protofibril antibody such as lecanemab. In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR-tau243 and/or E-MTBR-tau243) measured in biofluid samples from the subject is comparable to a positive control, e.g., a MTBR-tau243 level from an individual who has AD, e.g., early AD. In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR-tau243 and/or E-MTBR-tau243) measured in biofluid samples from the subject continues to change over time as AD progresses. In some embodiments, the tryptic MTBR- tau243 level changes (e.g., increases) as AD progresses, and the change occurs in at least one of CSF and plasma. In some embodiments, the level of tryptic MTBR-tau243 increases in at least one of, or both of, CSF and plasma as AD progresses. In some embodiments, the E- MTBR-tau243 level changes (e.g., increases) as AD progresses, and the change occurs in one or both of CSF and plasma. In some embodiments, the level of E-MTBR-tau243 increases in at least one of, or both of, CSF and plasma as AD progresses.

[201] In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR- tau243 or E-MTBR-tau243) in the biofluid samples obtained from the subject changes in response to treatment with an anti-Ap protofibril antibody (e.g., lecanemab). For example, the level of the MTBR-tau243 species, e.g., tryptic MTBR-243, may increase in CSF and/or plasma as AD progresses, but treatment with lecanemab may lead to a decrease in the level of the MTBR-tau243 species or a reduced rate of increase in the level of the MTBR-tau243 species. In some embodiments, the level of tryptic MTBR-tau243 shows a decrease (or a reduced rate of increase) in response to lecanemab treatment.

[202] In some embodiments, the level of the E-MTBR-tau243 species in biofluid samples obtained from the subject does not change in response to lecanemab treatment as compared to biofluid samples from an untreated and/or positive control patient, or, changes less with treatment than is observed in that patient from measurements of the tryptic MTBR- 243 species. In some embodiments, the level of MTBR-tau243 species, e.g., E-MTBR- tau243, continues to increase during treatment with lecanemab.

[203] In some embodiments, when the level of an MTBR-tau243 species has increased to a threshold suitable for treatment with an anti-tau antibody such as E2814, e.g., to the level in a positive control subject known to have accumulated tau in the brain (e.g., as measured by tau PET, e.g., a tau PET SUVR level of about 1.0, or tauPET SUVR imaging indicating that the subject is at least at Braak Stage I or II, where tau pathology is visible in the transentorhinal and entorhinal cortices), then an additional therapy is administered in addition or instead of lecanemab (e.g., a treatment with a combination of lecanemab and E2814). In some embodiments, an elevated level of MTBR-tau243 after treatment with lecanemab indicates that the subject has likely accumulated tau and/or tau pathology (e.g., when the MTBR-tau243 has increased, this indicates a progression of tauPET and/or tau pathology), indicating a patient may benefit from adding treatment with an anti-tau antibody such as E2814.

[204] In some embodiments, lecanemab treatment has the same effect on the levels of the MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR-tau243) whether measured in CSF or plasma from the subject. In some embodiments, the levels of the MTBR-tau243 species (e.g., tryptic MTBR-tau243) in both CSF and plasma show a decrease (or a reduced rate of increase) in response to lecanemab treatment. In some embodiments, treatment with an anti-tau antibody such as E2814 reduces levels of the MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR-tau243).

[205] In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR- tau243 or E-MTBR-tau243) may be monitored in CSF and/or plasma from the subject during treatment with the anti-Ap protofibril antibody (e.g., lecanemab) to determine how the subject is responding to the anti-Ap protofibril antibody, e.g., if the treatment with the anti- Ap protofibril antibody is an effective treatment or not.

[206] In some embodiments, the level of the MTBR-tau243 species in a biofluid sample from a subject undergoing treatment is compared to the level of the MTBR-tau243 species in a biofluid sample from a positive control, e.g, an individual who has AD, e.g., wherein a lower level in the subject indicates early stages of AD, whereas the same or a higher level relative to the positive control indicates a more advanced stage.

[207] In some embodiments, a decrease (or a reduced rate of increase) in the level of the MTBR-tau243 species in the biofluid sample from the subject undergoing treatment with the anti-Ap protofibril antibody (e.g., lecanemab), as compared to a positive control, indicates an effective treatment. In some embodiments, a decrease (or a reduced rate of increase) in the level of tryptic MTBR-tau243 in the subject undergoing treatment with the anti-Ap protofibril antibody (e.g., lecanemab), as compared to a positive control, indicates an effective treatment. In some embodiments, a decrease (or a reduced rate of increase) in the level of CSF tryptic MTBR-tau243 in the subject undergoing treatment with the anti-Ap protofibril antibody (e.g., lecanemab), as compared to a positive control, indicates an effective treatment. In some embodiments, a decrease (or a reduced rate of increase) in the level of plasma tryptic MTBR-tau243 in the subject undergoing treatment with the anti-Ap protofibril antibody (e.g., lecanemab), as compared to a positive control, indicates an effective treatment. Where treatment is effective, a further dose of lecanemab may be administered, e.g., as a part of an ongoing treatment dosing regimen or as part of a maintenance dosing regimen. MTBR-tau243 and anti-tau antibody treatment

[208] Without being bound by theory, increases in the level of MTBR-tau243 species, e.g., tryptic MTBR-tau243 or E-MTBR-tau243, in biofluid samples (e.g., CSF and/or plasma) from a subject, may be observed at a later timepoint in disease progression than when increases in the level of p-tau217 and/or p-tau217R are observed in the biofluid samples from the same subject. At the same time, again without being bound by theory, MTBR-tau243 levels may be elevated relative to a control (e.g., as measured in a sample from a healthy subject) at any stage of the disease. Thus, in some embodiments, the two markers may be used to refine disease staging and to select treatment with anti-amyloid therapies such as lecanemab (e.g., if increased levels of p-tau217 and/or p-tau217R, either alone or in combination with increased levels of MTBR-tau243) are observed in samples from a subject) and to select add-on or replacement anti-tau therapy such as E2814 (e.g., if increased levels of MTBR-tau243 species are observed).

[209] In some embodiments, the levels of the MTBR-tau243 species in a biofluid sample from a subject undergoing treatment are compared with the levels of the MTBR-tau243 species in a biofluid sample from a control, e.g., an individual who does not have AD. In some embodiments, the control is an individual who has no or low tau accumulation. In some embodiments, the levels of the MTBR-tau243 species in a biofluid sample from a subject undergoing treatment are compared with a control that is a reference or threshold level of the MTBR-tau243 species, as determined based on measurements from a population of individuals who do not have AD and/or has no or low tau accumulation; or determined by modeling. In some embodiments, a change in the level of the MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR-tau243) in biofluid samples (e.g., CSF and/or plasma) from a subject during treatment with the anti-Ap protofibril antibody (e.g., lecanemab), e.g., an increased level of MTBR-tau243 compared to threshold or control indicates that the treated patient has progressed to a more advanced stage of disease (e.g., intermediate or high tau accumulation, intermediate or high amyloid, worsening of clinical symptoms of AD, etc.). In some embodiments, such a patient is administered an additional therapy (e.g., an anti-tau antibody such as E2814). For example, if a subject treated with lecanemab shows an increase in the level of the MTBR-tau243 species relative to the control (e.g., where the level in the treated subject does not decrease or does not show a reduction in the rate of increase), the subject may be administered an additional therapy such as E2814 (in addition or in lieu of lecanemab treatment). [210] In some embodiments, the levels of the MTBR-tau243 species in a biofluid sample from a subject undergoing treatment are compared with the levels of the MTBR-tau243 species in a biofluid sample from a positive control, e.g., an individual who has AD and/or whose AD is progressing or has progressed. In some embodiments, the positive control is an individual who shows amyloid positivity, tau progression, and/or clinical symptoms of AD, and/or who is not receiving treatment for AD. In some embodiments, the levels of the MTBR-tau243 species in a biofluid sample from a subject undergoing treatment are compared with a positive control that is a threshold level of the MTBR-tau243 species, as determined based on measurements from a population of individuals who have AD, amyloid positivity, tau progression, and/or clinical symptoms of AD, and/or who is not receiving treatment for AD; or a threshold determined by modeling.

[211] In some embodiments, when the level of the MTBR-tau243 species increases in a biofluid sample (e.g., in CSF and/or plasma) from a subject receiving lecanemab, the subject is administered an anti-tau antibody such as E2814. In some embodiments, when the level of the MTBR-tau243 species increases in a biofluid sample (e.g., in CSF and/or plasma) from a subject receiving lecanemab, and the increase is comparable to a positive control, the subject is administered an anti-tau antibody such as E2814. In some embodiments, when the subject is administered an anti-tau antibody such as E2814, a reduction in MTBR-tau243 species is observed.

[212] In some embodiments, when the level of CSF tryptic MTBR-tau243 increases in a subject receiving lecanemab, and the increase is comparable to a positive control (e.g., a control subject identified as having tau accumulation, e.g., as determined by tau PET, meriting treatment with an anti-tau antibody such as E2814), the subject is administered E2814. In some embodiments, when the level of plasma tryptic MTBR-tau243 increases in a subject receiving lecanemab, and the increase is comparable to a positive control, the subject is administered E2814. In some embodiments, when the level of CSF E-MTBR-tau243 increases in a subject receiving lecanemab, and the increase is comparable to a positive control, the subject is administered E2814. In some embodiments, when the level of plasma E-MTBR-tau243 increases in a subject receiving lecanemab, and the increase is comparable to a positive control, the subject is administered E2814. p-tau217, MTBR-tau243, and treatment for AD

[213] In some embodiments, a subject is administered a therapy (e.g., an anti-tau antibody such as E2814) in addition to the anti-Ap protofibril antibody (such as lecanemab) when the level of an MTBR-tau243 species is higher than a set threshold, e.g., a threshold indicating the subject has intermediate or high tau accumulation in the brain. In some embodiments, the subject is selected for treatment with E2814 when the level of MTBR- tau243 (e.g., CSF tryptic MTBR-tau243 or CSF E-MTBR-tau243 ) is about 300 - 700 pg/mL, e.g., about 300 - 400 pg/mL, 400 - 500 pg/mL, 500 - 600 pg/mL, or 600 - 700 pg/mL. In some embodiments, the level of MTBR-tau243 is about 300 - 350 pg/mL, 450 - 500 pg/mL, 500 - 550 pg/mL, 550 - 600 pg/mL, or 650 - 700 pg/mL.

[214] In some embodiments, the level of p-tau217 and/or p-tau217R changes as AD progresses. In some embodiments, level of p-tau217 and/or p-tau217R in a biofluid sample from the subject changes (e.g., increases) as AD progresses, and the change occurs in at least one of CSF and plasma. In some embodiments, the level of p-tau217 and/or p-tau217R increases in at least one of CSF and plasma as AD progresses. In some embodiments, the level of p-tau217 and/or p-tau217R is a biomarker for early stages of AD, e.g., pre- AD, early AD, and/or stages where clinical symptoms of AD may be absent or minimal, and/or stages where amyloid centiloid levels are around 20, and/or tau PET SUVR levels are below about 1.12. In some embodiments, the level of p-tau217 and/or p-tau217R increases in early stages of AD progression.

[215] In some embodiments, the level of p-tau217 and/or p-tau217R in the biofluid sample from the subject changes in response to treatment with an anti-Ap protofibril antibody (e.g., lecanemab). For example, where the level of p-tau217 and/or p-tau217R increases in CSF and/or plasma as AD progresses, treatment with lecanemab may lead to a decrease in the level of p-tau217 and/or p-tau217R or a reduced rate of increase in the level of p-tau217 and/or p-tau217R.

[216] In some embodiments, the level of p-tau217 and/or p-tau217R may be monitored in CSF and/or plasma during treatment with the anti-Ap protofibril antibody (e.g., lecanemab) to determine how the subject is responding to the anti-Ap protofibril antibody, e.g., if the treatment with the anti-Ap protofibril antibody is an effective treatment or not.

[217] In some embodiments, a decrease (or a reduced rate of increase) in the level of the p-tau217 and/or p-tau217R in a biofluid sample from the subject undergoing treatment with the anti-Ap protofibril antibody (e.g., lecanemab), as compared to a positive control (e.g., an individual with AD amyloid positivity, tau pathology, and/or clinical symptoms of AD; or a threshold level reflective thereof), indicates an effective treatment. Where treatment is effective, a further dose of lecanemab may be administered. [218] In some embodiments, an increase in the level of p-tau217 and/or p-tau217R in CSF and/or plasma indicates a subject has early AD and is ready for treatment with an anti- Ap protofibril antibody (e.g., lecanemab). In some embodiments, a subsequent increase in the level of an MTBR-tau243 species after commencing treatment with lecanemab indicates that the subject has progressed to or beyond to a stage where the subject should be administered an additional therapy (e.g., an anti-tau antibody such as E2814). In some embodiments, the stage is a stage of early AD, intermediate AD, and/or a stage where the subject has intermediate or high levels of tau accumulation as measured by tauPET SUVR. In some embodiments, lecanemab and the anti-tau antibody are administered in conjunction. In some embodiments, lecanemab is no longer administered and the anti-tau antibody is administered alone. In some embodiments, the level of p-tau217 and/or p-tau217R in the biofluid sample (e.g., CSF and/or plasma) may be measured in a subject after commencement of the anti-tau therapy (e.g., E2814 therapy). In some embodiments, a reduction in the level of p-tau217 and/or p-tau217R in CSF and/or plasma from the subject indicates the anti-tau therapy is effective. In some embodiments, where therapy is effective, a further dose of the anti-tau therapy is administered.

[219] Aspects of the present disclosure relate to methods in which a level of a MTBR- tau243 species (e.g., tryptic MTBR-tau-243 or E-MTBR-tau243) in CSF and/or plasma of a subject is measured in conjunction with a level of p-tau217 (or the level of a ratio of p- tau217/tau217) and used to diagnose and/or treat subjects having, suspected of having AD, or at risk for developing AD. The methods relate to selecting a subject for treatment, treating a subject with a treatment, monitoring treatment efficacy, adjusting a treatment regimen, or detecting a decrease in a brain Ap level or detecting a decrease in a brain tau level, e.g., after administering a treatment. In some embodiments, the treatment is an anti-Ap protofibril antibody (e.g., lecanemab) and, optionally, an anti-tau antibody (e.g., E2814).

[220] An aspect of the present disclosure relates to a method of selecting a subject for a treatment with an anti-Ap protofibril antibody and an anti-tau antibody, wherein the method comprises: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR- tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the first p-tau217 concentration and/or the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD).

[221] In some embodiments, a method of selecting a subject for a treatment with an anti- Ap protofibril antibody and an anti-tau antibody comprises obtaining measurements of a p- tau217 concentration and a MTBR-tau243 concentration at different times. In some embodiments, a method of selecting a subject having, suspected of having, or at risk for developing AD for a treatment with an anti-Ap protofibril antibody and an anti-tau antibody, comprises: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD). In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample; and in step b), selecting the subject for the first treatment with the anti-Ap protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD. In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step d), selecting the subject for a second treatment with the anti-tau antibody if the second p-tau217 concentration and the MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD. [222] An aspect of the present disclosure relates to a method of treating or preventing AD in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration and/or the first MTBR-tau243 concentration are elevated compared to a first control sample, e.g., a sample from an individual who does not have AD; c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration are elevated compared to the first p-tau217 concentration and the second MTBR-tau243 concentration.

[223] p-tau217 and MTBR-tau243 concentrations may be measured at different time points during a method of treating AD. An aspect of the present disclosure relates to a method of treating or preventing Alzheimer’s disease (AD) in a subject having, suspected of having AD, or at risk for developing AD, comprising: a) obtaining a measurement of a p- tau217 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., a p-tau217 concentration in an individual who does not have AD; c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., a MTBR- tau243 concentration in an individual who does not have AD. In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR- tau243 concentration in an individual who does not have AD. In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 and the MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[224] p-tau217 and p-tau243 concentrations may be used in methods for reducing tau tangles. One aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), may comprise: a) obtaining a measurement of a first p-tau217 concentration and a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the first p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD; e) optionally obtaining a measurement of a third p-tau217 concentration and a third MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the third p-tau217 concentration as compared to the second p-tau217 concentration and in the third MTBR-tau243 concentration as compared to the second MTBR-tau243 concentration, indicates a reduction in tau tangles.

[225] p-tau217 and MTBR-tau243 concentrations may be measured at different time points during a method of reducing tau tangles. An aspect of the present disclosure relates to a method of reducing tau tangles comprises: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); e) obtaining a measurement of a second MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the second MTBR-tau243 concentration after the second treatment as compared to the MTBR-tau243 concentration after the first treatment, indicates a reduction in tau tangles. In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR- tau243 concentration in an individual who does not have AD. In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[226] p-tau217 and p-tau243 concentrations may be used in methods of preventing or treating Alzheimer’s disease (AD), e.g., by indicating how a treatment regimen may be adjusted. An aspect of the present disclosure relates to a method of preventing or treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody; b) comparing the first p-tau217 concentration and the first MTBR-tau243 to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) adjusting the treatment regimen to further administer a therapeutically effective amount of an anti-tau antibody if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample.

[227] In some embodiments, the method further comprises: d) obtaining a measurement of a third p-tau217 concentration and a third MTBR-tau243 concentration in a third biofluid sample, e.g., a CSF or blood sample, from the subject; e) comparing the third p-tau217 concentration and the third MTBR-tau243 concentration to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); and f), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody and/or the anti-tau antibody, if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample.

[228] In some embodiments, the control sample is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status. In some embodiments, the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

[229] p-tau217 and p-tau243 concentrations may be used in methods of monitoring treatment efficacy in a subject, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody. An aspect of the present disclosure relates to a method relates to a method of monitoring treatment efficacy in a subject having, suspected of having AD, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second p-tau217 concentration and/or a change in the second MTBR-tau243 concentration, as compared to the first p-tau217 concentration and the first MTBR-tau243 concentration, is an indicator of treatment efficacy. [230] In some embodiments, a decrease or reduction in increase in the second p-tau217 concentration as compared to the first p-tau217 concentration and/or in the second MTBR- tau243 concentration as compared to the first MTBR-tau243 concentration indicates an effective treatment. In some embodiments, a lack of a decrease or lack of a reduction in increase in the second p-tau217 concentration as compared to the first p-tau217 concentration and/or in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration indicates a non-effective treatment, or that additional treatments need to be added to an initial course of therapy.

[231] p-tau217 and p-tau243 concentrations may be used in methods of detecting a decrease in a measure of AD pathology, e.g., a brain Ap level and/or a brain tau level, in a subject who is receiving a treatment for AD. One aspect of the present disclosure relates to a method of detecting a decrease in a measure of AD pathology, e.g., a brain Ap level and/or a brain tau level, in a subject who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, in comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR- tau243 concentration, wherein a decrease between the second p-tau217 concentration and the first p-tau217 concentration and a decrease between the second MTBR-tau243 concentration and the first MTBR-tau243 concentration indicates a decrease of a measure of AD pathology (e.g., a brain Ap level and/or a brain tau level). In some embodiments, the measure of AD pathology is a brain Ap level. In some embodiments, the measure of AD pathology is a brain tau level.

Biomarker use with anti-tau antibodies

[232] In some embodiments, when an anti-tau antibody is administered, it is E2814. In some embodiments, E2814 may be administered according to one of the following regimens, alone or in combination with lecanemab:

[233] In some embodiments, treatment with an anti-tau antibody such as E2814 leads to a reduction in levels of MTBR-tau243 (e.g., tryptic MTBR-tau243 and/or E-MTBR-tau243) in the CSF and/or in the plasma. In some embodiments, treatment with an anti-tau antibody such as E2814 lowers tryptic MTBR-tau243 levels by at least 40%, e.g., by 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or over 95%. In some embodiments, treatment with an anti-tau antibody such as E2814 lowers E-MTBR-tau243 levels by at least 40%, e.g., by 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or over 95%.

[234] In some embodiments, E2814 is administered in conjunction with lecanemab. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 2 weeks (biweekly). In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 2 weeks. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 2 weeks. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 2 weeks.

[235] In some embodiments, the subject is switched to a maintenance dosing regimen of lecanemab, e.g., after 18 or 24 months and/or after levels of biomarkers such as Abeta 42:40 ratio and/or pTau217/pRtau217R indicate the subject is amyloid negative. In some embodiments, the maintenance dosing regimen is 360 mg of lecanemab administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, the maintenance dosing regimen is 250 mg of lecanemab administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, the maintenance dosing regimen is 10 mg/kg of lecanemab administered intravenously once every 4 weeks.

[236] Exemplary maintenance dosing regimens may comprise both E2814 and lecanmab. For example, in some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks.

[237] In some embodiments, the anti-Ap protofibril antibody is lecanemab. In some embodiments, the anti-Ap protofibril antibody lecanemab comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). In some embodiments, the anti-Ap protofibril antibody lecanemab comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[238] In some embodiments, the anti-Ap protofibril antibody comprises the CDRs of lecanemab. In some embodiments, the anti-Ap protofibril antibody comprises the variable regions of lecanemab.

[239] In some embodiments, the anti-tau antibody E2814 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3). In some embodiments, the anti-tau antibody E2814 comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

Selecting a subject for treatment

[240] One aspect of the present disclosure relates to a method of selecting a subject for a treatment comprising an anti-Ap protofibril antibody, wherein the method comprises a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for treatment if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and/or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., a MTBR- tau243 concentration in an individual who has AD. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[241] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a p- tau217 concentration in the biofluid sample from the subject; in step b), selecting the subject for treatment if the p-tau217 concentration is elevated compared to a p-tau217 concentration in the control sample or if the p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample.

[242] In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD). For example, the subject may have symptoms of AD, such, cognitive impairment or high levels of amyloid PET or tau PET, or levels of one or more biomarkers in addition to MTBR-tau243 (e.g., Ap42, Ap40, AP42/40 ratio, total tau, or phosphorylated tau (p-tau 181, p-tau217, and/or p-tau231) indicate that the subject may have AD. In some embodiments, the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, comorbidities (e.g., vascular disease and/or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity. In some embodiments, the subject has severe AD. In some embodiments, the subject has moderate AD. In some embodiments, the subject has mild AD. In some embodiments, the subject has early-AD. In some embodiments, the subject has pre- AD.

[243] In some embodiments, the MTBR-tau243 species is a peptide fragment, such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). Other exemplary MTBR-tau243 peptides are listed in Table 9. In some embodiments, MTBR- tau243-256 may be deamidated, for example, on residue N255. In some embodiments, a patient selected for treatment with lecanemab does not have elevated E-MTBR-tau243 (e.g., the patient has preclinical AD or early AD). In some embodiments, elevated levels of MTBR- tau243-256 in a sample (e.g., a CSF sample or preferably a blood sample) from a subject as compared to a sample from a control (e.g., an individual who does not have AD) indicate that the subject has a more advanced disease, e.g., AD in Braak stages III, IV, V, or VI, e.g., stage V or stage VI. In some embodiments, such a patient is administered lecanemab and a second agent, e.g., an anti-tau antibody, e.g., E2814.

[244] In some embodiments, the MTBR-tau243 species is CSF tryptic MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma tryptic MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[245] In some embodiments, a subject is selected for treatment with an anti-Ap protofibril antibody (e.g., lecanemab) when the level of MTBR-tau243 (e.g., CSF tryptic MTBR-tau243 or E-MTBR-tau243) is about 300 - 700 pg/mL, e.g., about 300 - 400 pg/mL, 400 - 500 pg/mL, 500 - 600 pg/mL, or 600 - 700 pg/mL. In some embodiments, the level of MTBR-tau243 is about 300 - 350 pg/mL, 450 - 500 pg/mL, 500 - 550 pg/mL, 550 - 600 pg/mL, or 650 - 700 pg/mL.

[246] In some embodiments, a subject is selected for treatment with an anti-Ap protofibril antibody (e.g., lecanemab) when a level of ptau217 and/or ptau-217R is elevated in a biofluid sample from the subject as compared to a control sample (e.g., a sample from a subject who does not have AD), but the level of an MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR-tau243) is not elevated in the biofluid sample. In some embodiments, high levels of p-tau217 and/or p-tau217R but little or no increase in level of a MTBR-tau243 species in a subject as compared to a control indicates an early Braak stage, e.g., stage I or stage II. In some embodiments, high levels of p-tau217/np-tau217 and MTBR- tau243 species from a subject as compared to a control may indicate a later stage of AD, e.g., Ap+, CDR >1, or Braak stage III or higher. In some embodiments, when an elevated level of p-tau217 and/or p-tau217R and a low level of a MTBR-tau243 species indicates early AD, the patient is administered lecanemab. In some embodiments, when a high level of p-tau217 and/or p-tau217R indicate more advanced AD (e.g., Braak stage, e.g., stages V or VI), the patient is administered lecanemab and a second agent, e.g., an anti-tau agent (e.g., E2814).

[247] In some embodiments, levels of MTBR-tau243 (e.g., a MTBR-tau243 species such as tryptic MTBR-tau243 and/or E-MTBR-tau243) are used to determine or predict the stage of AD in a subject. Without being bound by theory, MTBR-tau243 may correlate with amyloid CL and/or tau PET SUVR, either alone or in conjunction with measurements of one or more CSF biomarkers (e.g., AP42/40 ratio, p-taul81, or total tau), and/or plasma biomarkers (e.g., AP42/40 ratio, p-taul81, p-tau217, or p-tau217R). In some embodiments, MTBR-tau243 may correlate with amyloid CL, wherein a MTBR-tau243 level (e.g., CSF tryptic MTBR-tau243 and/or CSF E-MTBR-tau243) is used to determine that a subject has a baseline level of amyloid that is <20 CL, <50 CL, 20 CL, or 50 CL. In some embodiments, the CSF MTBR-tau243 may correlate with amyloid CL levels in either tau negative or tau positive subjects, as determined by tau PET SUVR levels. In some embodiments, the tau positive subjects have a tau PET SUVR that is about <1, 1-1.126, 2.126-1.5, 1.5-2, or >2. In some embodiments, CSF MTBR-tau243 is a proxy for global tau PET SUVR, wherein a CSF MTBR-tau243 level (e.g., CSF tryptic MTBR-tau243 and/or CSF E-MTBR-tau243) is used to determine that a subject has a baseline level of tau PET SUVR that is about <1, 1-1.126, 2.126-1.5, 1.5-2, or >2. In some embodiments, the subjects with these tau PET SUVR levels have amyloid CL levels of about <50, 50-75, 75-100, or >100.

Monitoring treatment efficacy

[248] An aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody (e.g., lecanemab), wherein the method comprises a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second MTBR-tau243 concentration ratio as compared to first MTBR-tau243 concentration is an indicator of treatment efficacy. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[249] In some embodiments, a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates an effective treatment.

[250] In some embodiments, a lack of a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control, indicates a non-effective treatment.

[251] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p-tau217 concentration is an indicator of treatment efficacy. In some embodiments, a decrease from the first p-tau217 concentration to the second p-tau217 concentration, or reduction in a rate of increase from the first p-tau217 concentration to the second p-tau217 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first p-tau217 to a second tau217 concentration in an individual who has AD and is not treated, indicates an effective treatment. In some embodiments, a lack of a decrease from the first p-tau217 concentration to the second p-tau217 concentration and from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in a rate of increase between the first and second p-tau217 concentrations and MTBR-tau243 concentrations, as compared to rates in a placebo control, indicates a non-effective treatment.

[252] In some embodiments, the measurement of the first MTBR-tau243 concentration may be obtained from the subject prior to treatment. In some embodiments, the measurement of the first MTBR-tau243 concentration is a measurement of the MTBR-tau243 concentration in a subject who had already begun treatment without having a prior measurement of the MTBR-tau243 concentration.

[253] In some embodiments, a decrease in the second MTBR-tau243 concentration as compared to first MTBR-tau243 concentration ratio indicates an effective treatment.

[254] In some embodiments, a lack of a decrease in the second MTBR-tau243 concentration as compared to first MTBR-tau243 concentration indicates a less effective treatment. In some embodiments, a lack of a decrease in the second MTBR-tau243 concentration as compared to first MTBR-tau243 concentration indicates no or less reduction in tau tangles. In some embodiments, the lack of a decrease is no change in the MTBR-243 concentration. In some embodiments, the lack of a decrease is an increase.

[255] In some embodiments, steps b) and c) of the method of monitoring treating efficacy may be repeated at least once in order to continue monitoring the treatment efficacy over time. In an exemplary example, the method further comprises, after step c), obtaining a measurement of a third MTBR-tau243 concentration in a third biofluid sample, e.g., a CSF or blood sample, from the subject at a time point after obtaining the second biofluid sample and comparing the third MTBR-tau243 concentration to an earlier measurement of the MTBR- tau243 concentration (e.g., the first and/or the second MTBR-tau243 concentration), wherein a change in the third MTBR-tau243 concentration as compared to the earlier MTBR-tau243 concentration is an indicator of treatment efficacy. In some embodiments, steps b) and c) may be repeated for as long as the subject receives treatment. In some embodiments, steps b) and c) may be repeated at regular intervals, e.g., once weekly, biweekly, monthly, quarterly, semiannually, or yearly.

[256] In some embodiments, the method of monitoring treatment efficacy may further comprise, after step c), a further step of d) modifying the treatment by administering a modified treatment comprising a further therapeutically effective dose of the anti-Ap protofibril antibody. For example, if the treatment is not effective, the dose may be modified by increasing the size of the dose, increasing the frequency of administration, and/or changing the route of administration. In some embodiments, an additional therapeutic may be added, e.g., an anti-tau antibody such as E2814. Conversely, if the treatment is effective, the dose may be modified by decreasing the size of the dose, increasing the frequency of administration, and/or changing the route of administration. In some embodiments, the subject may be switched from a treatment administered according to a treatment dosing regimen to a treatment administered according to a maintenance dosing regimen. In some embodiments, the treatment may be discontinued. In some embodiments, steps b) and c) may be repeated for as long as the subject receives treatment, e.g., after the subject receives a modified treatment. In some embodiments, steps b) and c) may be repeated if the subject no longer receives treatment, e.g., to continue monitoring treatment efficacy after the treatment has been discontinued.

[257] In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD). For example, the subject may have symptoms of AD, such, cognitive impairment or high levels of amyloid PET or tau PET, or levels of one or more biomarkers in addition to MTBR-tau243 (e.g., Ap42, Ap40, AP42/40 ratio, total tau, or phosphorylated tau (p-tau 181, p-tau217, and/or p-tau231) indicate that the subject may have AD. In some embodiments, the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, comorbidities (e.g., vascular disease and/or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity. In some embodiments, the subject has early-AD. In some embodiments, the subject has pre-AD.

[258] In some embodiments, the MTBR-tau243 species is a peptide fragment, such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243. [259] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[260] In some embodiments, maintained or reduced levels of E-MTBR-tau243 indicate treatment efficacy. In some embodiments, elevated levels of MTBR-tau243-256 in a sample over time (e.g., a CSF sample or preferably a blood sample) indicate that the subject has progressed to a later form of AD while on treatment, e.g., Braak stages III, IV, V, or VI, e.g., stage V or stage VI. In some embodiments, when the E-MTBR-tau243 indicates progression to a later stage of disease, at least one additional therapy is provided, e.g., an anti-tau antibody, e.g., E2814. The additional therapy may be provided in conjunction with or in lieu of lecanemab treatment.

[261] In some embodiments, the subject receiving lecanemab at a late Braak stage, may respond more slowly to lecanemab treatment than a subject at an earlier stage, such that levels of MTBR-tau243 (e.g., MTBR-tau243-256) in a sample from a subject being treated with lecanemab may remain elevated as compared to sample from a control for longer period of time before an effect of lecanemab is observed.

Adjusting a treatment regimen

[262] A further aspect of the present disclosure relates to a method of preventing or treating Alzheimer’s disease (AD) (e.g., by adjusting a treatment regimen) in a subject having, suspected of having, or at risk for developing AD adjusting a treatment regimen, wherein the method comprises a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, b) comparing the MTBR-tau243 concentration to a control sample, e.g., a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and/or comparing the MTBR-tau243 concentration to a positive control, e.g., a MTBR-tau243 concentration in an individual who has AD; and c) adjusting the treatment regimen, e.g., by adjusting the size of the dose, the frequency of administration, and/or the route of administration, if the MTBR-tau243 concentration differs from the control sample or if the MTBR-tau243 concentration differs from the positive control sample.

[263] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a p- tau217 concentration in the biofluid sample from the subject; in step b), comparing the p- tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the control sample and/or comparing the p-tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample; and in step c), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody, if the p- tau217 concentration and the MTBR-tau243 concentration in the sample differ from the control sample or if the p-tau217 concentration and the MTBR-tau243 concentration in the sample differ from the p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample.

[264] In some embodiments, the control is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

[265] In some embodiments, the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

[266] In some embodiments, the control sample is a measurement of a MTBR-tau243 concentration obtained from a biofluid sample, e.g., a CSF or blood sample, from a control subject. The control subject may be an individual who does not have AD. In some embodiments, the control sample is a measurement of a previous MTBR-tau243 concentration obtained from a biofluid sample, e.g., a CSF or blood sample from the subject receiving the treatment. For example, the control sample may have been obtained from the subject prior to the treatment, or at an earlier time during the course of treatment, prior to performing the steps of the method.

[267] In some embodiments, the measurement of the MTBR-tau243 concentration may be obtained prior to treatment. In some embodiments, the measurement of the MTBR-tau243 concentration is a first measurement of the MTBR-tau243 concentration in a subject who had already begun treatment without having a prior measurement of the MTBR-tau243 concentration.

[268] In some embodiments, the treatment regimen (also called a “dosing regimen” or “treatment dosing regimen”), comprises a schedule specifying doses of the anti-Ap protofibril antibody administered per unit of time, including the number of doses over a given time period and the elapsed time between doses. In some embodiments, the treatment regimen comprises administering the anti-Ap protofibril antibody at a specified dose, according to a schedule (e.g., on a repetitive basis).

[269] In some embodiments, adjusting the treatment regimen comprises increasing the size of the dose, increasing the frequency of administration, and/or changing the route of administration of the anti-Ap protofibril antibody if the MTBR-tau243 concentration is higher than the MTBR-tau243 concentration in the control sample (e.g., a sample from an individual who does not have AD). In some embodiments, an additional therapeutic may be added, e.g., an anti-tau antibody such as E2814. In some embodiments, the anti-tau antibody may be administered at a dose of 500 mg - 4500 mg (e.g., 500 mg, 750 mg, 1000 mg, 1500 mg, 3000 mg, 4500 mg), as described herein (Section C, Anti-Tau Antibodies).

[270] In some embodiments, adjusting the treatment regimen comprises decreasing the size of the dose, decreasing the frequency of administration, and/or changing the route of administration if the MTBR-tau243 concentration is lower than the control sample. In some embodiments, a treatment regimen comprising intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered biweekly, may be adjusted to comprise intravenous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered monthly. In some embodiments, a treatment regimen comprising subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 720 mg, administered weekly, may be adjusted to comprise subcutaneous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, 360 mg, or 250 mg, e.g., administered weekly. In some embodiments, a treatment regimen comprising subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, may be adjusted to comprise subcutaneous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 360 mg, or 250 mg, e.g., administered weekly. In some embodiments, a treatment regimen comprising intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered biweekly, may be adjusted to comprise subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly. In some embodiments, a treatment regimen comprising subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, or administered biweekly, may be adjusted to comprise intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject. [271] In some embodiments, the subject may be switched from a treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody (e.g., an initiation dose) administered according to an initiation dosing regimen to a treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody (e.g., a maintenance dose) administered according to a maintenance dosing regimen. In some embodiments, the initiation dosing regimen comprises intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered biweekly and the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered monthly. In some embodiments, the initiation dosing regimen comprises subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 720 mg, administered weekly, and the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, 360 mg, or 250 mg, e.g., administered weekly. In some embodiments, the initiation dosing regimen comprises subcutaneous administration the anti- Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, and the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 360 mg, or 250 mg, e.g., administered weekly. In some embodiments, the initiation dosing regimen comprises intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered biweekly, and the maintenance dosing regimen comprises subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly. In some embodiments, the initiation dosing regimen comprises subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, administered weekly and the maintenance dosing regimen comprises intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered monthly.

[272] In some embodiments, the treatment may be discontinued.

[273] In some embodiments, without being bound by theory, the maintenance dose may maintain therapeutically effective concentrations of the anti-Ap protofibril antibody in the subject and/or to maintain or continue to reduced levels of Ap protofibril in the brain of the treated subject. In some embodiments, the maintenance dose also maintains reduced levels of tau, e.g., as indicated by reduced levels of MTBR-tau243, e.g., due to the prevention of tangle formation downstream of amyloid. In some embodiments, reduction in tau (e.g., MTBR- tau243) is an effect of reduction of Ap protofibrils mediated by the anti-Ap protofibril antibody. Exemplary maintenance doses are disclosed herein in Sections A6 (Switch to a maintenance dose) and D (Dosage Regimens and Routes).

[274] In some embodiments, the steps a) and b) of the method of adjusting a treatment regimen may be repeated at least once in order to monitor the efficacy of the adjusted treatment regimen and optionally, to further adjust the treatment regimen. In an exemplary example, the method further comprises, after step c), obtaining a measurement of a further MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject at a time point after adjusting the treatment regimen, and comparing the further MTBR-tau243 concentration to the MTBR-tau243 concentration from prior to adjusting the treatment regimen or to a control sample (e.g., a MTBR-tau243 concentration in an individual who does not have AD, a MTBR-tau243 concentration obtained from the subject prior to the treatment, or a MTBR-tau243 concentration obtained from the subject at an earlier time during the course of treatment, prior to performing the steps of the method). In some embodiments, if the further MTBR-tau243 concentration still differs from the control sample, the treatment may be adjusted further. The steps a) and b) may be repeated for as long as the subject receives the treatment or the adjusted treatment. In some embodiments, steps b) and c) may be repeated if the subject no longer receives treatment, e.g., to continue monitoring treatment efficacy after the treatment has been discontinued. In some embodiments, steps b) and c) may be repeated at regular intervals, e.g., once weekly, biweekly, monthly, quarterly, semiannually, or yearly.

[275] In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD). For example, the subject may have symptoms of AD, such, cognitive impairment or high levels of amyloid PET or tau PET, or levels of one or more biomarkers in addition to MTBR-tau243 (e.g., Ap42, Ap40, AP42/40 ratio, total tau, or phosphorylated tau (p-tau 181, p-tau217, and/or p-tau231) indicate that the subject may have AD. In some embodiments, the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, comorbidities (e.g., vascular disease and/or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity. In some embodiments, the subject has early-AD. In some embodiments, the subject has pre-AD.

[276] In some embodiments, the MTBR-tau243 species is a peptide fragment, such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[277] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

Detecting a decrease in a brain A|J level or a brain tan level

[278] An aspect of the present disclosure relates to a method of detecting a decrease in a brain Ap level in a subject in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, wherein the method comprises a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain Ap level in the subject. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[279] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p-tau217 concentration indicates a decrease of the brain Ap level in the subject.

[280] An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau level in a subject receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, wherein the method comprises a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease in the second MTBR-tau243 concentration and the first MTBR-tau243 concentration, or a reduction in a rate of increase between the first and second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain tau level in the subject. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[281] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change from the first p-tau217 concentration to the second p-tau217 concentration indicates a decrease of the brain tau level in the subject.

[282] In some embodiments, a decrease in a brain tau level is a decrease in tau tangles. Tau tangles may be reduced, for example, by preventing, reducing, and/or slowing formation of new tau tangles; and/or by promoting, increasing, and/or speeding up breakdown of existing tau tangles. In some embodiments, tau tangles are detected by tauPET.

[283] An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau PET level in a subject receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, wherein the method comprises a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decreased concentration in the second sample relative to the first sample indicates a decrease of a brain tau PET level in the subject. In some embodiments, the anti-Ap protofibril antibody is lecanemab. In some embodiments, the subject showing a decrease in MTBR-tau243 concentration and an associated decrease in brain tau PET level is receiving an anti-tau antibody (e.g., E2814) in addition to lecanemab.

[284] In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD). For example, the subject may have symptoms of AD, such, cognitive impairment or high levels of amyloid PET or tau PET, or levels of one or more biomarkers in addition to MTBR-tau243 (e.g., Ap42, Ap40, AP42/40 ratio, total tau, or phosphorylated tau (p-tau 181, p-tau217, and/or p-tau231) indicate that the subject may have AD. In some embodiments, the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, comorbidities (e.g., vascular disease and/or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity. In some embodiments, the subject has early-AD. In some embodiments, the subject has pre-AD.

[285] In some embodiments, the MTBR-tau243 species is a peptide fragment of MTBR- tau243, such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR- tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[286] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

A method of reducing tau tangles

[287] In various embodiments, a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprises: a) obtaining a measurement of a first MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and/or if the first MTBR-tau243 concentration is comparable to a positive control sample, e.g., compared to a MTBR-tau243 concentration in an individual who has AD; and c) obtaining a measurement of a second MTBR-tau243 concentration, wherein a decrease in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration indicates a reduction in tau tangles, and/or a rate of increase from the first MTBR-tau243 concentration to the first MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[288] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample from the subject; in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration is elevated compared to a p-tau217 concentration in the control sample or if the first p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample; and in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample, wherein a decrease in the second p-tau217 concentration as compared to the first p- tau217 concentration or a decrease in the rate of increase from the first p-tau217 concentration to the second p-tau217 concentration as compared to the rate of increase in the positive control indicates a reduction in tau tangles.

[289] In some embodiments, tangles are reduced by preventing, reducing, and/or slowing formation of new tau tangles; and/or by promoting, increasing, and/or speeding up breakdown of existing tau tangles, as evidenced by a reduction in MTBR-tau243 in a sample taken after treatment.

[290] In various embodiments, a method for identifying tau tangles in a subject comprises a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) identifying tau tangles in the subject if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD).

[291] In some embodiments, a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody (e.g., lecanemab) may be administered to the subject in whom tau tangles have been identified. In some embodiments, measurements of further MTBR- tau243 concentration may be obtained from further biofluid samples (e.g., a further CSF or blood sample) in order to determine if the treatment has changed the MTBR-tau243 concentration. In some embodiments, a reduction in MTBR-tau243 concentration over time indicates that the treatment is reducing tau tangles. [292] In some embodiments, the MTBR-tau243 species is a peptide fragment, such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[293] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

A method of treating a subject

[294] An aspect of the present disclosure relates to method of treating a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), wherein the method comprises: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody (e.g., lecanemab) if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and/or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., comparable to a MTBR-tau243 concentration in an individual who has AD. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[295] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a p- tau217 concentration in the biofluid sample from the subject; and in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a p-tau217 concentration in a control sample, or if the p-tau217 concentration is comparable to a p- tau217 concentration in the positive control sample. In some embodiments, the method further comprises c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is elevated as compared to the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration is comparable to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject. In some embodiments, the method further comprises c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is less than the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject, wherein the further therapeutically effective dose of the anti-Ap protofibril antibody is administered according to a maintenance dosing regimen.

[296] In some embodiments, a method of treating a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD) is provided, wherein the method comprises: a) obtaining a measurement of a ptau-217 concentration or a ratio of p-tau217 to total tau217 in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody (e.g., lecanemab) if the ptau217 concentration or a ratio of p-tau217 to total tau217 is elevated compared to a control sample, e.g., compared to a an individual who does not have Alzheimer’s disease (AD), and/or if the ptau217 concentration or a ratio of p-tau217 to total tau217 is comparable to a positive control sample, e.g., comparable to an individual who has AD; c) ) obtaining a measurement of an MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the MTBR-tau243 concentration is elevated as compared to a control sample, e.g., compared to a an individual who does not have Alzheimer’s disease (AD), and/or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., comparable to an individual who has AD; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject in conjunction with a therapeutically effective dose of an anti-tau antibody, e.g., E2814.

[297] In some embodiments, the disorder (e.g., disease) is Alzheimer’s disease (AD). In some embodiments, the disorder is early AD. In some embodiments, the disorder is pre- AD. In some embodiments, the disorder is a neurological disorder (e.g., a neurodegenerative disorder or disease) characterized by Ap peptide-containing soluble and/or insoluble Ap aggregates. Exemplary disorders include but are not limited to Down’s Syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, and Lewy Body Dementia.

[298] In some embodiments, treating the disorder comprises at least one of inhibiting the disorder, slowing progression of the disorder, delaying progression, arresting its development, reversing progression of disorder (e.g., reversing aggregation of Ap fibrils and/or tau), preventing the onset or development of the disorder, relieving or ameliorating one or more symptoms or underlying condition(s) of the disorder, curing the disorder, improving one or more clinical metrics, or preventing reoccurrence of one or more symptoms of the disorder. In some embodiments, treating a disorder comprises at least one of reducing a brain Ap level, reducing a brain tau level, reducing tau tangles, slowing an increase in brain tau level, slowing tau tangle formation, improving cognition, and altering biomarkers associated with AD pathology.

[299] In some embodiments, the method of treating the disorder further comprises steps of monitoring treatment efficacy and/or adjusting a treatment regimen. In some embodiments, the method further comprises, after steps of a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody such as lecanemab, applying further step c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject; d) determining that the second MTBR-tau243 concentration is less than the first MTBR-tau243 concentration; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[300] In some embodiments, the further therapeutically effective dose is an adjusted dose (e.g., the size of the dose, the frequency of administration, and/or the route of administration is adjusted as compared to the treatment first administered to the subject). In some embodiments, the further therapeutically effective dose is an adjusted dose administered as part of an initiation dosing regimen, wherein both the treatment first administered to the subject and the further therapeutically effective dose are part of the initiation dosing regimen.

[301] In some embodiments, the further therapeutically effective dose of the anti-Ap protofibril antibody (e.g., lecanemab) is administered as part of a maintenance dosing regimen, e.g., a maintenance dosing regimen that follows an initiation dosing regimen. [302] In some embodiments, the MTBR-tau243 species is a peptide fragment such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[303] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[304] In some embodiments, elevated levels of MTBR-tau243-256 in a sample (e.g., a CSF sample or preferably a blood sample) from a subject as compared to a sample from a control indicate that the subject has AD in Braak stages III, IV, V, or VI, e.g., stage V or stage VI.

Switch to a maintenance dosing regimen

[305] In some embodiments, an initiation dosing regimen is a dosing regimen in which a dose of the anti-Ap protofibril antibody (e.g., lecanemab), e.g., a therapeutically effective dose, is administered at a regular dosing interval on a repetitive basis. A therapeutically effective dose may be an initiation dose, a treatment dose, or a first dose. In an initiation dosage regimen (also called an initiation dosing regimen) the initiation dose of the anti-Ap protofibril antibody may be administered at an interval (e.g., daily, weekly, biweekly, or monthly), for a period of time, e.g., until the subject shows evidence of improved AD pathology and/or slowed progression of AD. An initiation dosing regimen may comprise administration of one or more therapeutically effective doses which differ from each other, e.g., a first therapeutically effective dose and a further therapeutic effective dose that has been changed from (e.g., adjusted relative to) the first therapeutically effective dose.

[306] In some embodiments, a maintenance dosing regimen is a dosing regimen in which a dose of the anti-Ap protofibril antibody (e.g., lecanemab), e.g., a therapeutically effective dose, is administered at a regular dosing interval on a repetitive basis in order to maintain therapeutically effective concentrations of the anti-Ap protofibril antibody in the subject and/or to maintain or continue to reduce levels of Ap protofibril in the brain of the treated subject. In some embodiments, the maintenance dosing regimen is sufficient to maintain reduced concentrations of MTBR-tau243 in biofluids (e.g., CSF or blood) of the treated subject. In some embodiments, the maintenance dosing regimen comprises intravenously administering lecanemab at a dose of 10 mg/kg relative to the weight of the subject, once every 4 weeks. In some embodiments, the maintenance dosing regimen comprises subcutaneously administering lecanemab at a dose of 360 mg or 250 mg once every week. The therapeutically effective dose administered according to a maintenance dosing regimen may be called a maintenance dose and may be administered at a regular interval on a repetitive basis. In some embodiments, each maintenance dose of the anti-Ap protofibril antibody may be administered daily, weekly, biweekly, or monthly. In some embodiments, the maintenance dose may be a dose that differs from the initiation dose. For example, the maintenance dose may be an adjusted dose in which the size of the dose, the frequency of administration, and/or the route of administration is adjusted as compared to one or more doses in the initiation dosing regimen.

[307] In some embodiments, the method of treating the subject comprises administration of the treatment (e.g., a therapeutically effective dose of the anti-Ap protofibril antibody) according to an initiation dosing regimen, after which the subject is switched to a maintenance dosing regimen.

[308] In some embodiments, one or more different steps or measurements may trigger the switch from the initiation dosing regimen to the maintenance dosing regimen.

[309] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject is at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD.

[310] In some embodiments, the subject is switched to a maintenance dosing regimen when additional biomarker measurements show evidence of improved AD pathology and/or slowed progression of AD. In some embodiments, the additional biomarker measurement is at least one of a decrease in amyloid or tau positron emission tomography (PET); an increase in cerebrospinal fluid level of Ap42 and/or AP42/40 ratio; a decrease in cerebrospinal fluid level of total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np- tau205, p-tau217/np-tau217 and/or tau231/np-tau231), cerebrospinal fluid level of neurogranin, and/or cerebrospinal fluid level of neurofilament light peptide (NfL); and a change in blood biomarkers as measured in the serum or plasma (e.g. increased levels of Ap42 and/or AP42/40 ratio; decreased plasma levels of plasma total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., p-tau!81/np-tau!81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light (NfL), as compared to the biomarker measurement(s) obtained from a control sample. In some embodiments, the control sample may be a sample from an individual who has AD. In some embodiments, the control sample may be a sample from the subject prior to treatment. In some embodiments, the control sample may be a sample from an individual who did not receive a therapeutically effective dose of an Ap protofibril antibody, e.g., a subject who receives no treatment, or a subject who receives a placebo. In some embodiments, the control sample is a sample from an individual who did not receive lecanemab. In some embodiments, a control is a reference measurement, e.g., an averaged measurement that combines population data from more than one subject and is representative of a subject who does not receive treatment.

[311] In some embodiments, the subject is switched to a maintenance dosing regimen when a decrease in tau PET SUVr is measured in the subject as compared to control sample, e.g., a sample from an individual who has AD or a sample from the subject prior to treatment.

[312] In some embodiments, the subject is switched to a maintenance dosing regimen when a low tau PET level as measured by PET SUVr is detected in the subject, e.g., a tau PET SUVr of about 1.1, preferably about 1.06, as measured with a MK6240 PET scan, e.g., of whole cortical gray matter. In some embodiments, the maintenance dosing regimen comprises administering a maintenance dose that maintains a tau PET SUVr level at or below 1.06.

[313] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen at least 6 months (e.g., 6 months, or 12 months, or 18 months, or 24 months, or 36 months) after the start of the initiation dosing regimen.

[314] In some embodiments, the maintenance dosing regimen differs from the initiation dosing regimen in the size of dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody.

[315] Exemplary dosing regimens comprising administration of initiation doses and maintenance doses of the anti-Ap protofibril antibody are disclosed in International Application No. PCT/US2024/033125, the contents of which are incorporated herein.

[316] Exemplary routes of administration of the anti-Ap protofibril antibody may be intravenous, subcutaneous, or a combination of both. In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject. In some embodiments, wherein the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 2 weeks.

[317] Following the switch to the maintenance dosing regimen as described herein, the maintenance dosing regimen may comprise a different (e.g., lower) frequency of administration than the initiation dose. In some embodiments, the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks.

[318] In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg. In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[319] Following the switch to the maintenance dosing regimen as described herein, the maintenance dosing regimen may comprise a dose of the anti-Ap protofibril antibody differs from (e.g., is lower than) the initiation dose.

[320] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg. For example, if the initiation dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg, the maintenance dosing regimen may comprise subcutaneous administration of the anti- Ap protofibril antibody at a therapeutically effective dose of 500 mg, 360 mg, or 250 mg. In some embodiments, the initiation dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 500 mg, and the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

[321] Following the switch to the maintenance dosing regimen as described herein, the maintenance dosing regimen may comprise a different (e.g., a lower) frequency of administration than the initiation dose.

[322] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[323] Following the switch to the maintenance dosing regimen as described herein, the maintenance dosing regimen may comprise a route of administration than the initiation dose. [324] In some embodiments, the initiation dosing regimen comprises intravenous administration of one or more initiation doses of the anti-Ap protofibril antibody, while the maintenance dosing regimen comprises subcutaneous administration of one or more maintenance doses of the anti-Ap protofibril antibody. In some embodiments, the initiation dosing regimen comprises subcutaneous administration of one or more initiation doses of the anti-Ap protofibril antibody, while the maintenance dosing regimen comprises intravenous administration of one or more maintenance doses of the anti-Ap protofibril antibody.

[325] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when the MTBR-tau243 concentration in a biofluid sample (e.g., a CSF or blood sample) from the subject is reduced when compared to a control sample (e.g., a control sample from a subject who has AD, or a reference measurement obtained from the subject prior to treatment with the anti-Ap protofibril antibody). In some embodiments, the subject is switched after 18 months of administration of the anti-Ap protofibril antibody according to the initiation dosing regimen, e.g., if the MTBR-tau243 concentration in the biofluid from the sample is reduced compared to a control sample after 18 months. In some embodiments, the subject is switched after 24 months of administration of the anti-Ap protofibril antibody according to the initiation dosing regimen, e.g., if the MTBR-tau243 concentration in the biofluid from the sample is reduced compared to a control sample after 24 months.

[326] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered biweekly, after which the subject is switched to a maintenance dosing regimen comprising intravenous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered monthly. In some embodiments, the initiation dosing is administered for 18 months or for 24 months, if the MTBR-tau243 concentration in the biofluid from the sample is reduced compared to a control sample.

[327] In some embodiments, initiation dosing regimen comprises intravenous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered biweekly, after which subject is switched to a maintenance dosing regimen comprising subcutaneous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 500 mg, 360 mg, or 250 mg, administered weekly. In some embodiments, the initiation dosing is administered for 18 months or for 24 months, if the MTBR-tau243 concentration in the biofluid from the sample is reduced compared to a control sample. In some embodiments, the subcutaneous doses are administered using a vial-syringe. In some embodiments, the subcutaneous doses are administered using an auto-injector.

[328] In some embodiments, initiation dosing regimen comprises subcutaneous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, after which the subject is switched to a maintenance dosing regimen comprising subcutaneous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 360 mg or 250 mg, administered weekly. In some embodiments, the initiation dosing is administered for 18 months or for 24 months, if the MTBR-tau243 concentration in the biofluid from the sample is reduced compared to a control sample. In some embodiments, the subcutaneous doses are administered using a vial-syringe. In some embodiments, the subcutaneous doses are administered using an auto-injector.

[329] In some embodiments, initiation dosing regimen comprises subcutaneous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, after which the subject is switched to a maintenance dosing regimen comprising intravenous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 10 mg/kg relative to the weight of the subject, administered monthly. In some embodiments, the subcutaneous doses are administered using a vial-syringe. In some embodiments, the subcutaneous doses are administered using an auto-injector.

Combination therapy

[330] In some embodiments, the initiation dosing regimen further comprises administration of at least one Alzheimer’s disease medication other than the anti-Ap protofibril antibody.

[331] In some embodiments, the initiation dosing regimen comprises administration of a therapeutically effective dose of an anti-tau antibody sequentially or simultaneously with administration of the anti-Ap protofibril antibody.

[332] In some embodiments, the anti-Ap protofibril antibody is lecanemab. In some embodiments, the anti-tau antibody is E2814.

[333] In some embodiments, the anti-Ap protofibril antibody is lecanemab. In some embodiments, the anti-Ap protofibril antibody lecanemab comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). In some embodiments, the anti-Ap protofibril antibody lecanemab comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[334] In some embodiments, the anti-Ap protofibril antibody comprises the CDRs of lecanemab. In some embodiments, the anti-Ap protofibril antibody comprises the variable regions of lecanemab.

[335] In some embodiments, the anti-tau antibody E2814 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3). In some embodiments, the anti-tau antibody E2814 comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

[336] In some embodiments, the anti-tau antibody comprises the CDRs of E2814. In some embodiments, the anti-tau antibody comprises the variable regions of E2814.

[337] In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose once every 4 weeks.

[338] In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose between 500 mg - 4500 mg (e.g., 500 mg, 750 mg, 1000 mg, 1500 mg, 3000 mg, 4500 mg). For example, in some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose of 750 mg once every 4 weeks. In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose of 1500 mg once every 4 weeks. In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose of 3000 mg once every 4 weeks. In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose of 4500 mg once every 4 weeks. In some embodiments, the anti-tau antibody is intravenously administered at a dose of 750 mg once every four weeks for 12 weeks, a dose of 1500 mg once every four weeks for 12 weeks, a dose of 3000 mg once every four weeks for 12 weeks, and a dose of 4500 mg once every four weeks for 12 weeks. [339] In some embodiments, the initiation dosing regimen comprises pre-dosing with the anti-tau antibody (e.g., E2814) before the first administration of the anti-Ap protofibril antibody (e.g., lecanemab). In some embodiments, the subject receiving pre-dosing with the anti-tau antibody has pre- AD (e.g., the subject is asymptomatic for AD).

[340] In some embodiments, the initiation dosing regimen comprises pre-dosing with the anti-Ap protofibril antibody (e.g., lecanemab) before the first administration of the anti-tau antibody (e.g., E2814). In some embodiments, the subject receiving pre-dosing with the anti- Ap antibody has AD (e.g., early AD).

[341] In some embodiments, pre-dosing with the anti-tau antibody (e.g., E2814) comprises administration of a therapeutically effective dose of the anti-tau antibody for 52 weeks before the first administration of the anti-Ap protofibril antibody. In some embodiments, after 52 weeks of administration of the anti-tau antibody, the anti-Ap protofibril antibody is administered for 52 weeks.

[342] In some embodiments, pre-dosing with the anti-Ap protofibril antibody comprises administration of a therapeutically effective dose of the anti-Ap protofibril antibody for 52 weeks before the first administration of the anti-tau antibody. In some embodiments, after 52 weeks of administration of the anti-Ap protofibril antibody, the anti-tau antibody is administered for 52 weeks.

[343] Exemplary embodiments of a combination therapy combining an anti-Ap protofibril antibody and an anti-tau antibody are disclosed in International Application Nos. PCT/IB2021/000937 and PCT7US2022/079509, each of which are incorporated by reference herein.

[344] In some embodiments, the subject may be administered a therapeutically effective dose of an anti-Ap protofibril antibody (e.g., lecanemab) but a measurement of a MTBR- tau243 concentration in a biofluid sample from the subject indicates that administration of at least one additional Alzheimer’s disease medication may be beneficial. For example, if the MTBR-tau243 concentration remains elevated compared to a reference/threshold or control sample (e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), then a therapeutically effective dose of an anti-tau antibody (e.g., E2814) may be administered. In some embodiments, administration of the anti-Ap protofibril is discontinued when the anti-tau antibody is administered. In some embodiments, administration of the anti-Ap protofibril antibody is continued when the anti-tau antibody is administered. [345] In some embodiments, the MTBR-tau243 species is a peptide fragment such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[346] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in tCSF or plasma.

[347] In some embodiments, elevated levels of MTBR-tau243-256 in a sample (e.g., a CSF sample or preferably a blood sample) from a subject as compared to a sample from a control indicate that the subject has AD in Braak stages III, IV, V, or VI, e.g., stage V or stage VI.

[348] In some embodiments, the subject is administered a therapeutically effective dose of an anti-Ap protofibril antibody (e.g., lecanemab), until the MTBR-tau243-256 level (e.g., in a plasma or CSF sample) indicates that the subject has later stage AD, e.g., in Braak stage V or VI, and then a therapeutically effective dose of an additional agent, e.g., an anti-tau antibody (e.g., E2814) is also administered, e.g., in combination or in lieu of the lecanemab.

[349] In some embodiments, a subject may be administered an anti-tau antibody (e.g., E2814) when a measurement of an E-MTBR-tau243 concentration in a biofluid sample from the subject is not elevated relative to a control. In some embodiments, lecanemab is administered in conjunction once a measurement of an E-MTBR-tau243 concentration in a biofluid sample from the subject is elevated relative to a control.

[350] In some embodiments, a subject may be administered a therapeutically effective dose of lecanemab, e.g., as a pre-treatment, but a measurement of a MTBR-tau243 concentration in a biofluid sample from the subject indicates that administration of at least one additional Alzheimer’s disease medication may be beneficial, e.g., when the E-MTBR- tau243 concentration in a biofluid sample from the subject indicates a patient has reached Braak Stages V or VI. In some embodiments, if the MTBR-tau243 concentration remains elevated compared to a reference/threshold or control sample (e.g., compared to a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD), even after administration of the anti-Ap protofibril antibody, then a therapeutically effective dose of an anti-tau antibody (e.g., E8214) may be administered. In some embodiments, administration of the anti-Ap protofibril antibody is discontinued when the anti-tau antibody is administered, e.g., when the E-MTBR-tau243 concentration in a biofluid sample from the subject indicates a patient has reached Braak Stages V or VI. In some embodiments, administration of the anti-Ap protofibril antibody is continued when the anti-tau antibody is administered.

[351] In some embodiments, the MTBR-tau243 species is a peptide fragment such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[352] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[353] In some embodiments, elevated levels of MTBR-tau243-256 in a sample (e.g., a blood sample) from a subject as compared to a sample from a control indicate that the subject has AD in Braak stages III, IV, V, or VI, e.g., stage V or stage VI. Accordingly, in some embodiments, the subject is administered a therapeutically effective dose of an anti-tau antibody (e.g., E2814), but the MTBR-tau243-256 level indicates that the subject has AD in Braak stage III, IV, V, or VI, so then a therapeutically effective dose of anti-Ap protofibril antibody (e.g., lecanemab) may be administered.

[354] In some embodiments, a subject may be initially administered a therapeutically effective dose of lecanemab, based on a determination of levels of p-tau217 (and/or p- tau217R) in a biofluid sample from the subject (e.g., when levels of p-tau217 and/or p- tau217R are elevated as compared to the levels of p-tau217 and/or p-tau217R in a biofluid sample from a control, e.g., an individual who does not have AD). In some embodiments, after a period of time, a measurement of a MTBR-tau243 level in a biofluid sample from the subject (e.g., an elevated level relative to a healthy control or as compared to the level in a sample taken from the patient at an earlier time point) indicates that administration of at least one additional Alzheimer’s disease medication may be beneficial. For example, the MTBR- tau243 concentration in a biofluid sample from the subject may be elevated as compared to the MTBR-tau243 concentration in a biofluid sample from a control (e.g., an individual who does not have AD, even after the subject has received the anti-Ap protofibril antibody, e.g., indicating that the subject has reached Braak Stages V or VI. In some embodiments, the at least one additional treatment comprises an anti-tau antibody (e.g., E8214). In some embodiments, the p-tau217 levels are reduced by treatment with lecanemab, but the MTBR- tau243 concentration is elevated as compared to the MTBR-tau243 concentration in a biofluid sample from a control (e.g., an individual who does not have AD). In some embodiments, adding the anti-tau antibody (e.g., E8214) leads to a reduction or slowing of the increase in the MTBR-tau243 concentration.

[355] In some embodiments, the subject is switched from an initiation dosing regimen as described herein to a maintenance dosing regimen when a further measurement of MTBR- tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject is at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD, wherein the maintenance dosing regimen comprises administering at least one maintenance dose of an anti-Ap protofibril antibody (e.g., lecanemab), at least one maintenance dose of the anti-tau antibody, or both. In some embodiments, the maintenance dosing regimen comprises administering at least one maintenance dose of lecanemab, e.g., by intravenous administration or subcutaneous administration at the doses and intervals described herein. In some embodiments, the maintenance dosing regimen comprises administering at least one maintenance dose of E2814. In some embodiments, the maintenance dosing regimen comprises administration of at least one maintenance dose of the E2814 and administration of at least one maintenance dose of lecanemab. In some embodiments, the maintenance dosing regimen maintains reduced levels of MTBR-tau243, amyloid, and/or tau.

[356] In some embodiments, the maintenance dosing regimen comprises administration of both the anti-tau antibody (e.g., E2814) and the anti-Ap protofibril antibody (e.g., lecanemab) according to a maintenance dosing regimen. In some embodiments, the maintenance dosing regimen comprises administration of the anti-tau antibody (e.g., E2814) according to a maintenance dosing regimen, while administration of the anti-Ap protofibril antibody (e.g., lecanemab) is not altered from the initiation dosing regimen. In some embodiments, the maintenance dosing regimen comprises administration of the anti-Ap protofibril antibody (e.g., lecanemab) according to a maintenance dosing regimen, while administration of the anti-tau antibody (e.g., E2814) is not altered from the initiation dosing regimen. For example, in an exemplary initiation dosing regimen, E2814 may be intravenously administered at a therapeutically effective dose of 750 mg - 4500 mg

(e.g. ,1500 mg or 3000 mg), once every 4 weeks, while lecanemab may be intravenously administered at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject, once every 2 weeks. In a further exemplary initiation dosing regimen, E2814 may be intravenously administered at a therapeutically effective dose of 750 mg - 4500 mg (e.g.,1500 mg), once every 4 weeks, while lecanemab may be subcutaneously administered at a therapeutically effective dose of 720 mg or 500 mg, once every week. At a later time, reduced levels of a biomarker (e.g., MTBR-tau243 concentration) may indicate that the subject may be switched to a maintenance dosing regimen for lecanemab. In some embodiments, the maintenance dosing regimen may comprise intravenous administration of lecanemab at a dose of 10 mg/kg, once every 4 weeks, without changing the dosing regimen for E2814. In some embodiments, the maintenance dosing regimen may comprise subcutaneous administration of lecanemab at a dose of 360 mg or 250 mg, once every week, without changing the dosing regimen for E2814.

[357] In some embodiments, a subject is selected for treatment with an initiation dosing regimen comprising administration of lecanemab and/or the anti-tau antibody (e.g., E2814), based on a measurement of an elevated MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject, as compared to a sample from a control.

[358] In some embodiments, the biomarker p-tau217 and/or p-tau217R may be used to select a treatment comprising administration of a therapeutically effective dose of an anti-Ap protofibril antibody such as lecanemab (e.g., according to an initiation dose as disclosed herein). In some embodiments, during the course of treatment, a measurement of a MTBR- tau243 (e.g., a MTBR-tau243 species such as tryptic MTBR-tau243 or E-MTBR-tau243) concentration in a biofluid sample from the subject indicates that administration of at least one additional Alzheimer’s disease medication may be beneficial. For example, if the MTBR- tau243 concentration remains elevated or increases compared to the MTBR-tau243 concentration from a reference/threshold or control sample (e.g., compared to a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD), then a therapeutically effective dose of an anti-tau antibody (e.g., E2814) may be administered. In some embodiments, administration of the anti-Ap protofibril is discontinued when the anti- tau antibody is administered. In some embodiments, administration of the anti-Ap protofibril antibody is continued when the anti-tau antibody is administered. In some embodiments, administration of the anti-Ap protofibril antibody is continued at a maintenance dosing regimen when the anti-tau antibody is administered

[359] In some embodiments, a combination of MTBR-tau243 and p-tau217R may be used to select a subject for treatment with an anti-Ap protofibril antibody (e.g., lecanemab) and an anti-tau antibody (e.g., E2814). [360] In some embodiments, E2814 is administered in conjunction with lecanemab, e.g., wherein the lecanemab is administered subcutaneously. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 500 mg of lecanemab is administered subcutaneously once weekly using an autoinjector device (e.g., as 2 consecutive injections of 250 mg (2x1.25 mL of 200 mg/mL SC formulation). In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 500 mg of lecanemab is administered subcutaneously once weekly using an autoinjector device (e.g., as 2 consecutive injections of 250 mg (2x1.25 mL of 200 mg/mL SC formulation). In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 500 mg of lecanemab is administered subcutaneously once weekly using an autoinjector device (e.g., as 2 consecutive injections of 250 mg (2x1.25 mL of 200 mg/mL SC formulation). In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 500 mg of lecanemab is administered subcutaneously once weekly using an autoinjector device (e.g., as 2 consecutive injections of 250 mg (2x1.25 mL of 200 mg/mL SC formulation).

[361] In some embodiments, E2814 is administered in conjunction with lecanemab, e.g., wherein the lecanemab is administered intravenously. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 2 weeks. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 2 weeks. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 2 weeks. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 2 weeks.

[362] In some embodiments, E2814 is administered in conjunction with lecanemab, e.g., wherein the lecanemab is administered intravenously. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks.

[363] In some embodiments, the subject is switched to a maintenance dosing regimen of lecanemab, for example, if one or more measurements of MTBR-tau243 taken during the course of the combination treatment indicate that the treatment is effective or after at least 18 months of treatment with lecanemab. In some embodiments, the subject is switched to a maintenance dosing regimen of lecanemab if the level of p-tau217 and/or p-tau217R decreases, and/or a change is observed in another measurement known to reflect lecanemab efficacy, such as an increase in the AP42/40 ratio, a decrease in p-taul81, p-tau205, p-tau231, total tau, amyloid centiloid, and/or tau PET SUVR. In some embodiments, the maintenance dosing regimen is 360 mg of lecanemab administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, the maintenance dosing regimen is 250 mg of lecanemab administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, the maintenance dosing regimen is 10 mg/kg of lecanemab administered intravenously once every 4 weeks.

[364] Exemplary maintenance dosing regimens of lecanemab may be administered in combination with E2814. For example, in some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly.

[365] In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly.

[366] In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg/kg of lecanemab is administered intravenously once every 4 weeks.

[367] In some embodiments, the MTBR-tau243 is a peptide fragment such as MTBR- tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[368] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[369] In some embodiments, elevated levels of MTBR-tau243 (e.g., tryptic MTBR- tau243 and/or E-MTBR-tau243) in a sample (e.g., a blood sample) from a subject as compared to a sample from a control (e.g., an individual who does not have AD) indicate that the subject has early AD, e.g., in Braak stages I, II, or III, whereupon the subject is administered treatment comprising lecanemab first, and then administered a combination of lecanemab and the anti-tau antibody, e.g., once a level of tryptic MTBR-tau243 and/or E- MTBR-tau243 indicates a patient has progressed to Braak stages III, IV, V, or VI, e.g., stage V or stage VI. In some embodiments, levels of MTBR-tau243-256 in a sample (e.g., a blood sample) from a subject that are not elevated as compared to a sample from a control indicate that the subject has pre- AD or early AD, e.g., Braak stages I, II, or III, whereupon the subject is administered treatment comprising the anti-tau antibody first. In some embodiments, the subject is later administered a combination of lecanemab and the anti-tau antibody, e.g., once the level of MTBR-tau243 is elevated in a sample from the patient, as compared to a control level. Assay for MTBR-tau243 in biofluids

[370] In some embodiments, a measurement of MTBR-tau243 concentration is obtained from a biofluid sample from a subject. In some embodiments, the biofluid sample is CSF. In some embodiments, the biofluid sample is blood. Accordingly, in some embodiments, MTBR-tau243 is CSF MTBR-tau243. In some embodiments, MTBR-tau243 is CSF E- MTBR-tau243. In some embodiments, MTBR-tau243 is CSF tryptic MTBR-tau243. In some embodiments, MTBR-tau243 is plasma MTBR-tau243. In some embodiments, MTBR- tau243 is plasma E-MTBR-tau243. In some embodiments, MTBR-tau243 is plasma tryptic MTBR-tau243.

[371] In some embodiments, MTBR-tau243 may be identified in a CSF sample by LC/MS. In some embodiments, tau species from CSF obtained from a subject are immunoprecipitated with a domain-specific anti-tau antibody, followed by analysis by LC/MS to calculate CSF biomarker levels (Horie et al., Nat Med, 2023; 29, 1954-1963) or plasma biomarker levels (Horie et al., Nat Med, doi: 10.1038/s41591-025-03617-7). A chemical extraction method may be used after immunoprecipitation (Horie et al., Brain, 2021; 144(2): 515-527). The CSF MTBR-tau243 level may be expressed as a concentration, e.g., in pg/mL. Exemplary methods for detecting cleaved fragments of tau may be found in WO2024044637A2, the contents of which are incorporated herein by reference in their entirety.

[372] In some embodiments, the MTBR-tau243 concentration obtained from the sample from the subject is compared to a MTBR-tau243 concentration obtained from a control sample. In some embodiments, the control sample is from an individual who does not have Alzheimer's disease. For example, the individual may be a healthy subject. In some embodiments, the control sample is a reference measurement may be an average of measurements taken from more than one reference subject.

Additional biomarkers

[373] In some embodiments, the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment.

[374] In some embodiments, the change and/or difference in the measurement is selected from (a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) decreased cerebrospinal fluid levels of ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), neurogranin, and/or neurofilament light chain (NfL), and (d) decreased blood serum or plasma levels of a ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL).

[375] In some embodiments, the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology during and/or after treatment.

[376] In some embodiments, the change and/or difference in the measurement is selected from (a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) increased cerebrospinal fluid levels of ratio of Api-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), neurogranin, and/or neurofilament light chain (NfL), and (d) increased blood serum or plasma levels of a ratio of Api-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL).

[377] In some embodiments, the subject shows a change and/or difference in a measurement of MTBR-tau243, in combination with one or more additional biomarkers associated with AD pathology prior to treatment. For example, the subject may show elevated levels of MTBR-tau243, in combination with one or more of (a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) decreased cerebrospinal fluid levels of ratio of A 1- 42/1-40 and/or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np- taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), neurogranin, and/or neurofilament light chain (NfL), and (d) decreased blood serum or plasma levels of a ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p- tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p- taul81/np-taul81, p-tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL). In some embodiments, the combination of biomarkers comprises E-MTBR-tau243 and at least one of p-tau205/np-tau205 and p-tau217/np-tau217.

[378] In some embodiments, different biomarkers are used to detect different stages of AD progression. The different biomarkers may be used in combination. In some embodiments, the combination of biomarkers may be used to diagnose, select a patient for treatment, or stage AD. In some embodiments, the combination of biomarkers is MTBR- tau243 and an AP42/40 ratio, where a reduced AP42/40 ratio compared to a control indicates a later disease stage. In some embodiments, the combination of biomarkers is MTBR-tau243 and p-tau205 (e.g., a ratio of p-tau205/np-tau205), where the ratio of p-tau205 level may increase earlier in disease progression than the MTBR-tau243 and can be used as an indicator of earlier disease stage. In some embodiments, the combination of biomarkers is MTBR- tau243 and p-tau231 (e.g., a ratio of p-tau231/np-tau231). In some embodiments, the combination of biomarkers is MTBR-tau243 and p-tau217 (e.g., a ratio of p-tau217/np- tau217). For example, high levels of p-tau217/np-tau217 and MTBR-tau243 from a subject as compared to a control may indicate a late stage of AD, e.g., Ap+, CDR >1, or Braak stage III or higher. In some embodiments, high levels of p-tau217/np-tau217 but little or no increase in MTBR-tau243 levels in a subject as compared to a control indicates an earlier Braak stage, e.g., stage I or stage II. In some embodiments, when the combination of biomarkers indicates early AD, the patient is administered lecanemab. In some embodiments, when the combination of biomarkers indicates more advanced AD (e.g., Braak stage, e.g., stages V or VI), the patient is administered lecanemab and a second agent, e.g., an anti-tau agent (e.g., E2814).

[379] In some embodiments, the combination of biomarkers may be used to monitor AD treatment. Increases in the biomarkers may indicate disease progression, e.g., Ap+, CDR >1, or Braak stage III or higher. In some embodiments, the combination of biomarkers is MTBR- tau243 and an AP42/40 ratio. In some embodiments, the combination of biomarkers is MTBR-tau243 and p-tau217 (e.g., a ratio of p-tau217/np-tau217). In some embodiments, the combination of biomarkers is MTBR-tau243 and p-tau205 (e.g., a ratio of p-tau205/np- tau205). In some embodiments, the combination of biomarkers is MTBR-tau243 and p- tau231 (e.g., a ratio of p-tau23 l/np-tau231). For example, a patient may be administered lecanemab and monitored for levels of p-tau217/np-tau217 and MTBR-tau243. In some embodiments, increased levels of p-tau217/np-tau217 but little or no increase in MTBR- tau243 levels in a subject as compared to a control may indicate an earlier Braak stage, e.g., stage I or stage II.

[380] In some embodiments, the MTBR-tau243 species in the combination is a peptide fragment such as MTBR-tau243-254 or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255.

Amyloid PET

[381] PET imaging enables visualization of amyloid plaques in the brain, which were previously detected only by examining the brain at autopsy. Amyloid PET is a valuable tool for diagnosing AD and monitoring progression of the disease, as it has a high predictive accuracy for the presence of AD pathology (Hansson et al., Nature Medicine, 2021. 27: 954- 963; Therriault et al., Nature Reviews Neurology, 2024. 20: 232-244). Amyloid PET may be used in conjunction with other biomarker measures, including any of those disclosed herein, preferably a blood or CSF marker, e.g. MTBR-tau243 in blood or CSF.

[382] As used herein, the term “Amyloid PET” refers to Amyloid positron emission tomography imaging. In some embodiments, PET imaging (also referred to as a PET scan) is performed to assess for amyloid pathology. In some embodiments, amyloid PET is assessed with a PET tracer and uses the same tracer in follow-up assessments. In some embodiments, the amyloid PET tracer may be florbetaben (e.g., 18F-Florbetaben (Neuraceq®)), florbetapir (e.g., 18F-Florbetapir (Amyvid®)), and/or flutametamol (e.g., 18F-Flutemetamol (Vizamyl®)).In some embodiments, the PET imaging uses a florbetapir tracer. In some embodiments, the PET imaging uses a flutemetamol tracer. In some embodiments, the PET imaging uses a florbetaben tracer. Other exemplary amyloid PET tracers may be [1 lC]PiB or [18F]NAV4694 (flutafuranol).

[383] Amyloid positron emission tomography (PET) imaging can be used to confirm the presence of amyloid pathology in the brain of early AD subjects in the screening phase of the study and/or to evaluate the effects of the at least one anti-Ap antibody on amyloid levels in the brain, both by whole brain analysis (e.g., the average of 5-6 cortical regions) and brain region analysis. In some embodiments, the PET scan uses florbetaben (e.g., 18F -Florbetaben (Neuraceq®)), florbetapir (e.g., 18F-Florbetapir (Amyvid®)), and/or flutametamol (e.g., 18F- Flutemetamol (Vizamyl®)). In some embodiments, the PET scan uses florbetapir. In some embodiments, the PET scan uses a flutemetamol tracer. In some embodiments, the PET scan uses a florbetaben tracer. In some embodiments, amyloid plaque load can be identified by a PET imaging uptake visual read, e.g., by a trained radiologist. In some embodiments, 2 readers (1 designated as Primary Reader) visually assess the images to determine whether the scan is positive or negative for amyloid. In further embodiments, four regions of the brain are assessed for uptake of the imaging agent: the temporal lobes, the occipital lobes, the prefrontal cortex, and the parietal cortex and a positive amyloid scan has either 1 region with intense gray matter uptake that is greater than the white matter uptake and extends to the outer edges of the brain, or 2 regions with areas of reduced gray -white contrast. In further embodiments, if disagreement occurs between 2 readers, both meet to review the scan for a consensus read.

[384] In some embodiments, amyloid plaque load can be identified by a standard uptake value ratio (SUVr) as compared to a reference region. Methods for calculating amyloid PET SUVr are known in the art and may include those described herein. One exemplary method for quantitative analysis (e.g, computing) of SUVr is the PMOD PNEURO Biomedical Image Quantification Software (PMOD Technologies, Zurich, Switzerland. In some embodiments, PET images are first assessed for subject movement in the X, Y, and Z planes and corrected for motion, if needed, before individual images (e.g., 5-minute emission frames) are averaged, e.g., using a PMOD Averaging Function (PET frames averaged to increase the signal to noise ratio). In some embodiments, corresponding MRIs from subjects are prepared (e.g., using matrix size reduction processing, cropping of the MRI to include only the brain, segmentation to separate images into binary maps of gray matter, white matter, and CSF, and stripping the image of skull leaving only brain mask). In some embodiments, the averaged PET images and prepared MRIs are matched using the PMOD Matching Function, placing the images in the same orientation. In some embodiments, a Brain Normalization function, e.g., as provided by PMOD software, is used along with Brain Norm and Rigid Matching transformation matrices, to produce an averaged PET. In some embodiments, this averaged PET which is normalized to the MNInst space (Senjem et al, 2005) that is in the same orientation as the subject’s segmented MRI for quantitative analysis. In some embodiments, the PMOD Mask Function is used to mask the brain and zero the image outside of the mask to create a Normalized Gray Matter PET and a Normalized White Matter PET. Standard uptake values (SUVs) may be calculated for all gray matter mapped regions and the 3 white matter regions (pons, cerebellar white, and subcortical white) using PMOD software calculated using the normalized PET, subject weight, and injected dose of tracer to arrive at the units of SUVs. In some embodiments, the SUVr is the ratio of the global cortical average as compared to a reference region of choice. In some embodiments, a whole cerebellum mask is used as the reference region. In some embodiments, the reference region is subcortical white matter, derived whole cerebellum, whole cerebellum adjusted by subcortical white matter, cerebellar gray matter, and composite reference regions consisting of cerebellar cortex, pons subcortical white matter, and cerebella white matter.

[385] In some embodiments, the amyloid beta plaque levels in the brain are evaluated using PET imaging. In some embodiments, the PET imaging uses an amyloid PET tracer. In some embodiments, the PET imaging uses florbetaben (e.g., 18F-Florbetaben (Neuraceq®)), florbetapir (e.g., 18F-Florbetapir (Amyvid®)), and/or flutametamol (e.g., 18F-Flutemetamol (Vizamyl®))In some embodiments, the PET imaging uses a florbetapir tracer. In some embodiments, the PET imaging used a flutemetamol tracer. In some embodiments, the PET imaging uses a florbetaben tracer. In some further embodiments, different tracers may yield different results. In some embodiments, the adjusted mean reduction threshold is dependent upon the tracer used.

[386] In some embodiments, a subject’s brain amyloid level is determined by visual reads of amyloid PET images and expressed as a PET standard uptake value ratio (SUVr value). In some embodiments, a brain amyloid level is reduced after administration of an anti- Ap protofibril antibody (e.g., lecanemab), as described herein.

[387] In some embodiments, MTBR-tau243 may be a proxy for amyloid PET in a subject, wherein increased levels of MTBR-tau 243 (e.g., tryptic MTBR-tau243 and/or E- MTBR-tau243 from CSF and/or plasma) in a subject over time indicate increased amyloid PET.

Tau PET

[388] PET imaging enables visualization of tau accumulation in the brain, which was previously detected only by examining the brain at autopsy. Tau PET is a valuable tool for diagnosing AD and monitoring progression of the disease, particularly as the tau NFT burden is strongly correlated with severity of clinical AD symptoms (Hansson et al., Nature Medicine, 2021. 27: 954-963; Therriault et al., Nature Reviews Neurology, 2024. 20: 232- 244). Tau PET may be used in conjunction with other biomarker measures, including any of those disclosed herein, preferably a blood or CSF marker, e.g. MTBR-tau243 in blood or CSF.

[389] Tau PET also correlates strongly with MTBR-tau243, supporting the use of MTBR-tau243 as a proxy for tau PET. In some embodiments, the use of MTBR-tau243 may reduce the need for tau PET measurements. In some embodiments, MTBR-tau243 may be used as a single marker measure for effects of amyloid and/or tau antibodies on tau accumulation, simplifying biofluid assays. In some embodiments, MTBR-tau243 may be used with an anti-Ap protofibril antibody (e.g., lecanemab) to track the effects of the antibody on tau pathology.

[390] As used herein, “tau PET” refers to tau positron emission tomography. In some embodiments, PET imaging (e.g., a PET scan) is performed to assess tau pathology.

[391] In some embodiments, tau PET is assessed with a PET tracer and uses the same tracer in follow-up assessments. In some embodiments, the tau PET tracer may be an arylquinoline derivatives (e.g., [18F]THK5317 and [18F]THK5351), a pyridoindole derivative (e.g., [18F]AV-1451 also known as [18F]-flortaucipir), or a phenyl/pyridinyl- butadienyl-benzothiazone/benzothiazolium (PBB) derivative such as [11C]PBB3. In some embodiments, the PET tracer is [18F]-RO-948, [18F]-PI-2620, [18F]-JNJ-311, and [18F]- GTP1.

[392] Tau positron emission tomography (PET) imaging can be used to confirm the presence of tau pathology in the brain of early AD subjects in the screening phase of the study and/or to evaluate the effects of the at least one anti-Ap protofibril antibody on amyloid levels in the brain, both by whole brain analysis (e.g., the average of 5-6 cortical regions) and brain region analysis (e.g., in a temporal brain region). In some embodiments, the PET scan uses a [18F]MK-6240 (florquinitau) tracer. In some embodiments, tau load can be identified by a PET imaging uptake visual read, e.g., by a trained radiologist. In embodiments, regions of the brain are assessed for uptake of the imaging agent. In some embodiments, the temporal region is assessed for a tau PET level. In some embodiments, the frontal region is assessed for a tau PET level. In some embodiments, the parietal region is assessed for a tau PET level. In some embodiments, the occipital region is assessed for a tau PET level. In some embodiments, the cingulate region is assessed for a tau PET level. In some embodiments, the temporal region comprises the medial temporal region. In some embodiments, the medial temporal region comprises the hippocampus, the entorhinal cortex, the parahippocampus, and/or the anterior medial/lateral temporal lobes. In some embodiments, the temporal region comprises the meta-temporal region. In some embodiments, the meta-temporal region comprises the amygdala, the entorhinal cortex, the parahippocampus, the middle/interior and posterior temporal lobe, and/or the fusiform region. In some embodiments, the temporal region comprises the temporal lobe. In some embodiments, the temporal lobe comprises the superior anterior/posterior temporal lobe, the middle/inferior temporal lobe, the posterior temporal lobe, and/or the fusiform cortex. In some embodiments, the whole cortical gray matter is assessed for a tau PET level. In some embodiments, the reference region used for assessing a tau PET level is the ventral cerebellum (Cb).

[393] In some embodiments, a “tau PET level” can be identified by a standard uptake value ratio (SUVr) as compared to a reference region as measured by tau PET imaging. As used herein, a “tau PET level”, “tau level in a brain” and “tau load” are used interchangeably. As used herein a tau PET level refers to a measurement of a level of tau in a brain region, e.g., a temporal region, by PET. Methods for calculating tau PET SUVr are known in the art and may include those described herein. In some embodiments, a Standard Uptake Value Ratio Quantitative analysis of amyloid levels is completed using PMOD PNEURO Biomedical Image Quantification Software (PMOD Technologies, Zurich, Switzerland). In some embodiments, PET images are first assessed for subject movement in the X, Y, and Z planes and corrected for motion, if needed, before individual images (e.g., 5-minute emission frames) are averaged, e.g., using a PMOD Averaging Function (PET frames averaged to increase the signal to noise ratio). In some embodiments, corresponding MRIs from subjects are prepared (e.g., using matrix size reduction processing, cropping of the MRI to include only the brain, segmentation to separate images into binary maps of gray matter, white matter, and CSF, and stripping the image of skull leaving only brain mask). In some embodiments, the averaged PET images and prepared MRIs are matched using the PMOD Matching Function, placing the images in the same orientation. In some embodiments, a Brain Normalization function, e.g., as provided by PMOD software, is used along with Brain Norm and Rigid Matching transformation matrices, to produce an averaged PET. In some embodiments, this averaged PET which is normalized to the MNInst space (Senjem et al, 2005) that is in the same orientation as the subject’s segmented MRI for quantitative analysis. In some embodiments, the PMOD Mask Function is used to mask the brain and zero the image outside of the mask to create a Normalized Gray Matter PET and a Normalized White Matter PET. Standard uptake values (SUVs) may be calculated for all gray matter mapped regions and the 3 white matter regions (pons, cerebellar white, and subcortical white) using PMOD software calculated using the normalized PET, subject weight, and injected dose of tracer to arrive at the units of SUVs. In some embodiments, the SUVr is the ratio of the global cortical average as compared to a reference region of choice. In some embodiments, a whole cerebellum mask is used as the reference region. In some embodiments, the reference region is subcortical white matter, ventral cerebellum, derived whole cerebellum, whole cerebellum adjusted by subcortical white matter, cerebellar gray matter, and composite reference regions consisting of cerebellar cortex, pons subcortical white matter, and cerebella white matter.

[394] In some embodiments, a tau PET level is assessed with a PET tracer. In some embodiments, the PET tracer is [18F]MK-6240. In some embodiments, a tau PET level can be used to classify patients as having different levels of tau. For example, in some embodiments, a patient may be classified as having a low level of tau if the tau PET level is below a threshold value. The threshold value may be identified as tau levels in the whole cortex, or, alternatively, in a particular region of the interest. In some embodiments, the threshold value may be a tau PET level measured in the whole cortex (e.g., whole cortical gray matter). In some embodiments, the threshold values are cut-offs for classifying a patient as having a low tau PET level, an intermediate tau PET level, or a high tau PET level. In some embodiments, a patient may be classified as having a low level of tau if a level of tau as measured in a particular region of the interest, e.g., whole cortical gray matter, by PET using, e.g., an MK tracer, is below about 1.1, e.g., below about 1.0. In some embodiments, a patient may be classified as having a low level of tau if the tau PET level as measured using an MK tracer is below 1.06. In some embodiments, a patient may be classified as having an intermediate level of tau if the tau PET level as measured by MK tracer is between about 1.1 and 3.0, or between 1.06 and 2.91. In some embodiments, a patient may be classified as having a high level of tau if the tau PET level as measured by MK tracer is above about 3.0, e.g., above 2.91. In some embodiments, the thresholds for tau PET levels are <1.06 (low levels), 1.06 to 2.91 (intermediate levels), and > 2.91 (high levels), when the tau PET levels are determined in the whole cortex, e.g., using the PET tracer is [18F]MK-6240. In some embodiments, cut-offs may be determined according to tau PET levels in a particular brain region. As would be understood by one of ordinary skill in the art, the threshold values for classifying patients as having low, intermediate, or high tau PET levels may vary based on the methodology used to determine a tau level in the brain, e.g., depending on the tau PET methodology and tracer used in the tau PET imaging. In some embodiments, the threshold value may be determined using a common scale for tau PET which reflects analysis methods and/or measurements obtained with different tau PET tracers.

[395] In some embodiments, MTBR-tau243 may be a proxy for tau PET in a subject, wherein increased levels of MTBR-tau 243 (e.g., tryptic MTBR-tau243 and/or CSF E- MTBR-tau243 from CSF and/or plasma) in a subject over time indicate increased tau PET. Subjects having AD, suspected of having AD, or at risk of developing AD

[396] Subjects treated herein include those having AD or suspected of having AD. In some embodiments, the subject shows changes (e.g., an increase, a decrease, a change in the rate and/or extent of an increase, or a change in the rate and/or extent of the decrease) in one or more biomarkers associated with AD pathology (e.g., the biomarkers described above), as compared with a reference measurement. In some embodiments, the reference measurement may be a measurement taken from the same subject, e.g., at an earlier point in time, or a measurement in a part of the subject’s body, tissue, or fluids where the biomarkers levels do not change in response to AD pathology. In some embodiments, the reference measurement may be a measurement taken from another subject, such as a healthy control subject, or may be an average of measurements taken from more than one reference subject.

[397] In some embodiments, the subject may show a change and/or a difference in a measurement of MTBR-tau243 prior to treatment, e.g., an increase in MTBR-tau243 as compared to the reference measurement, e.g., as compared to an earlier measurement in the subject or as compared to a control subject who does not have AD.

[398] In some embodiments, in addition to or in lieu of an MTBR-tau243 measurement, the subject may show a change and/or a difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment, e.g., one or more of (a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) decreased cerebrospinal fluid levels of Api-42 (e.g., a decreased ratio of Api-42/1-40) and/or increased total total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau23 l/np-tau231), neurogranin, and/or neurofilament light chain (NfL), and (d) decreased blood serum or plasma levels of Api-42 (e.g., a decreased ratio of Api-42/1-40 in the plasma or serum), and/or increased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL), as compared to a reference measurement (e.g., measurement from a healthy control). In some embodiments, the subject may show a change in the ratio of phosphorylated to nonphosphorylated Tau 217 (P-Tau217/NP-Tau217 ratio, also called P-Tau217R or pTau217R) in blood plasma or serum, e.g., the ratio may be increased in subjects who have, are suspected of having, or are at risk of developing AD. Without being bound by theory, biomarkers as disclosed herein may be effective for predicting amyloid PET status (Rissman et al., 2024, Alzheimers & Dementia, 20(2): 1214-1224; Janelidze et al., 2022, Alzhimer’s & Dementia, 18:283-293) and for detecting and diagnosing AD (Hampel et al., 2023, Neuron, 111(18):2781-2799). In some embodiments, at least one of p-tau217/np-tau217, AP42/AP40, and p-taul81/np-taul81 may be used to predict amyloid PET status. In some embodiments, a measurement of p-tau217 and/or AP42/AP40 may be used to predict amyloid PET status. In some embodiments, a combination of p-tau217 and AP42/AP40 may be used to predict amyloid PET status. In some embodiments, the ratios of p-tau217/np-tau217 and AP42/AP40 may be used in combination to predict amyloid PET status. In some embodiments, MTBR- tau243, e.g., MTBR-tau243-254 or MTBR-tau243-256 (E-MTBR-tau243) or MTBR-tau243- 256 (deamidated, e.g., on residue N255) may be used in combination with one or more of p- tau217/np-tau217, AP42/AP40, p-taul81/np-taul81, p-tau205/np-tau205, and p-tau231/np- tau231 to predict amyloid PET status.

[399] In some embodiments, the subject is amyloid-positive, e.g., as indicated by a PET assessment, a CSF assessment of AP(l-42), MRI, and/or retinal amyloid accumulation.

[400] In some embodiments, a subject has AD, e.g., has been diagnosed with AD. For example, the subject may have been diagnosed with (a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and/or has been diagnosed as having mild Alzheimer’s disease dementia; (b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging - Alzheimer’s Association (NIA-AA) core clinical criteria; (c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; (d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last 1 year before treatment, e.g., as corroborated by an informant; (e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or (f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.

[401] In some embodiments, the subject has early AD. The subject with early AD may have symptoms ranging in severity from mild cognitive impairment due to AD - intermediate likelihood to mild Alzheimer’s disease dementia. In some embodiments, subjects with early AD have MMSE scores of 22 to 30 and Clinical Dementia Rating (CDR) global range 0.5 to 1.0. [402] In some embodiments, the subject has a low tau PET level in a global brain measurement, for example, as measured by tau PET. A low level of tau PET may refer to a low level of tau aggregation as imaged by PET scan imaging, e.g., a low level of cortical tau aggregation. In some embodiments, a subject with low tau PET also has accumulation of tau in certain brain regions, e.g., one or more early Braak regions or a composite of regions where tau accumulates in early AD. In some embodiments, a subject may be classified as having a low level of tau if a level of tau as measured by PET using an MK tracer (e.g., MK6240) is below about 1.1, e.g., below about 1.0. In some embodiments, a patient may be classified as having a low level of tau if the tau PET level as measured using an MK tracer is below 1.06. In some embodiments, a patient may be classified as having an intermediate level of tau if the tau PET level as measured by MK tracer is between about 1.1 and 3.0, e.g., between 1.06 and 2.91. In some embodiments, a patient may be classified as having a high level of tau if the tau PET level as measured by MK tracer is above about 3.0, e.g., above 2.91.

[403] In some embodiments, a subject is suspected of having AD, e.g., based on one or more biomarkers and/or cognitive symptoms of dementia.

[404] In some embodiments, a subject is at risk for developing AD but has not yet exhibited cognitive symptoms of dementia.

[405] In some embodiments, a subject may have risk factors for AD, wherein the risk factors are related to age or genetic mutations. In some embodiments, the subject is ApoE4- positive. In some embodiments, the subject is at least 65 years old, e.g., 65 to 80 years old. In some embodiments, the subject is 55 to 64 years old and has at least one risk factor chosen from: (i) a first degree relative diagnosed with dementia onset before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing. In some embodiments, a subject at risk for AD has elevated brain amyloid, e.g., as measured by and/or confirmed by PET assessment, but does not exhibit any detectable cognitive symptoms. In some embodiments, a subject at risk for AD has a change in a biomarker such as amyloid PET; tau in the brain, e.g., as measured by positron emission tomography (PET), cerebrospinal fluid levels of one or more of Api-42 (or a ratio of Ap 1-42/1 -40 in the cerebrospinal fluid), total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non- phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), neurogranin, and neurofilament light chain (NfL), and/or a change in a blood serum or plasma levels of one or more of Api-42 (or a ratio of Api-42/1-40), total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL), relative to a control subject or population.

[406] In some embodiments, a subject at risk for developing AD may have pre- AD (also referred to as preclinical AD, in which subjects are cognitively unimpaired but have elevated amyloid in the brain, e.g., as based on a change in one or more biomarkers associated with AD pathology). For example, the subject may show a change in one or more biomarkers associated with AD pathology, but no cognitive impairment, e.g., as measured by clinical symptoms of AD. In some embodiments, the subject has a Global Clinical Dementia Rating (CDR) score of 0. In some embodiments, the subject has a Mini -Mental State Examination (MMSE) score greater than or equal to 27, with educational adjustments. In some embodiments, the subject has a Wechsler Memory Scale-IV Logical Memory (subscale) II (WMS-IV LMII) score better than one standard deviation below age-adjusted mean in the WMS-IV LMII; namely a score of greater than 15 for a subject of age ranging from 50 to 64 years, of greater than 12 for a subject of age ranging from 65 to 69 years, of greater than 11 for a subject of age ranging from 70 to 74 years, of greater than 9 for a subject of age ranging from 75 to 79 years, and of greater than 7 for a subject of age ranging from 80 to 90 years.

[407] In some embodiments, a subject at risk for developing AD has a genetic mutation for a dominantly inherited Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP.

[408] In some embodiments, the subject has a mutation in APP.

[409] In some embodiments, the subject has a dominantly inherited Alzheimer’s disease (DIAD).

[410] In some embodiments, the subject has mild-to-moderate AD, e.g., where mild AD may be associated with Mini-Mental State Examination [MMSE] scores >20) and may be characterized by forgetfulness and difficulties with activities of daily living (ADLs). Moderate AD may be associated with MMSE scores of about 10-19 and may be characterized by marked memory loss and a requirement for significant assistance with ADLs.

[411] In some embodiments, the subject has AD at a late Braak stage, e.g., stage III or higher. Anti-Ap protofibril antibodies

[412] In some embodiments, an anti-Ap protofibril antibody used in the methods disclosed herein is an antibody capable of binding to an Ap protofibril, or an antigen binding fragment thereof. In some embodiments, the anti-Ap protofibril antibody is lecanemab, and comprises one or more of the sequences listed in Tables 1-4, e.g., comprising a complete set of 6 complementarity determining regions (CDRs) and/or a complete set of variable regions and/or a complete set of heavy and light chain sequences from the tables. In some embodiments, the anti-Ap protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1 , HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). In some embodiments, the anti-Ap protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-Ap protofibril antibody comprises human heavy and light chain variable region frameworks. In some embodiments, the anti-Ap protofibril antibody comprises a human IgGl heavy chain constant region, and a human Ig kappa light chain constant region. In some embodiments, the anti-Ap protofibril antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 9 and a light chain comprising an amino acid sequence of SEQ ID NO: 10. “CDRs” used herein in the context of an antibody sequence or structure refers to complementarity determining regions, that provide the main determinants of antigen binding. Generally, the antigen-binding site has six CDRs; three in the VH (HCDR1, HCDR2, HCDR3), and three in the VL (LCDR1, LCDR2, LCDR3). The CDRs may be determined according to the Kabat numbering scheme, which may be determined by according to the Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991, hereafter referred to as “Kabat report”).

[413] In some embodiments, the at least one anti-Ap protofibril antibody comprises a human constant region. In some embodiments, the human constant region of the at least one anti-Ap protofibril antibody comprises a heavy chain constant region chosen from IgGl, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variation thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the heavy chain constant region is chosen from IgGl and allelic variations thereof. The amino acid sequence of human IgGl constant region is known in the art and set out in SEQ ID NO: 11.

[414] In some embodiments, the human constant region of the at least one anti-Ap antibody comprises a light chain constant region chosen from K-k-chain constant regions and any allelic variation thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the light chain constant region is chosen from K and allelic variations thereof. The amino acid sequence of human K chain constant region is known in the art and set out in SEQ ID NO: 12.

[415] In some embodiments, the at least one anti-Ap protofibril antibody is lecanemab (also BAN2401, LEQEMBI, or lecanemab-irmb)). The terms “BAN2401” and “lecanemab” are used interchangeably and refer to a humanized IgGl monoclonal version of mAbl58, which is a murine monoclonal antibody raised to target protofibrils and disclosed in WO 2007/108756 and Journal of Alzheimer’s Disease 43: 575-588 (2015). Lecanemab comprises three heavy chain complementarity determining regions as described in Table 1 : (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3) and is described in WO 2007/108756 and in Journal of Alzheimer’s Disease 43:575-588 (2015). Lecanemab comprises (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8 (Table 2). The full length sequences of heavy chain and light chain of Lecanemab are set forth in SEQ ID NOs: 9 and 10 and are described in WO 2007/108756 and in Journal of Alzheimer’s Disease 43:575-588 (2015).

[416] In some embodiments, the anti-Ap protofibril antibody to be used in treatment is present in a concentration of at least 80 mg/mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration of at least 100 mg/mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration of at least 200 mg/mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration of at least 250 mg/mL. In some embodiments, the antibody is present in a concentration ranging from 80 mg/mL to 300 mg/mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration ranging from 85 mg/mL to 275 mg/mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration ranging from 90 mg/mL to 250 mg/mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration ranging from 95 mg/mL to 225 mg/mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration ranging from 100 mg/mL to 200 mg/mL. In some embodiments, the antibody is present in a concentration of 80 mg/mL, 90 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, 200 mg/mL, 210 mg/mL, 220 mg/mL, 230 mg/mL, 240 mg/mL, 250 mg/mL, 260 mg/mL, 270 mg/mL, 280 mg/mL, 290 mg/mL, or 300 mg/mL. In some embodiments, the antibody is present in a concentration of 100 mg/mL. In some embodiments, the antibody is present in a concentration of 200 mg/mL. In some embodiments, the antibody is present in a concentration of 250 mg/mL. In some embodiments, the antibody is present in a concentration of 300 mg/mL. In some embodiments, the antibody is lecanemab.

[417] In some embodiments, the anti-Ap protofibril antibody may be administered intravenously, subcutaneously, or a combination of both. In some embodiments, the anti-Ap protofibril antibody is intravenously administered at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject, once every 2 weeks. In some embodiments, the anti-Ap protofibril antibody is subcutaneously administered at a therapeutically effective dose (e.g., 500 mg) once every week. Additional exemplary dosages and dosing regimens are described below in Section D.

[418] As used herein, a “fragment” or “antigen binding fragment” of an anti-Ap protofibril antibody comprises a portion of the antibody, for example comprising an antigenbinding or a variable region thereof. In some embodiments, an antibody (e.g., an anti-Ap protofibril antibody) as used herein may refer to a full-length antibody comprising variable and constant regions, and/or an antigen-binding fragment of an antibody, e.g., a fragment comprising CDRs of the heavy and light chain, the heavy and light chain variable regions, the heavy and light chains of the antibody, and/or any fragments, variations, or alternative formats thereof. Accordingly, in any embodiment disclosed herein, a full-length antibody or a fragment of the antibody (e.g., an antigen-binding fragment) may be used, preferably a full antibody such as lecanemab. Non-limiting examples of fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, diabodies, linear antibodies, and singlechain antibody molecules.

[419] In some embodiments, the anti-Ap protofibril antibody (e.g., lecanemab, or an antigen-binding fragment thereof) reduces cerebral amyloid angiopathy (CAA), amyloid beta peptide deposits in the walls of small to medium blood vessels in the central nervous system and meninges. Anti-Tau Antibodies

[420] In some embodiments, the anti-tau antibody administered herein is an anti-tau antibody or antigen binding fragment thereof that is capable of binding to human tau. In some embodiments, the anti-tau antibody is E2814.

[421] In some embodiments, the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3), as defined by Kabat (Table 6). In some embodiments, the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) from a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 22 (e.g., as defined by Kabat or IMGT). In some embodiments, the anti-tau antibody comprises a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 22 (Table 7).

[422] In some embodiments, the anti-tau antibody comprises the CDRs of E2814. In some embodiments, the anti-tau antibody comprises the variable regions of E2814.

[423] In some embodiments, the anti-tau antibody comprises a human constant region. In some embodiments, the human constant region comprises a heavy chain constant region chosen from IgGl, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variation thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the heavy chain constant region comprises SEQ ID NO: 23 (Table 8).

[424] In some embodiments, the human constant region of the anti-tau antibody comprises a light chain constant region chosen from K and X-chain constant regions and any allelic variation thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the light chain constant region comprises SEQ ID NO: 24 (Table 8).

[425] In some embodiments, the anti-tau antibody comprises E2814 or an antigen binding fragment thereof. E2814 is disclosed in US 2019/0112364 Al as clone 7G6- HCzu25/LCzul8, the sequences of which are incorporated by reference herein.

[426] In some embodiments, the anti-tau antibody is any of those disclosed in US 2019/0112364 Al, the disclosure of which is fully incorporated herein by reference. In some embodiments, the anti-tau antibody comprises the CDR and/or variable region sequences from antibody clone 7G6-HCzu25/LCzul8 as disclosed in US 2019/0112364 Al, the sequences of which are incorporated by reference herein. In some embodiments, the anti-tau antibody is produced by antibody-producing cells deposited with the American Type Culture Collection (10801 University Blvd., Manassas, Va. 20110-2209) on Oct. 11, 2017 with Accession No. PTA-124524.

[427] In some embodiments, the anti-tau antibody is administered twice daily. In some embodiments, the anti-tau antibody is administered once daily. In some embodiments, the anti-tau antibody is administered weekly. In some embodiments, the anti-tau antibody thereof is administered twice weekly. In some embodiments, the anti-tau antibody is administered three times weekly. In some embodiments, the anti-tau antibody is administered every 2 weeks. In some embodiments, the anti-tau antibody is administered every four weeks or monthly.

[428] In some embodiments, the anti-tau antibody is administered at a dose ranging from 200 mg to 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 500 mg to 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 1000 mg to 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 1500 mg to 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 3000 mg to 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 200 mg to 3000 mg. In some embodiments, the anti-tau antibody is administered at a dose of 200 mg to 1500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 200 mg to 1000 mg. In some embodiments, the anti-tau antibody is administered at a dose of 200 mg to 500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 200 mg, 500 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, or 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 750 mg. In some embodiments, the anti-tau antibody is administered at a dose of 1000 mg. In some embodiments, the anti-tau antibody is administered at a dose of 1500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 3000 mg. In some embodiments, the anti-tau antibody is administered at a dose of 4500 mg.

[429] In some embodiments, an anti-Ap protofibril antibody is administered in conjunction with the anti-tau antibody, wherein anti-Ap protofibril antibody is administered every two weeks at a dose of 10 mg/kg and the anti-tau antibody is administered every four weeks at a dose of 1500 mg.

[430] A further aspect of the present disclosure relates to methods comprising optional administration of the anti-tau antibody (e.g., E2814) in conjunction with administration of an anti-Ap protofibril antibody, e.g., when the anti-Ap protofibril antibody is administered to a subject based on a measurement of a MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample. In some embodiments, the MTBR-tau243 concentration in the biofluid sample from the subject is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD). In some embodiments, the anti-Ap protofibril antibody may be administered simultaneously with or sequentially to the anti-tau antibody. In some embodiments, a subject may be pretreated with the anti-Ap protofibril antibody before the measurement of the MTBR-tau243 concentration is obtained and before the anti-tau antibody is administered.

[431] In some embodiments, the anti-tau antibody (e.g., administered in conjunction with the anti-Ap protofibril antibody) is administered until a change in the level of a biomarker in a sample is observed (e.g., a decrease in MTBR-tau243) in a biofluid sample (e.g., a CSF or blood sample) relative to the level in a sample taken from the subject prior to administration. In some embodiments, MTBR-tau243 can be measured in a sample taken from a subject at one point in time, and a second sample can be taken from a subject at a later point in time to measure the change in MTBR-tau243 in a subject. In some embodiments, the level of MTBR- tau243 in a sample taken from a subject after administration is reduced relative to the level of MTBR-tau243 in a sample taken from the subject before administration.

[432] In some embodiments, administration of the anti-tau antibody (e.g., administered in conjunction with the anti-Ap protofibril antibody) is increased due to an increase in the amount of MTBR-tau243 in a subject. In some embodiments, administration of the anti-tau antibody is decreased due to a decrease in the amount of MTBR-tau243 in a subject. Methods for measuring MTBR-tau243 in CSF are known in the art, such as immunoassays and mass spectrometry (Horie et al., 2023. Nat Med 29, 1954-1963).

[433] In some embodiments, the anti-tau antibody (e.g., administered in conjunction with the anti-Ap protofibril antibody) is administered until a change in the spread of tau as measured by PET is detected. In some embodiments, Tau PET can be used to confirm the presence of and/or measure the amount of tau in the brain of AD subjects. In some embodiments, a tau PET scan can be taken at one point in time, and a second tau PET scan can be taken at a second point later in time to measure the spread of tau in a subject. In some embodiments, administration of the anti-tau antibody is increased due to tau spread as measured by PET is observed in a patient. In some embodiments, the tau PET is MK-6240 Tau PET. [434] In some embodiments, MTBR-tau243 may be measured in addition to, or instead of, tau PET.

[435] As used herein, a “fragment” or “antigen binding fragment” of an anti-tau antibody comprises a portion of the antibody, for example comprising an antigen-binding or a variable region thereof. In some embodiments, an antibody (e.g., an anti-Ap protofibril antibody) as used herein may refer to a full-length antibody comprising variable and constant regions, and/or an antigen-binding fragment of an antibody, e.g., a fragment comprising CDRs of the heavy and light chain, the heavy and light chain variable regions, the heavy and light chains of the antibody, and/or any fragments, variations, or alternative formats thereof. Accordingly, in any embodiment disclosed herein, a full-length antibody or a fragment of the antibody (e.g., an antigen-binding fragment) may be used, preferably a full antibody such as E2814. Non-limiting examples of fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, diabodies, linear antibodies, and single-chain antibody molecules.

Treatment Regimens and Routes of Administration

[436] As described herein, administration of a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody may comprise administration of one or more doses of the anti-Ap protofibril antibody according to an initiation dosing regimen. In some embodiments, one or more doses of the anti-Ap protofibril antibody may be administered according to a maintenance dosing regimen. In some embodiments, administration of a treatment according to a treatment regimen (also called a dosage regimen or dosing regimen) may comprise administration of one or more doses of the anti-Ap protofibril antibody according to an initiation dosage regimen and optionally, administration of one or more doses of the anti-Ap protofibril antibody according to a maintenance dosage regimen.

[437] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject, administered once every 2 weeks. In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg, administered once every week.

[438] In some embodiments, the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks. [439] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg. For example, if the initiation dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg, the maintenance dosing regimen may comprise subcutaneous administration of the anti- Ap protofibril antibody at a therapeutically effective dose of 500 mg, 360 mg, or 250 mg. In some embodiments, the initiation dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 500 mg, and the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

[440] Additional variations of the initiation dosing regimen and maintenance dosing regimen are described herein.

[441] In some embodiments, the anti-Ap protofibril antibody may be administered daily, once weekly, also called “weekly”, or every other week, also called “biweekly”, or monthly, also called “every 4 weeks.” In some embodiments, the anti-Ap protofibril antibody may be administered intravenously and/or subcutaneously. In some embodiments, a dosage regimen comprises administration of at least one initiation dose (also called a treatment dose) and at least one maintenance dose. In some embodiments, the dosing regimen comprises administration of at least one dose of the anti-Ap protofibril antibody via one route of administration. In some embodiments, the dosing regimen comprises administration of at least one dose of the anti-Ap protofibril antibody via more than one route of administration (e.g., initially administering an antibody intravenously and then switching to subcutaneous administration).

[442] In some embodiments, the anti-Ap protofibril antibody is administered intravenously, e.g., by an injection into a peripheral vein. In an upper extremity, the median basilic or cephalic veins of the arm or the metacarpal veins in the hand’s dorsum may be used. In a lower extremity, the dorsal venous plexus of the foot may be used.

[443] In some embodiments, the anti-Ap protofibril antibody is administered subcutaneously. In a subcutaneous injection, the anti-Ap protofibril antibody is injected into the tissue layer between the skin and muscle, such as a fatty tissue just below the skin. In some embodiments, the subcutaneous administration is injected into the abdomen (e.g., at or under the level of the belly button), thigh (e.g., front of the thigh), or upper arm (e.g., back or side of the upper arm). In some embodiments, a volume of the injection administered subcutaneously is less than 2 mL. [444] In some embodiments, the anti-Ap protofibril antibody is subcutaneously administered using a vial and syringe (also called “vial/syringe” or “syringe/vial” or “SC Vial”). For example, the anti-Ap protofibril antibody in a subcutaneous formulation may be removed from a vial into a syringe and then injected from the syringe into the subject.

[445] In some embodiments, the anti-Ap protofibril antibody is administered using an autoinjector (also called an “auto-injector,” “Al,” “Al Device,” or “SC Al”). An exemplary auto-injector is the YpsoMate™ 2.25 mL Al Device, which has been approved in the United States (US) and Europe as a presentation for Ajovy® (fremanezumabv-frm). In some embodiments, an autoinjector may comprise a plastic PLAJEX™ syringe, a tapered needle (24G-29G), a V spring, a spring force, and component colors. It may be a single-use, disposable injection device consisting of a housing with a content viewing window, a spring activated mechanism, and integrated needle safety feature. In some embodiments, a 2.25 mL PLAJEX™ syringe may be prefilled with the anti-Ap protofibril antibody. At least one Al Device may be needed to administer the dose of the anti-Ap protofibril antibody.

[446] In some embodiments, the anti-Ap protofibril antibody is administered intravenously for at least one dose, and subcutaneously for at least one dose. For example, the anti-Ap protofibril antibody (e.g., LECANEMAB) may be administered to a subject intravenously, e.g., once weekly, for a period of time, such as 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 months, after which the antibody may be administered subcutaneously. In some embodiments, the anti-Ap protofibril antibody may be administered subcutaneously using a vial-syringe, and then later administered subcutaneously using an Al. In some embodiments, the anti-Ap protofibril antibody may be administered subcutaneously using a vial-syringe or an Al, and then later administered intravenously.

[447] In some embodiments, the method of treatment comprises switching between an intravenous or subcutaneous dose, or from an initiation to a maintenance dose, at a set time point (e.g., after 18 months or after 24 months). In some embodiments, the method of treatment comprises using a biomarker level to determine switching between an intravenous or subcutaneous dose or from an initiation to a maintenance dose, e.g., when measured at or after a set time point (e.g., after 18 months or after 24 months). In some embodiments, a maintenance dose is administered subcutaneously (e.g., as one or more subcutaneous injections).

[448] In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[449] In some embodiments, lecanemab is supplied as a solution for intravenous use and is a preservative-free, sterile, clear to opalescent and colorless to pale yellow solution for intravenous use by infusion after dilution. In some embodiments, LEQEMBI may be supplied in single-dose vials available in concentration of 500 mg/5 mL (100 mg/mL) or 200 mg/2 mL (100 mg/mL). In some embodiments, each mL of solution contains 100 mg of lecanemab- irmb and arginine hydrochloride (42.13 mg), histidine (0.18 mg), histidine hydrochloride monohydrate (4.99 mg), polysorbate 80 (0.50 mg), and Water for Injection at an approximate pH of 5.0. In some embodiments, LEQEMBI is diluted in 250 mL of 0.9% Sodium Chloride Injection, USP. In some embodiments, a dosage of LEQEMBI is 10 mg/kg, relative to the weight of the subject.

Initiation Doses

[450] In some embodiments, the anti-Ap protofibril antibody may be administered to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) according to a dosage regimen (also called a dosing regimen) in which a dose, e.g., a therapeutically effective dose, is administered at a regular dosing interval on a repetitive basis. In some embodiments, the dose may be called an initiation dose, a treatment dose, or a first dose. The initiation dose may be administered to a subject according to a dosage regimen (e.g., an initiation dosage regimen, also called an initiation dosing regimen) in which an initiation dose of the anti-Ap protofibril antibody may be administered at an interval (e.g., daily, weekly, biweekly, or monthly), for a period of time, e.g., until the subject shows evidence of improved AD pathology and/or slowed progression of AD. In some embodiments, the period of time is at least 6 months, 9 months, 12 months, 18 months, or 24 months. In some embodiments, the period of time is 9 months (about 36 weeks). In some embodiments, the period of time is 12 months (about 52 weeks). In some embodiments, the period of time is 15 months (about 60 weeks). In some embodiments, the period of time is 18 months (about 72 weeks). In some embodiments, the period of time is about 24 months (about 104 weeks). In some embodiments, the period of time is about 30 months, 36 months, 42 months, 48 months, 54 months, or 60 months. In some embodiments, the initiation dose may be administered until the subject has a decreased MTBR-tau243 concentration, shows a reduction in Ap levels (e.g., is amyloid negative), and/or shows a reduction in tau aggregation (e.g., a reduction in tau PET SUVR levels), as compared to a baseline measurement obtained from the subject before treatment, e.g., as measured after at least 12, 18, or 24 months of treatment. In some embodiments, the initiation dose may be administered until the levels of MTBR-tau243, brain Ap, brain tau, or additional biomarkers (e.g., CSF or blood biomarkers as described herein) show a slowing of an increase in levels and/or maintenance of constant levels during at least 2 timepoints measured before, during, and/or after treatment.

[451] In some embodiments, at least one initiation dose of the anti-Ap protofibril antibody is administered intravenously to the subject. An exemplary dosage regimen may comprise intravenously administering the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg/kg. In some embodiments, lecanemab is administered intravenously, once weekly, at a dose of 10 mg/kg, e.g., for at least 18 months or at least 24 months, or e.g., until the subject is amyloid-negative or until one or more other biomarker levels are reached (e.g. a change in a biomarker discussed herein). In some embodiments, lecanemab is administered intravenously, biweekly, at a dose of 10 mg/kg, e.g., for at least 18 months or at least 24 months, or e.g., until the subject is amyloid-negative, or until one or more other biomarker levels are reached (e.g. a change in a biomarker discussed herein).

[452] In some embodiments, at least one initiation dose of the anti-Ap protofibril antibody (e.g., lecanemab) is administered subcutaneously, e.g., by vial-syringe or by autoinjector. An exemplary dosage regimen may comprise subcutaneously administering the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 720 mg. In some embodiments, the dose may be administered in one single injection of 720 mg. In some embodiments, the dose of 720 mg may be administered in two concurrent, e.g., sequential, injections of 360 mg (e.g., 2 x 1.8 mL of 400 mg/2 mL or 2 x 1.8 mL of 200 mg/mL). In some embodiments, lecanemab is administered subcutaneously, once weekly, at a dose of 720 mg, e.g., for 18 months. In some embodiments, lecanemab is administered subcutaneously, once weekly, at a dose of 720 mg, e.g., for 24 months. In some embodiments, lecanemab is administered subcutaneously, once weekly, at a dose of 720 mg, e.g., for at least 18 months or at least 24 months, or e.g., until the subject is amyloid-negative, or until one or more other biomarker levels are reached (e.g., a change in a biomarker discussed herein). In some embodiments, lecanemab is administered subcutaneously, weekly, at a dose of 720 mg, e.g., for at least 18 months or at least 24 months, or e.g., until the subject is amyloid-negative, or until one or more other biomarker levels are reached (e.g., a change in a biomarker discussed herein). The dose of 720 mg may be administered in two concurrent, e.g., sequential, injections of 360 mg (e.g., 2 x 1.8 mL of 400 mg/2 mL or 2 x 1.8 mL of 200 mg/mL).

[453] In some embodiments, different initiation doses of the anti-Ap protofibril antibody (e.g., lecanemab) may be administered. In some embodiments, a subcutaneous dose of the anti-Ap protofibril antibody (e.g., lecanemab) may be administered at more than one dose. For example, a subject may be transitioned from a first dose of the antibody for a first period of time to a second dose of the antibody for a second period of time. For example, a dose of 720 mg may be administered subcutaneously, once weekly, for a first period of time, after which a dose of 500 mg may be administered subcutaneously, once weekly, for a second period of time. In some embodiments, the 720 mg dose is administered in 2 consecutive injections of 360 mg (2x1.8 mg of 200 mg/mL subcutaneous formulation) for the first period of time, and then the 500 mg dose is administered in 2 consecutive injections of 250 mg (2x1.25 mL of 200 mg/mL subcutaneous formulation) for the second period of time. In some embodiments, the first period of time is less than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months, or less than a period of time until the subject is amyloid negative, or one or more biomarker levels as discussed herein are reached. In some embodiments, the first period of time is less than 18 months. In some embodiments, the second period comprises the first period of time plus the remainder of 18 months, so that the first and second time periods are about 18 months in total. In some embodiments, a subject may receive the subcutaneous dose of 720 mg of the anti-Ap protofibril antibody (e.g., lecanemab) weekly, via an autoinjector, for a first period of time, and then a subcutaneous dose of 500 mg of the anti-Ap protofibril antibody (e.g., lecanemab) weekly, via an autoinjector, for a second period of time.

[454] In some embodiments, an initiation dosing regimen of the Ap protofibril antibody (e.g., lecanemab) may comprise administration of the antibody at more than one dose and/or via more than one mode of administration. In some embodiments, a subject may be transitioned from a first dose of the antibody, administered intravenously, for a first period of time, to a second dose of the antibody, administered either intravenously or subcutaneously, for a second period of time. In some embodiments, the subject may be transitioned from a first dose of the antibody, administered intravenously, for a first period of time, to a second dose of the antibody, administered subcutaneously, for a second period of time. For example, a first dose of 10 mg/kg may be administered to the subject intravenously, biweekly, for at first period of time (e.g., 6 months or 12 months), after which a second dose of 720 mg or less (e.g., 500 mg) maybe administered for a second period of time (e.g., 6 months or 12 months). In some embodiments, the initiation dosage regimen comprising a first dose of the Ap protofibril antibody (e.g., lecanemab) administered intravenously a first period of time, and a second dose of the Ap protofibril antibody administered subcutaneously for a second period of time may be followed by a maintenance dosing regimen, such as a maintenance dosing regimen comprising subcutaneous administration of the antibody at a dose of 360 mg weekly, or subcutaneous administration of the antibody at a dose of 250 mg weekly. In some

I l l embodiments, a subject’s exposure to an anti-Ap protofibril antibody depends on whether the dose was administered using a vial/syringe or an Al. In some embodiments, exposure to the antibody when using an Al is greater than when using a vial/syringe. Accordingly, the dose subcutaneously administered using an Al may be lower than a dose subcutaneously administered using a vial/syringe. In some embodiments, where a target systemic exposure is based on an intravenous administration (e.g., 10 mg/kg biweekly), the exposure from the dose subcutaneously administered using an Al method may be higher than that obtained using a vial/syringe method. Accordingly, the dose administered subcutaneously using an Al may be lower than a dose administered subcutaneously using a vial/syringe. In some embodiments, the systemic exposure from a dose intravenously administered at 10 mg/kg biweekly is about equal to a dose subcutaneously administered at 720 mg weekly using a vial/syringe method, or to a dose subcutaneously administered at 500 mg weekly using an Al method. For example, the dosage of the anti-Ap protofibril antibody subcutaneously administered using an Al method may be about 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the dosage subcutaneously administered using a vial/syringe method. In some embodiments, the dosage of the anti-Ap protofibril antibody subcutaneously administered using an Al method 65%, 66%, 67%, 68%, 69%, or 70% of the dose subcutaneously administered using a vial/syringe method.

[455] In some embodiments, at least one initiation dose of the anti-Ap protofibril antibody (e.g., lecanemab) is administered subcutaneously by autoinjector (Al). An exemplary dosage regimen may comprise subcutaneously administering the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, e.g., using an Al. The dose of 500 mg may be administered in a single injection of 500 mg. The dose of 500 mg may be administered in two concurrent, e.g., sequential, injections of 250 mg (e.g., 2 x 1.25 mL of 400 mg/2 mL, which is also 2 x 1.25 mL of 200 mg/mL). In some embodiments, lecanemab is administered subcutaneously using an Al, once weekly, at a dose of 500 mg for 18 months. In some embodiments, lecanemab is administered subcutaneously using an Al, once weekly, at a dose of 500 mg for 24 months. In some embodiments, lecanemab is administered subcutaneously using an Al, weekly, at a dose of 500 mg, e.g., for at least 18 months or at least 24 months, or e.g., until the subject is amyloid-negative. In some embodiments, lecanemab is administered subcutaneously using an Al, biweekly, at a dose of 500 mg, e.g., for at least 18 months or at least 24 months, or e.g., until the subject is amyloid-negative. The dose of 500 mg may be administered in a single injection of 500 mg. The dose of 500 mg may be administered in two concurrent, e.g., sequential, injections of 250 mg (e.g., 2 x 1.25 mL of 400 mg/2 mL or 2 x 1.25 mL of 200 mg/mL).

[456] In some embodiments, at least one of the dose, frequency of administration, or mode of administration of the anti-Ap protofibril antibody may be selected and/or changed to achieve a target systemic exposure (e.g., AUC) to the antibody. In some embodiments, a target systemic exposure is the same regardless of the mode of administration. For example, an exemplary target systemic exposure may be achieved when the anti-Ap protofibril antibody is intravenously administered at 10 mg/kg biweekly. The same target systemic exposure may be achieved when the anti-Ap protofibril antibody is subcutaneously administered at 720 mg, e.g., weekly. In some embodiments, the same target systemic exposure may be achieved when the anti-Ap protofibril antibody is subcutaneously administered at 500 mg, e.g., weekly. In some embodiments, a patient first receives the anti- Ap protofibril antibody (e.g., lecanemab) intravenously administered at 10 mg/kg dose, and later receives the antibody subcutaneously administered at a dose (e.g., 720 mg weekly or 500 mg weekly) that achieves about the same target systemic exposure as the intravenous dose. In some embodiments, the anti-Ap protofibril antibody is subcutaneously administered at a dose (e.g., 720 mg or 500 mg weekly) selected to achieve a target systemic exposure calculated to be equivalent to that achieved by intravenous administration at 10 mg/kg biweekly, whether or not the patient has previously received an intravenous administration of the antibody. In some embodiments, the anti-Ap protofibril antibody is subcutaneously administered at a dose (e.g., 720 mg or 500 mg) weekly. In some embodiments, the anti-Ap protofibril antibody is subcutaneously administered at a dose of 500 mg weekly. In some embodiments, the anti-Ap protofibril antibody is subcutaneously administered at a dose (e.g., 720 mg or 500 mg) biweekly. In some embodiments, administering a low dose of the anti-Ap protofibril antibody (e.g., in an initiation dose) or reducing the dose (e.g., in either an initiation dose or in a subsequent maintenance dose) may lower or reduce the patient’s risk for developing ARIA, while still retaining the ability to improve AD pathology or slow progression of AD. For example, the dose of the anti-Ap protofibril antibody may be reduced by lowering the dose in each administration, reducing the frequency of administration, or changing the method of administration. The reduced dose may be adequate to clear Ap and reduce or slow one or more of tau aggregation, expression of biomarkers of AD, cognitive decline, and/or indicators of AD pathology. In another example, a patient may be on a treatment dose and then moved, e.g., after 18 months or after 24 months of treatment, to a maintenance dose that is lower or administered less frequently while stabilizing or continuing to see reduced levels of brain Ap protofibril, e.g., as measured by continued changes in amyloid PET scans and/or one or more biomarkers of amyloid. In some embodiments, the subject has AD, is suspected of having AD, or is at risk for AD. In some embodiments, the subject has AD, e.g., early AD. In some embodiments, the subject has pre-AD.

Maintenance Doses

[457] In some embodiments, a maintenance dose of the anti-Ap protofibril antibody may be administered to the subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD). The maintenance dose may be a dose administered to maintain therapeutically effective concentrations of the anti-Ap protofibril antibody in the subject and/or to maintain or continue to reduce levels of Ap protofibril in the brain of the treated subject.

[458] Without being bound by theory, it has been found by the inventors that after an initiation regimen of an anti-Ap protofibril antibody such as lecanemab in a subject, a maintenance dosing regimen may be administered at a reduced frequency or dosage, or a different route of administration, while holding level or continuing to reduce Ap protofibrils in the brain.

[459] In some embodiments, the maintenance dose may be administered to a subject according to a dosage regimen (e.g., a dosing regimen is sufficient to maintain reduced concentrations of MTBR-tau243 in biofluids (e.g., CSF or blood) of the treated subject. In some embodiments, the maintenance dosage regimen (also called a maintenance dosing regimen) is administered at a regular interval on a repetitive basis. In some embodiments, each maintenance dose of the anti-Ap protofibril antibody may be administered daily, weekly, biweekly, or monthly.

[460] Administering at least one maintenance dose of the anti-Ap protofibril antibody, e.g., according to a maintenance regimen which succeeds a treatment regimen, may prevent a return to baseline (e.g., pretreatment) levels of markers of AD pathology. For example, when a treatment regimen is stopped or interrupted, amyloid PET may rebound and/or plasma biomarkers, e.g., the p-taul81 levels and the AP42/40 ratio, may return to baseline pretreatment levels. This effect has been corroborated by predicted rates of early amyloid reaccumulation based on data from gantenerumab and donanemab, as well as observations from a gap period in Study 201, a multicenter, double-blind, placebo-controlled, Phase 2b trial conducted in 856 patients with early AD. A core study in Study 201 evaluated key efficacy assessments, including clinical change on the AD Composite Score (ADCOMS) as the primary endpoint at 12 months and as key secondary endpoints, ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and AD Assessment Scale-Cognitive Subscale 14 (ADAS-Cogl4) at 18 months. Following analysis of the 18-month core phase, an intervening off-treatment period (gap period) ranging from 9-59 months (mean 24 months) was taken, which was followed by an OLE with 10 mg/kg IV bi-weekly lecanemab dosing to assess long-term safety and tolerability. Subjects who stopped treatment showed an increase in amyloid PET by approximately 7 Centiloids (21% return to pretreatment baseline) and an increase in p-taul81 and the AP42/40 ratio indicating return of 24%, and 47%, respectively, to pre-treatment baseline levels. Thus, in some embodiments, continued treatment with at least one maintenance dose of the anti-Ap protofibril antibody may maintain suppression of the disease progression rate and/or prevent reaccumulation of AD pathology which may occur if treatment is stopped.

[461] In some embodiments, a maintenance dose may be administered after a preset time period, e.g., after completion of an initiation dosage regimen. For example, a maintenance dose may be administered after about 18 months of treatment with an initiation dose, or the maintenance dose may be administered after about 24 months of treatment with an initiation dose. In some embodiments, the maintenance dose is administered after about 30 months of treatment with an initiation dose. In some embodiments, the maintenance dose is administered after about 36 months of treatment with an initiation dose. In some embodiments, the maintenance dose is administered after about 48 months of treatment with an initiation dose.

[462] In some embodiments, the maintenance dose may be the same as the initiation dose. In some embodiments, a maintenance dose may be lower than the initiation dose. In some embodiments, a maintenance dose may be administered less frequently than the initiation dose. This may reduce the burden for subjects and their caregivers associated with frequent administration of the anti-Ap protofibril antibody (e.g., lecanemab), while still maintaining the efficacy seen with treatment according to the initiation dose. In some embodiments, the maintenance dose may be administered by a different route of administration than the initiation dose. For example, an initiation dose may be administered intravenously, after which the maintenance dose is administered subcutaneously. In some embodiments, an initiation dose may be administered subcutaneously, after which the maintenance dose is administered intravenously. In some embodiments, the maintenance dose may be administered by the same route of administration as the initiation does. For example, an initiation dose may be administered intravenously, after which the maintenance dose is also administered intravenously. In some embodiments, an initiation dose may be administered subcutaneously, after which a maintenance dose is also administered subcutaneously.

[463] In some embodiments, a maintenance dosage regimen comprises administering maintenance doses over a period of time. For example, the maintenance doses may be administered for about 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 60 months, or for the remainder of the subject’s life. In some embodiments, the maintenance doses are administered until the subject shows evidence of improved AD pathology and/or slowed progression of AD, e.g., until the subject is amyloid negative.

[464] In some embodiments, a maintenance dosage regimen comprises administering maintenance doses at intervals. The intervals may be weekly, biweekly, or monthly.

[465] In some embodiments, the maintenance dose of the anti-Ap protofibril antibody (e.g., lecanemab) is 10 mg/kg, administered intravenously. An exemplary maintenance dosage regimen may comprise intravenously administering lecanemab monthly at dose of 10 mg/kg. In some embodiments, an exemplary maintenance dosage regimen may comprise intravenously administering lecanemab biweekly at a dose of 10 mg/kg. In some embodiments, an exemplary maintenance dosage regimen may comprise intravenously administering lecanemab weekly at a dose of 10 mg/kg. In an exemplary embodiment, the initiation dosing regimen comprises intravenously administering lecanemab biweekly at a dose of 10 mg/kg, and a maintenance dosage comprises intravenously administering lecanemab every four weeks (monthly) at a dose of 10 mg/kg.

[466] In some embodiments, the maintenance dose of the anti-Ap protofibril antibody (e.g., lecanemab) is 720 mg, administered subcutaneously. In some embodiments, the subcutaneous dose of 720 mg is administered in two concurrent, e.g., sequential injections of 360 mg (e.g., 2 x 1.8 mL of 400 mg/2 mL) of the subcutaneous formulation. An exemplary maintenance dosage regimen may comprise subcutaneously administering lecanemab weekly at dose of 720 mg. In some embodiments, an exemplary maintenance dosage regimen may comprise subcutaneously administering lecanemab biweekly at a dose of 720 mg. In some embodiments, the 720 mg dose of lecanemab is subcutaneously administered, e.g., weekly or biweekly, using a vial-syringe. In some embodiments, the 720 mg dose of lecanemab is subcutaneously administered, e.g., weekly or biweekly, using an Al.

[467] In some embodiments, the maintenance dose of the anti-Ap protofibril antibody (e.g., lecanemab) is 500 mg, administered subcutaneously. In some embodiments, the subcutaneous dose of 500 mg is administered in two concurrent, e.g., sequential injections of 250 mg (e.g., 2 x 1.25 mL of 400 mg/2 mL) of the subcutaneous formulation. An exemplary maintenance dosage regimen may comprise subcutaneously administering lecanemab weekly at dose of 500 mg. In some embodiments, an exemplary maintenance dosage regimen may comprise subcutaneously administering lecanemab biweekly at a dose of 500 mg. In some embodiments, the 500 mg dose of lecanemab is subcutaneously administered, e.g., weekly or biweekly, using an Al.

[468] In some embodiments, the maintenance dose of the anti-Ap protofibril antibody (e.g., lecanemab) is 360 mg, administered subcutaneously. In some embodiments, the subcutaneous dose is administered in a single injection of 360 mg (e.g., 1 x 1.8 mL of 400 mg/2 mL) of the subcutaneous formulation. An exemplary maintenance dosage regimen may comprise subcutaneously administering lecanemab weekly at dose of 360 mg. In some embodiments, an exemplary maintenance dosage regimen may comprise subcutaneously administering lecanemab biweekly at a dose of 360 mg. In some embodiments, the 360 mg dose of lecanemab is subcutaneously administered, e.g., weekly or biweekly, using an Al. In some embodiments, the 360 mg dose of lecanemab is subcutaneously administered, e.g., weekly or biweekly, using a vial-syringe.

[469] In some embodiments, the maintenance dose of the anti-Ap protofibril antibody (e.g., lecanemab) is 250 mg, administered subcutaneously. In some embodiments, the subcutaneous dose of 250 mg is administered in a single injection of 250 mg (e.g., 1 x 1.25 mL of 400 mg/2 mL) of the subcutaneous formulation. An exemplary maintenance dosage regimen may comprise subcutaneously administering lecanemab weekly at dose of 250 mg. In some embodiments, an exemplary maintenance dosage regimen may comprise subcutaneously administering lecanemab biweekly at a dose of 250 mg. In some embodiments, the 250 mg dose of lecanemab is subcutaneously administered, e.g., weekly or biweekly, using an Al.

[470] In some embodiments, the subject has AD, is suspected of having AD, or is at risk for AD. In some embodiments, the subject has AD, e.g., early AD. In some embodiments, the subject has pre- AD.

[471] In some embodiments, the subject receives an initiation dose (e.g., according to an initiation dosing regimen) with a first anti-Ap protofibril antibody, and then receives a maintenance dose with a second anti-Ap protofibril antibody. In some embodiments, the first anti-Ap protofibril antibody may be the same as the second anti-Ap protofibril antibody, e.g., lecanemab may be administered during the initiation dose regimen and during the maintenance dose regimen. In some embodiments, the first anti-Ap protofibril antibody is not the same as the second anti-Ap protofibril antibody.

[472] In some embodiments, the subject receives an initiation dose (e.g., according to an initiation dosing regimen) with a first anti-Ap antibody and then receives a maintenance dose with a second anti-Ap antibody, wherein the second Ap antibody is an anti-Ap protofibril antibody.

[473] In some embodiments, the first anti-Ap antibody targets at least one form of Ap, e.g., Ap monomers, different forms of Ap oligomers (e.g., dimers, trimers, tetramers, pentamers, hexamers, nonamers, dodecamers), a paranucleus (e.g., a partially-folded monomer that forms a nucleus for fibril elongation), protofibrils, or mature fibrils (Chen et al., 2017, Acta Pharmacologica Sinica, 38, 1205-1235). In some embodiments, the Ap monomer may be an Ap peptides ranging in size from 37-49 residues. In some embodiments, the Ap monomer is Ap28, Ap37, Ap39, Ap40 or Ap42. For example, an exemplary anti-Ap antibody may bind preferentially to aggregated fibrillar Ap, to an N-terminally truncated form of Ap found in amyloid plaque cores, to soluble aggregates of Ap, to soluble and fibrillar Ap, and/or to monomeric Ap. In some embodiments, the anti-Ap antibody (e.g., aducanumab and gantenerumab) binds preferentially to aggregated fibrillar Ap, with low affinities for Ap monomers. For example, aducanumab and gantenerumab may bind preferentially to P-amyloid fibrils over protofibrils. In some embodiments, the anti-Ap antibody (e.g., donanemab) binds to an N-terminally truncated and pyroglutamated form of Ap (APpE3) that is found in amyloid plaque cores. Without being bound by theory, antibodies against APpE3 may differ in their binding properties to soluble and aggregated conformations of APpE3-42 (Bouter et al., Acta Neuropathol. 2022, 143(5): 601-603). In some embodiments, the anti-Ap antibody may react with oligomers, protofibrils, and fibrillar forms of Ap. In some embodiments, the anti-APpE3 antibody donanemab may react with amyloid plaques in cores. In some embodiments, the anti-Ap antibody (e.g., bapineuzumab) binds preferentially to soluble and fibrillar AP37. In some embodiments, the anti-Ap antibody (e.g., crenezumab) binds preferentially to multiple forms of aggregated Ap and to monomers. In some embodiments, the anti-Ap antibody (e.g., solanezumab) binds preferentially to soluble monomeric Ap39. In some embodiments, the anti-Ap antibody is an anti-Ap protofibril antibody (e.g., lecanemab) that binds preferentially to soluble aggregates of Ap (protofibrils and oligomers), while also binding moderately to plaques. In some embodiments, the anti-Ap antibody is associated with a greater risk for ARIA or CAA (Soderberg et al., Scientific Reports, 2024, 14: 10868). [474] In some embodiments, a first anti-Ap antibody (e.g., donanemab) may be administered to clear and/or reduce certain forms of Ap during the initiation dosage regimen, after which a second anti-Ap antibody (e.g., an anti-Ap protofibril antibody, such as lecanemab) may maintain low levels of Ap during the maintenance dosing regimen, for example, by clearing and/or reducing protofibrils and oligomers and preventing further aggregation into fibrils. In some embodiments, the first anti-Ap antibody may clear and/or reduce insoluble forms of Ap, e.g., fibrils and plaques.

[475] In some embodiments, the first anti-Ap antibody is selected from donanemab, aducanumab, bapineuzumab, crenezumab, solanezumab, and gantenerumab. In some embodiments, the first anti-Ap antibody is donanemab. In some embodiments, the second anti-Ap antibody is an anti-Ap protofibril antibody, e.g., it is lecanemab. In some embodiments, the first antibody is donanemab and the second antibody is lecanemab, wherein the lecanemab is administered by iv biweekly or monthly, e.g., at 10 mg/kg. In some embodiments, the first antibody is donanemab and the second antibody is lecanemab, wherein the lecanemab is administered by sc weekly, e.g., at 360 or 250 mg.

Exemplary Dosage Regimens

[476] In some embodiments, a treatment for AD comprises administration of an anti-Ap protofibril antibody (e.g., lecanemab) according to a dosage regimen comprising at least one initiation dosage regimen. In some embodiments, the dosage regimen comprises only an initiation dosage regimen, e.g., administration of the anti-Ap protofibril antibody according to a route, frequency, and dose that does not change. In some embodiments, the dosage regimen comprises an initiation dosage regimen and a maintenance dosage regimen. In some embodiments, the initiation dosage regimen and the maintenance dosage regimen differ in at least one of route of administration, frequency of administration, and dose administered at each interval.

[477] In some embodiments, a dosage regimen comprises intravenously administering lecanemab biweekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) at a dose of 10 mg/kg, e.g., for at least 18 months, 24 months, or e.g., until the subject is amyloid-negative, before switching to less frequent (e.g., monthly) intravenously administered maintenance dose, e.g., a dose of 10 mg/kg.

[478] In some embodiments, a dosage regimen comprises intravenously administering lecanemab biweekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) at a dose of 10 mg/kg, e.g., for at least 18 months, 24 months, or e.g., until the subject is amyloid-negative, before switching to an intravenously administered maintenance dose of 10 mg/kg, administered once monthly.

[479] In some embodiments, a dosage regimen comprises intravenously administering lecanemab biweekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) at a dose of 10 mg/kg, e.g., for at least 6 months, 18 months, or at least 24 months or e.g., until the subject is amyloid-negative, before switching to a weekly, subcutaneously administered maintenance dose, e.g., a dose of 360 mg. The weekly maintenance dose of 360 mg may be administered using an Al.

[480] In some embodiments, a dosage regimen comprises intravenously administering lecanemab biweekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) at a dose of 10 mg/kg, e.g., for at least 6 months, 18 months, or at least 24 months or e.g., until the subject is amyloid-negative, before switching to a weekly, subcutaneously administered maintenance dose, e.g., a dose of 250 mg. The weekly maintenance dose of 250 mg may be administered using an Al.

[481] In some embodiments, the dosage regimen comprises subcutaneously administering lecanemab weekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD), using either a vial-syringe or an Al, e.g., at a dose of 720 mg, e.g., for at least 18 months or at least 24 months or e.g., until a patient is amyloidnegative, before switching to a weekly subcutaneous maintenance dose, e.g., a dose of 360 mg, administered using an Al.

[482] In some embodiments, the dosage regimen comprises subcutaneously administering lecanemab weekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD), using either a vial-syringe or an Al, e.g., at dose of 720 mg administered in two concurrent, e.g., sequential, injections of 360 mg (2 x 1.8 mL of 400 mg/2 mL) of the subcutaneous formulation, e.g., for at least 18 months or at least 24 months, before switching to a weekly, subcutaneously administered maintenance dose, e.g., a dose of 360 mg, administered using an Al, e.g., in one injection of 1.8 mL of 400 mg/2 mL.

[483] In some embodiments, the dosage regimen comprises subcutaneously administering lecanemab weekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD), using an Al, e.g., at a dose of 500 mg, e.g., for at least 18 months or at least 24 months or e.g., until a patient is amyloid-negative, before switching to a weekly subcutaneous maintenance dose, e.g., a dose of 360 mg, administered using an Al.

[484] In some embodiments, the dosage regimen comprises subcutaneously administering lecanemab weekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD), using an Al, e.g., at dose of 500 mg administered in two concurrent, e.g., sequential, injections of 250 mg (2 x 1.25 mL of 400 mg/2 mL) of the subcutaneous formulation, e.g., for at least 18 months or at least 24 months, before switching to a weekly, subcutaneously administered maintenance dose, e.g., a dose of 360 mg, administered using an Al.

[485] In some embodiments, the dosage regimen comprises subcutaneously administering lecanemab weekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD), using an Al, e.g., at a dose of 500 mg, e.g., for at least 18 months or at least 24 months or e.g., until a patient is amyloid-negative, before switching to a weekly subcutaneous maintenance dose, e.g., a dose of 250 mg, administered using an Al.

[486] In some embodiments, the dosage regimen comprises subcutaneously administering lecanemab weekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD), using an Al, e.g., at dose of 500 mg administered in two concurrent, e.g., sequential, injections of 250 mg (2 x 1.25 mL of 400 mg/2 mL) of the subcutaneous formulation, e.g., for at least 18 months or at least 24 months, before switching to a weekly, subcutaneously administered maintenance dose, e.g., a dose of 250 mg, administered using an Al, e.g., in one injection of 1.25 mL of 400 mg/2 mL.

[487] Alternatively, in any of the embodiments discussed above, the maintenance dose may be administered to the subject biweekly instead of weekly.

[488] In some embodiments, a dosage regimen comprises subcutaneously administering (e.g., via a vial or an autoinjector method) an anti-Ap protofibril antibody (e.g., administering lecanemab) to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) at a dose 400-800 mg, e.g., 720 mg or 500 mg, e.g., at 500 mg, e.g., for at least 18 months or at least 24 months or until the subject is amyloid negative, before switching to a subcutaneous maintenance dosage regimen. In some embodiments, dosage regimen comprises subcutaneously administering lecanemab weekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD), e.g., by weekly subcutaneous injection of 500 mg before switching to a weekly subcutaneous maintenance dosage regimen. In some embodiments, a dosage regimen comprises subcutaneously administering lecanemab weekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD), e.g., by weekly subcutaneous injection of 500 mg in two concurrent, e.g., sequential, injections of 250 mg (e.g., 2 x 1.25 mL of 400 mg/2 mL) before switching to a subcutaneous maintenance dosage regimen. In some embodiments, the subcutaneous maintenance dose is 180 mg. In some embodiments, the subcutaneous maintenance dose is 250 mg. In some embodiments, the subcutaneous maintenance dose is 360 mg. In some embodiments, the subcutaneous maintenance dose is 500 mg. In some embodiments, the maintenance dose is administered weekly. In some embodiments, a subcutaneous maintenance dose of 250 mg is administered weekly.

[489] In some embodiments, a dosage regimen comprises subcutaneously administering lecanemab biweekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD), e.g., at a dose 400-800 mg, e.g., 720 mg or 500 mg, e.g., at a dose of 500 mg, e.g., for at least 18 months or at least 24 months or until a patient is amyloid-negative, before switching to a subcutaneous maintenance dosage regimen, e.g., comprising a maintenance dose of 250 mg, 360 mg, or 500 mg administered biweekly. In some embodiments, a dosage regimen comprises subcutaneously administering lecanemab biweekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) using a vial-syringe, e.g., at a dose of 500 mg, e.g., for at least 18 months or at least 24 months or until the subject is amyloid-negative, before switching to a weekly subcutaneous maintenance dosage regimen, e.g., comprising a maintenance dose of 250 mg, 360 mg, or 500 mg administered biweekly using a vial-syringe. In some embodiments, a dosage regimen comprises subcutaneously administering lecanemab biweekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) using an Al, e.g., at a dose of 500 mg, e.g., for at least 18 months or at least 24 months or until the subject is amyloid-negative, before switching to a biweekly subcutaneous maintenance dosage regimen, e.g., comprising a maintenance dose of 250 mg, 360 mg, or 500 mg administered biweekly using an Al. In some embodiments, any dose (e.g., 500 mg, 360 mg, or 250 mg) may be administered in a single injection. In some embodiments, a dosage regimen comprises subcutaneously administering lecanemab biweekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) using an vial-syringe, e.g., a biweekly subcutaneous injection of 500 mg in two concurrent, e.g., sequential, injections of 250 mg (2 x 1.25 mL of 400 mg/2 mL), e.g., for at least 18 months or at least 24 months, before switching to a biweekly maintenance dosage regimen, e.g., comprising a maintenance dose of 250 mg, 360 mg, or 500 mg administered weekly using a vial-syringe. In some embodiments, any dose (e.g., 500 mg, 360 mg, or 250 mg) may be administered in a single injection. In some embodiments, a dosage regimen comprises subcutaneously administering lecanemab biweekly to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) using an Al, e.g., weekly subcutaneous injection of 500 mg in two concurrent, e.g., sequential, injections of 250 mg (e.g., 2 x 1.25 mL of 400 mg/2 mL), e.g., for at least 18 months, or at least 24 months, or until the subject is amyloid-negative, before switching to a biweekly subcutaneous maintenance dosage regimen, e.g., comprising a maintenance dose of 250 mg, 360 mg, or 500 mg administered weekly using an Al. In some embodiments, a maintenance dose may be administered to a subject weekly, biweekly, or monthly.

[490] In some embodiments, dosage regimens may be interchanged. In some embodiments, intravenously administered doses and subcutaneously administered doses may be interchanged at any time. For example, a subject may initially receive one or more initiation dose of the antibody administered intravenously (e.g., 10 mg/kg biweekly), and then transition to further initiation doses of the antibody administered subcutaneously (e.g., 720 mg, 500 mg, 360 mg, or 250 mg) using a vial/syringe or an Al. In some embodiments, a subject may initially receive one or more initiation doses of the antibody subcutaneously (e.g., 720 mg, 500 mg, 360 mg, or 250 mg) using a vial/syringe or an Al, and then transition to further initiation doses of the antibody administered intravenously (e.g., 10 mg/kg biweekly). In some embodiments, one or more initiation doses may be administered intravenously, while one or more maintenance doses may be administered subcutaneously. In some embodiments, one or more initiation doses may be administered subcutaneously, while one or more maintenance doses may be administered intravenously.

[491] In some embodiments, a treatment for AD may be administered to a subject (e.g., a subject that has AD, is suspected of having AD, or is at risk for AD) according to an exemplary regimen in the table below.

[492] Table 10. Exemplary initiation and maintenance dosage regimens

[493] In some embodiments, treating a subject having Alzheimer’s disease, Pre- AD, or early Alzheimer’s disease, comprises administering lecanemab at a first dose (e.g., an initiation dose) for a first period of time and then at a second dose (e.g., a maintenance dose) for a second period of time. In some embodiments, a maintenance dose of the anti-protofibril Ap antibody (e.g., lecanemab) may be the same as an initiation dose but administered less frequently. For example, the initiation dose may be administered weekly, while the maintenance dose is administered biweekly or monthly.

[494] In some embodiments, a maintenance dose of the anti-protofibril Ap antibody (e.g., lecanemab) may be a lower dose than the initiation dose. For example, the initiation dose may be administered at a dose of 500 mg, while a maintenance dose is administered at a dose of 250 mg, or 360 mg.

[495] In some embodiments, a maintenance dose of the anti-protofibril Ap antibody (e.g., lecanemab) may be administered using a different method than an initiation dose. For example, the maintenance dose may be administered by an autoinjector, while the initiation dose was administered by intravenous infusion or subcutaneous vial and syringe injection. In some embodiments, a maintenance dose of the anti-protofibril Ap antibody (e.g., lecanemab) of 250 mg, 360 mg, or 500 mg may be subcutaneously administered by autoinjector after an initiation dose was intravenously administered (e.g., at a dose of 10 mg/kg biweekly). In some embodiments, a maintenance dose of the anti-protofibril Ap antibody (e.g., lecanemab) of 250 mg, 260 mg, or 500 mg may be subcutaneously administered by autoinjector after an initiation dose was subcutaneously administered by vial and syringe (e.g., at an initiation dose of 720 mg or 500 mg).

[496] In some embodiments, the method of treatment comprises using a biomarker level, e.g., a change in a biomarker indicating that the subject may be switched to a maintenance intravenous or subcutaneous dose. In some embodiments, the biomarker is measured at or after a set time point (e.g., after 18 months or after 24 months). In some embodiments, the change in the biomarker is measured relative to a reference measurement, such as a baseline measurement from the subject prior to treatment. In some embodiments, the change in the biomarker is at least one of decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32); decreased tau in the brain, e.g., as measured by positron emission tomography (PET), decreased cerebrospinal fluid levels of one or more of Api-42 (e.g., or a ratio of Ap 1-42/1 -40 in the cerebrospinal fluid), total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), neurogranin, and neurofilament light chain (NfL), and/or a change in a blood serum or plasma levels, e.g., an increase in Api-42 (e.g., an increase in a ratio of Api-42/1-40), a decrease in total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL).

[497] In some embodiments, treating a subject having Alzheimer’s disease, Pre- AD, or early Alzheimer’s disease comprises intravenously administering lecanemab and then using a change in a measurement of a biomarker to determine switching from an initiation dosage regimen to a maintenance dosage regimen (e.g., reducing the frequency of administration, changing the route or administration, and/or reducing the dose administered).

Composition comprising at least one anti-Ap protofibril antibody

[498] In some embodiments, the at least one anti-Ap protofibril antibody is comprised in a composition. In some embodiments, the composition consists of at least one anti-Ap protofibril antibody. In some embodiments, the antibody is present at a concentration of 50- 250 mg/ML, e.g., 100-200 mg/mL. In some embodiments, the composition comprises at least one anti-Ap protofibril antibody and further comprises at least one additional active and/or inactive component. In some embodiments, the at least one additional component can comprise one or more suitable physiologically acceptable excipients for human and/or veterinary use.

[499] The compositions of the present disclosure may be in the form of a solution and/or any other suitable form deemed appropriate by one of ordinary skill in the art. The route of administration of the compositions of the present disclosure may be any suitable route, including intravenous, subcutaneous, oral, and nasal. In some embodiments, the composition is formulated as a sterile, non-pyrogenic liquid for intravenous administration. In some embodiments, the composition is formulated for subcutaneous administration, e.g., in an auto-injector or syringe. In some embodiments, the composition is a saline solution.

[500] In some embodiments, the composition is a liquid dosage form comprising at least one anti-Ap protofibril antibody, such as lecanemab, and further comprising, for instance, arginine hydrochloride, histidine, and polysorbate 80. In some embodiments, the composition is a liquid dosage form comprising 25 mmol/L histidine, 200 mmol/L arginine, 0.05% polysorbate 80. PCT/IB2021/000155 (WO2021/186245) is incorporated herein by reference for suitable intravenous and subcutaneous formulations. Concomitant administration of at least one anti-Ap protofibril antibody and at least one Alzheimer’s disease medication other than lecanemab

[501] In some embodiments, provided herein is a method of treating a subject, e.g., one having Pre-AD or early Alzheimer’s disease, comprising a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering a therapeutically effective amount of at least one anti-Ap protofibril antibody such as lecanemab and a therapeutically effective amount of at least one Alzheimer’s disease medication other than lecanemab if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have AD.

[502] In some embodiments, provided herein is a method of reducing and/or slowing clinical decline in a subject, e.g., one having Pre-AD or early Alzheimer’s disease, comprising a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering a therapeutically effective amount of at least one anti-Ap protofibril antibody such as lecanemab and a therapeutically effective amount of at least one Alzheimer’s disease medication other than lecanemab, if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have AD. The at least one additional therapy may comprise an additional anti-Ap antibody such as aducanumab. In some embodiments, the at least one additional therapy may comprise a BACE inhibitor and/or an anti-tau antibody.

[503] In some embodiments, the at least one Alzheimer’s disease medication is chosen from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one Alzheimer’s disease medication is a combination of donepezil and memantine. In some embodiments, the at least one additional therapeutic agent comprises one or more of BACE inhibitors, gamma secretase inhibitors, gamma secretase modulators, Ap peptide generation inhibitors other than said at least one anti-Ap protofibril antibody, agents that lower Ap peptide levels other than said at least one anti-Ap protofibril antibody, and a combination thereof. In some embodiments, the at least one additional therapeutic agent is a BACE inhibitor. In some embodiments, the BACE inhibitor is chosen from CNP520, BI-1181181, LY2886721, LY3202626, PF-06751979, RG7129, atabecestat, elenbecestat, lanabecestat, and verubecestat. In some embodiments, the BACE inhibitor is elenbecestat. In some embodiments, the BACE inhibitor is chosen from CNP520, BI- 1181181, LY2886721, LY3202626, PF-06751979, RG7129, atabecestat, elenbecestat, lanabecestat, and verubecestat.

[504] In some embodiments, provided herein is a method of treating a subject having pre- AD, or a patient that is symptomatic for Alzheimer’s disease (e.g., early Alzheimer’s disease), comprising a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering a therapeutically effective amount of at least one anti-Ap protofibril antibody such as lecanemab and a therapeutically effective amount of an anti-tau antibody if the MTBR- tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR- tau243 concentration in an individual who does not have AD.

[505] In some embodiments, the anti-tau antibody is an antibody that binds to the microtubule binding region of tau (MTBR-tau). In some embodiments, the anti-tau antibody is E2814. In some embodiments, the anti-tau antibody is LY3303560, ABBV-8E12, BIIB076, PNT001, UCB0107 PRX005, Lu AF87908, BIIB092, R07105705, or JNJ-63733657. E2814 is disclosed in US 2019/0112364 Al as clone 7G6-HCzu25/LCzul8, the sequences of which are incorporated by reference herein.

[506] In some embodiments, provided herein is a method of reducing and/or slowing clinical decline in a subject, e.g., one having pre-AD, or a patient that is symptomatic for Alzheimer’s disease (e.g., early Alzheimer’s disease), comprising a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering a therapeutically effective amount of at least one anti-Ap protofibril antibody such as lecanemab and a therapeutically effective amount of E2814 if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have AD.

[507] In some embodiments, a patient that is symptomatic for Alzheimer’s disease is administered the anti-Ap protofibril antibody (e.g., lecanemab) for at least 24 weeks (e.g., as a pre-treatment), based on at least an MTBR-tau243 level measured in a biological sample, and is then administered the anti-tau antibody (e.g., E2814) in conjunction with the anti-Ap protofibril antibody. In some embodiments, a patient that is symptomatic for Alzheimer’s disease is administered the anti-Ap protofibril antibody, e.g., for 24 weeks or until the patient’s rate of increase in tau PET (e.g., in a temporal region) is reduced relative to a control subject having AD who does not receive the treatment. The patient is then administered the anti-tau antibody in conjunction with the anti-Ap protofibril antibody. In some embodiments, a patient that is symptomatic for Alzheimer’s disease is administered the anti-Ap protofibril antibody for 24 weeks or until the patient is amyloid negative, then administered the anti-tau antibody in conjunction with the anti-Ap protofibril antibody.

[508] In some embodiments, the patient is asymptomatic for Alzheimer’s disease (pre- AD) and is first administered an anti-tau antibody (e.g., E2814), e.g., for 52 weeks before being administered the anti-tau antibody in conjunction with an anti-Ap protofibril antibody (e.g., lecanemab). In some embodiments, such a subject is identified based on a tau PET level higher than in a control subject who does not have pre- AD. In some embodiments, a patient that is asymptomatic for Alzheimer’s disease is administered the anti-tau antibody for 52 weeks or until the patient’s rate of increase in tau PET is reduced relative to a control subject having AD who does not receive the treatment, then administered the anti-tau antibody in conjunction with the anti-Ap protofibril antibody. In some embodiments, a patient that is asymptomatic for Alzheimer’s disease is administered the anti-tau antibody for 52 weeks or until the patient is amyloid negative, then administered the anti-tau antibody in conjunction with the anti-Ap protofibril antibody.

[509] In some embodiments, a subject with a reduction in brain amyloid level is given a reduced dose or frequency of the anti-Ap protofibril antibody, alone or in combination with at least one additional therapy, e.g., a BACE inhibitor and/or anti-tau antibody.

Definitions

[510] The following are definitions of terms used in the present application.

[511] As used herein, the singular terms “a,” “an,” and “the” include the plural reference unless the context clearly indicates otherwise.

[512] The phrase “and/or,” as used herein, means “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Thus, as a non-limiting example, “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in some embodiments, to A only (optionally including elements other than B); in other embodiments, to B only (optionally including elements other than A); in yet other embodiments, to both A and B (optionally including other elements); etc.

[513] As used herein, “at least one” means one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[514] As used herein, “about” when used in connection with doses, amounts, or ratios, include the value of a specified dose, amount, or ratio or a range of the dose, amount, or ratio that is recognized by one of ordinary skill in the art to provide a therapeutic effect equivalent to that obtained from the specified dose, amount, or ratio. The term “about” may refer to an acceptable error for a particular value as determined by one of skill in the art, which depends in part on how the values is measured or determined. In some embodiments, the term “about” means within 5% of a given value or range.

[515] When a number is recited, either alone or as part of a numerical range, it should be understood that the numerical value can vary above and below the stated value by up to a variance of +/- 10% of the stated value.

[516] When a range of values is listed herein, it is intended to encompass each value and sub-range within that range. For example, “2.5 mg/kg to 10 mg/kg” is intended to encompass, for example, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 7.5 mg/kg, 8 mg/kg, 8.5 mg/kg, 9 mg/kg, 9.5 mg/kg, 10 mg/kg, 2.5 mg/kg to 3 mg/kg, 2.5 mg/kg to 4.5 mg/kg, 3 mg/kg to 4.5 mg/kg, 4.5 mg/kg to 8 mg/kg, 2.5 mg/kg to 9 mg/kg, and so forth.

[517] As used herein, “adjusted mean change from baseline” refers to the use of a statistical analysis to calculate the change in a biomarker value over time. In some embodiments, a linear mixed-effects model (MMRM) is used to account for at least one additional covariate to determine the adjusted mean change from baseline.

[518] Amyloid P 1-42 (Ap42) refers to an amyloid beta monomer from amino acid 1 to 42 of the full-length protein (Table 5, SEQ ID NO: 13). Amyloid P 1-40 (Api-40) refers to an amyloid beta monomer from amino acid 1 to 42 of the full-length protein (Table 5, SEQ ID NO: 14). [519] P-taul81 is human tau protein phosphorylated at threonine in position 181. P- tau217 is human tau protein phosphorylated at threonine in position 217. P-tau231 is human tau protein phosphorylated at threonine in position 231.

[520] Total tau or t-tau as used herein is a measure of total tau in a sample, e.g. a CSF sample, a plasma sample, a serum sample.

[521] MTBR-tau 243 is a peptide fragment of tau, spanning residues 243-254 in the microtubule-binding region of tau and is enriched in tau aggregates. MTBR-tau243 may be measured in a biofluid sample, e.g., CSF or blood, as a correlate of tau tangles, tau PET, and cognitive impairment.

[522] Patients with “preclinical AD” or “pre-AD” as described herein (also called patients who are “asymptomatic” for AD), are cognitively normal individuals with intermediate or elevated levels of amyloid in the brain and can be identified by asymptomatic stages with or without memory complaints and emerging episodic memory and executive function deficits. Cognitively normal can include individuals who are CDR 0, or individuals within the normal ranges of cognitive test scores (MMSE, International Shopping List Task, Logical Memory, etc.). Preclinical AD occurs prior to significant irreversible neurodegeneration and cognitive impairment and is typically characterized by the appearance of in vivo molecular biomarkers of AD and the absence clinical symptoms. Preclinical AD biomarkers that may suggest the future development of Alzheimer’s disease include, but are not limited to, one or more of intermediate or elevated levels of amyloid in the brain by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20- 32), fluorodeoxyglucose (FDG) PET, or tau positron emission tomography (PET), cerebrospinal fluid level of Apt -42 and/or Apt -42/1 -40 ratio, cerebrospinal fluid level of total tau, cerebrospinal fluid level of microtubule binding region (MTBR)-tau, cerebrospinal fluid level of neurogranin, cerebrospinal fluid level of neurofilament light chain (NfL), and blood biomarkers as measured in the serum or plasma (e.g. levels of Api-42, the ratio of two forms of amyloid-P peptide (Api-42/1-40 ratio, e.g., a ratio of between about 0.092-0.094 or below about 0.092), plasma levels of plasma total tau, phosphorylated tau (e.g., p-taul81, p- tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL)). For example, it has been found that subjects treated with elenbecestat (E2609), a P-site amyloid precursor protein cleaving enzyme (BACE) inhibitor, who had amyloid baseline positron emission tomography (PET) standard uptake value ratios (SUVr values) of 1.4 to 1.9, exhibited the greatest slowing of cognitive decline while on treatment. See Lynch, S. Y. et al. “Elenbecestat, a BACE inhibitor: results from a Phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer’s disease.” Poster P4-389, Alzheimer’s Association International Conference, July 22-26, 2018, Chicago, IL, USA. Similarly, it has been found that subjects having a baseline florbetapir amyloid PET SUVr levels below 1.2 do not exhibit enough cognitive decline to be detectable, whereas subjects having SUVr levels above 1.6 appear to correlate with a plateau effect in which amyloid level has reached a saturation level and treatment does not result in a change of cognitive measures. See Dhadda, S. et al., “Baseline florbetapir amyloid PET standard update value ratio (SUVr) can predict clinical progression in prodromal Alzheimer’s disease (pAD).” Poster P4-291, Alzheimer’s Association International Conference, July 22-26, 2018, Chicago, IL, USA.

[523] “Early AD” or “early Alzheimer’s disease,” as used herein, is a continuum of AD severity from mild cognitive impairment due to AD - intermediate likelihood to mild Alzheimer’s disease dementia. Subjects with early AD include subjects with mild Alzheimer’s disease dementia as defined herein and subjects with mild cognitive impairment (MCI) due to AD - intermediate likelihood as defined herein. In some embodiments, subjects with early AD have MMSE scores of 22 to 30 and Clinical Dementia Rating (CDR) global range 0.5 to 1.0. Other methods for detecting early AD disease may employ the tests and assays specified below, including the National Institute of Aging- Alzheimer’ s Association (NIA-AA) core clinical criteria for probable Alzheimer’s disease dementia in McKhann, G.M. et al., “The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging - Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’ s disease.” Alzheimer Dement. 2011; 7:263-9. Other methods include CDR-SB, ADCOMS Composite Clinical Score, the Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, modified iADRS, Wechsler Memory Scale-IV Logical Memory (subscale) I (WMS-IV LMI), and Wechsler Memory Scale-IV Logical Memory (subscale) II (WMS-IV LMII). In some embodiments, a subject with early AD has evidence of elevated amyloid in the brain or a positive amyloid load. In some embodiments, elevated amyloid in the brain or a positive amyloid load is indicated and/or confirmed by PET assessment. In some embodiments, elevated amyloid in the brain or a positive amyloid load is indicated and/or confirmed by a CSF assessment of markers such as Api-42 (e.g., a soluble CSF biomarker analysis). In some embodiments, elevated amyloid in the brain or a positive amyloid load is indicated and/or confirmed by measuring the level of p-tau!81. In some embodiments, elevated amyloid in the brain or a positive amyloid load is indicated and/or confirmed by an MRI. In some embodiments, elevated amyloid in the brain or a positive amyloid load is indicated by retinal amyloid accumulation. In some embodiments, more than one assessment method is used.

[524] “Amyloid” refers to fibers that are unbranched, usually extracellular, and found in vivo; in addition, the fibers bind the dye Congo Red and then show green birefringence when viewed between crossed polarizers. Amyloid-forming proteins have been identified and associated with serious diseases, including amyloid-P peptide (AP) with Alzheimer’s disease (AD), islet amyloid polypeptide (IAPP) with diabetes type 2, and prion protein (PrP) with the spongiform encephalopathies. As used herein, “amyloid,” “brain amyloid,” and “amyloid-P peptide (AP)” are used interchangeably. Ap exists in various conformational states: monomers, oligomers (e.g., different forms of Ap oligomers such as dimers, trimers, tetramers, pentamers, hexamers, nonamers, dodecamers), a paranucleus (e.g., a partially- folded monomer that forms a nucleus for fibril elongation), protofibrils (e.g., soluble, pre- fibrillar intermediates), and insoluble fibrils (plaques). Protofibrils are formed as intermediate species when Ap monomers aggregate into insoluble fibrils, and various species of soluble protofibrils have been implicated in AD pathogenesis (Hampel et al., Mol Psychiatry, 2021 : 26, 5481-550).

[525] Ap peptides generally exist in a dynamic continuum of conformational states such that species tend to progress from monomeric Ap, to soluble Ap assemblies that include a range of low molecular weight oligomers to higher molecular weight protofibrils, and finally to insoluble fibrils (plaques).

[526] In some embodiments, the subject has “elevated amyloid” or “intermediate amyloid.” As one of ordinary skill in the art will recognize, amyloid levels from amyloid PET can be reported using the Centiloid method in “centiloid” units (CL). (Klunk WE et al. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimer’s Dement. 2015; 11 : 1-15 el-4). The Centiloid method measures a tracer on a scale of 0 CL to 100 CL, where 0 is deemed the anchor-point and represents the mean in young healthy controls and 100 CL represents the mean amyloid burden present in subjects with mild to moderate severity dementia due to AD. (Id.) As is known to one of ordinary skill in the art, centiloid thresholds may vary, for example may be refined, based on new or additional scientific information. (See, e.g., http://www.gaain.org/centiloid-project.) An elevated level of amyloid can be set relative to a baseline threshold in a healthy control determined according to methods known to a person of ordinary skill in the art (POSA). For example, a centiloid value of 32.5 can be used as a threshold value for “elevated amyloid,” and an “intermediate amyloid” level refers to an Ap amyloid PET in the range of 20-32.5 CL (e.g., 30 CL). In another example, a centiloid value of 40 can be used as a threshold value for “elevated amyloid,” and an “intermediate amyloid” level refers to an Ap amyloid PET in the range of 20-40 CL.

[527] “ Tau” refers to tau proteins, which belong to the family of microtubule-associated proteins (MAPs), and are mainly expressed in neurons and found in the axons and dendrites. Tau proteins play an important role in the assembly of tubulin monomers into microtubules to constitute the cytoskeleton and serve as tracks for axonal transport. Tau proteins are translated from a single gene located on chromosome 17, with alternative mRNA splicing leading to the formation of 6 different central nervous system tau isoforms, of which 5 are found in the human adult brain. The isoforms differ, having either 3 (Rl, R3, and R4) or 4 (R1-R4) repeat-regions in the carboxy (C)-terminal part and variable occurrence of microtubule binding region (MTBR). The amino (N)-terminal domain, which establishes links between microtubules and other parts of the cytoskeleton, or the plasma membrane, has a variable occurrence of 0, 1, or 2 inserts of 29 amino acids.

[528] “ Tau pathology” refers to pathological forms of tau, such as intracellular fibrillary tangles and components thereof, which are described in Alzheimer’s disease (AD) and other neurodegenerative disorders, referred to as tauopathies. Aggregation of hyperphosphorylated tau into insoluble paired helical filaments (PHF) that accumulate in neurons to form neurofibrillary tangles (NFTs) are hallmarks of tau pathology. In AD, NFTs occur in a neuroanatomically characteristic pattern of increasing severity, generally defined according to the Braak stages 1 to 6, which correlate well with progressive neuronal loss and clinical decline. Extracellular tau seeds are also a pathological form of tau. Some tau seeds contain the tau MTBR.

[529] Subjects with “mild Alzheimer’s disease dementia,” or “mild AD dementia” as used herein, are subjects meeting the National Institute of Aging- Alzheimer’ s Association (NIA-AA) core clinical criteria for probable Alzheimer’s disease dementia in McKhann, G.M. et al., “The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging - Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.” Alzheimer Dement. 2011; 7:263-9. Also included herein are subjects who have a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater at screening and baseline and subjects that exhibit change in the score on the Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II). [530] Subjects with “MCI due to AD - intermediate likelihood,” as used herein are those identified as such in accordance with the NIA-AA core clinical criteria for mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood (see McKhann supra). For example, a subject may be symptomatic but not demented, with evidence of brain amyloid pathology making them less heterogeneous and more similar to mild Alzheimer’s disease dementia subjects in cognitive and functional decline as measured by the ADCOMS Composite Clinical Score defined herein. Also included are subjects who have a CDR score of 0.5 and a Memory Box score of 0.5 or greater at screening and baseline. Furthermore, subjects who report a history of subjective memory decline with gradual onset and slow progression over the last 1 year before screening, which is corroborated by an informant, are also included herein. Memory decline and/or episodic memory impairment can be assessed in a subject by change in the score on the Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II).

[531] The terms “patient” and “subject” are used interchangeably.

[532] As used herein, “MMSE” refers to the Mini-Mental State Examination, a cognitive instrument commonly used for screening purposes, but also often measured longitudinally in AD clinical trials having a 30 point scale with higher scores indicating less impairment and lower scores indicating more impairment, ranging from 0 (most impaired) to 30 (no impairment). In some embodiments, seven items measuring orientation to time and place, registration, recall, attention, language, and drawing may be assessed as part of the MMSE score. (Folstein, M.F. et al., “Mini-mental state. A practical method for grading the cognitive state of patients for the clinician.” J. Psychiatr. Res. 1975;12: 189-98.)

[533] As used herein, “ADAS-Cog” refers to Alzheimer’s Disease Assessment Scale- Cognitive. The ADAS-Cog is a widely used cognitive scale in Alzheimer's disease trials having a structured scale that evaluates memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope) and constructional praxis (copying geometric designs). (Rosen, W.G. etal., “A new rating scale for Alzheimer’s disease.” Am. J. Psychiatry 1984; 141 : 1356-64.) Ratings of spoken language, language comprehension, word finding difficulty, ability to remember test instructions, maze, and number cancellation may also be obtained. In some embodiments, ADAS-Cog refers to the use of the Alzheimer Disease Assessment Scale-Cognitive Subscalew (ADAS-Cogl4). In some embodiments, a modified version may be used herein and is scored from 0 to 90 points with a score of 0 indicating no impairment, and a score of 90 indicating maximum impairment. In some embodiments, the ADAS-Cogl4 tasks include memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope), constructional praxis (copying geometric designs), spoken language, language comprehension, word finding difficulty, ability to remember test instructions, maze, and number cancellation (Rosen et al, 1984).

[534] As used herein, “CDR-SB” refers to clinical dementia rating - sum of boxes. The CDR is a clinical scale that describes 5 degrees of impairment in performance on each of 6 categories of function including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. (Berg, L. et al., “Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment.” Ann. Neurol. 1988; 23:477- 84.) A sum of boxes score provides a measure of change where each category has a maximum possible score of 3 points and the total score is a sum of the category scores giving a total possible score of 0 to 18 with higher scores indicating more impairment.

[535] As used herein, “CDR global”, “global CDR” score and “global rating of dementia CDR” score is used interchangeably. As used herein, CDR global score is a rating of the degree of impairment obtained on each of the 6 categories of function from the 6 categories of the CDR scale and is synthesized into 1 global rating of dementia CDR score, (ranging from 0 to 3) where 0 indicates no cognitive impairment, 0.5 indicates mild cognitive impairment, and 1-3 indicates mild, moderate, severe dementia respectively. The global CDR score may be used as a clinical measure of severity of dementia. In some embodiments, a global CDR score may be used to determine if a patient has progressed or maintained a stage of AD, e.g., a higher score on a subsequent evaluation indicating progression of AD, e.g., an unchanged score indicating no progression of AD.

[536] As used herein, “ADCOMS” refers to Alzheimer’s Disease Composite Score, a composite clinical score based on an analysis of four ADAS-Cog items (delayed word recall, orientation, word recognition, and word finding difficulty), two Mini Mental State Examination (MMSE) items (orientation to time, and drawing), and all six CDR-SB items (personal care, community affairs, home and hobbies, memory, orientation, and judgment and problem solving), as discussed in the Examples and in Wang, J. et al., “ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials.” J. Neurol. Neurosurg. Psychiatry. 2016; 87:993-999. ADCOMS was developed to be particularly sensitive to disease progression during early stages of AD (i.e., preclinical AD or early AD). [537] In some embodiments, ADCOMS can be calculated using the following formula: where A_£(t), Bt(t) and C_£(t) are item scores at time t corresponding to items from ADAS- cog, reversed MMSE scores, and CDR-SB, respectively (Wang, J. etal., “ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials). ADCOMS is particularly sensitive to disease progression during early stages of AD, i.e., prodromal and mild AD.

[538] As used herein, “ADCS MCI-ADL” refers to the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL). The ADCS MCI-ADL is a clinical scale that assesses the competence level of a patient at six basic activities of daily living. Additional examples are discussed in Kreutzer J.S., DeLuca J., Caplan B. (eds) Encyclopedia of Clinical Neuropsychology. Springer, New York, NY.

[539] As used herein, “modified iADRS” or “iADRS” refers to a composite tool that combines scores from the ADAS Cogl4 (all items) and the ADCS MCI-ADL (all items). The modified iADRS score can be used to evaluate disease progression:

Modified iADRS score = [-l(ADAS-cogl4) +90] + ADCS MCI-ADL.

[540] As used herein, “ApoE4-positive” subjects and “ApoE4 carriers” refer to subjects who harbor the s4 variant of the apolipoprotein (APOE) gene. The s4 variant is one of several major alleles of the apolipoprotein gene. The gene is generally responsible for metabolism of fats. It has been found that carriers of the apolipoprotein s4 show significantly greater rates of amyloid retention when compared to non-carriers. (Drzezga, A. et al, “Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease.” Neurology. 2009; 72:1487-94.) In some embodiments, a subject treated herein is a heterozygous carrier of the apolipoprotein E s4 gene allele. In some embodiments, the subject is a homozygous carrier of the apolipoprotein E s4 gene allele. The terms “ApoE4-negative” and “ApoE4 noncarriers” are used interchangeably.

[541] As used herein, whether an early AD subject is “amyloid positive” or “amyloid negative” may be determined based on whether the subject has a positive amyloid load. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative as indicated by longitudinal positron emission tomography (PET) assessment of an imaging agent uptake into the brain, e.g., an amyloid imaging agent or a tau imaging agent. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by evaluation of a tau PET imaging assessment. In some embodiments, the subject is “amyloid negative” if PET SUVr negativity is below a threshold determined for an amyloid PET tracer. In some embodiments, the amyloid PET tracer may be florbetaben (e.g., 18F-Florbetaben (Neuraceq®)), florbetapir (e.g., 18F-Florbetapir (Amyvid®)), and/or flutametamol (e.g., 18F- Flutemetamol (Vizamyl®)). In some embodiments, the threshold for PET SUVr for an amyloid PET tracer is about 1.17, and a measurement below this threshold may indicate that the subject is “amyloid negative.” In some embodiments, the florbetapir amyloid PET SUVr threshold is about 1.17. In some embodiments, the florbetaben amyloid PET SUVr threshold is about 1.17. In some embodiments, the flutemetamol amyloid PET SUVr threshold is about 1.17. In some embodiments, a subject is determined to be amyloid-positive or amyloidnegative by evaluation of the level of a biomarker in a sample (e.g., a AP42/40 ratio) from a subject, alone or in combination with another method such as PET measurement of brain amyloid. In some embodiments, a subject is “amyloid negative” if the AP42/40 ratio in a sample is at or about above 0.092-0.094 e.g., at about 0.092. In some embodiments, a subject is “amyloid negative” if the AP42/40 ratio in a sample is above 0.092. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by a CSF assessment of the presence of amyloid pathology using assessments of markers such as p-taul81, alone or in combination with another method such as PET measurement of brain amyloid. In some embodiments, a qualitative visual read of PET scans may be used to determine amyloid positive and amyloid negative by categorizing subjects as having either “normal” or “abnormal” uptake on the basis of the PET image pattern. Readers will have been trained and certified to recognize brain PET images with abnormal or normal patterns of uptake, or the detection of amyloid is done through a semi -quantitative or quantitative approach. In some embodiments, a threshold will be set for quantitatively determining from a biomarker (e.g., serum or CSF) and/or PET scan whether an Ap brain load indicates a subject is amyloid-positive or negative. In some embodiments, a subject is determined to be amyloidpositive or amyloid-negative by an imaging method. An imaging method may be used to determine, calculate, or predict whether a subject is amyloid-positive or negative, even when the imaging method is not used to visualize amyloid directly. In some embodiments, the method uses MRI), and/or combines MRI and other imaging modalities such as PET. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by retinal amyloid accumulation. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by behavioral/cognitive phenotypes.

[542] As would be understood by one of ordinary skill in the art, digital, computerized, and/or conventional (e.g., pen and paper) cognitive tests may be used to detect early cognitive changes that may signal mild cognitive impairment and/or a risk for developing dementia, and thus may be used to identify subject in need of treatment as disclosed herein. Such tests, for example, may screen for cognitive impairment, and potentially identify individuals with MCI. Tests may use artificial intelligence to analyze cognitive test results to determine whether a case of mild cognitive impairment will escalate into Alzheimer’s within a year. Diagnosing the condition early, before symptoms have begun to appear, may be used to assist physicians identify subjects in need of treatment as disclosed herein sooner, potentially delaying onset or lessening the severity of the neurodegenerative disease.

[543] As used herein, the term “treat” refers to any administration or application of a therapeutic agent for a disease or disorder in a subject, and includes inhibiting the disease, slowing progression of the disease, delaying progression, arresting its development, reversing progression of disease (e.g., reversing build up of Ap fibrils), preventing the onset or development of the disease, relieving or ameliorating one or more symptoms or underlying condition(s) of the disease, curing the disease, improving one or more clinical metrics, or preventing reoccurrence of one or more symptoms of the disease. In some embodiments, treatment of AD in a subject comprises an administration, e.g., an intravenous infusion, of an anti-amyloid P (AP) protofibril antibody. In some embodiments, treatment of AD in a subject comprises a therapeutically effective dose by administration, e.g., an intravenous infusion, of an anti-amyloid P (AP) protofibril antibody.

[544] As used herein, the term “infusion” refers to an active administration of one or more agents with an infusion time of, for example, approximately 60 minutes. In some embodiments, an anti-amyloid P (AP) protofibril antibody, described herein is systemically administered to a human subject via infusion. In some embodiments, an anti -amyloid P (AP) protofibril antibody is alternatively administered to the human subject, e.g., by subcutaneous injection. In some embodiments, the subcutaneous injection is a weekly injection. In some embodiments, the subcutaneous injection is a biweekly injection. In some embodiments, an anti-amyloid P (AP) protofibril antibody is administered to the human subject by intravenous infusion.

[545] In some embodiments, the subject is administered a maintenance dose of a treatment. As used herein, the term “maintenance dose” refers to a dosage administered to a subject to maintain the desired therapeutic effect. In some embodiments, the maintenance dose is administered weekly, every two weeks, monthly, every two months, or every three months (quarterly) or every 24 weeks (every six months or semi-annually). In some embodiments, the maintenance dose comprises an anti-Ap protofibril antibody. In some embodiments, the maintenance dose is administered as an intravenous infusion. In some embodiments, the intravenous infusion is a 10 mg/kg dose of lecanemab administered monthly. In some embodiments, the maintenance dose is administered subcutaneously, orally, or nasally. In some embodiments, the maintenance dose is administered subcutaneously.

[546] In some embodiments, the maintenance dose is administered as a subcutaneous injection. In some embodiments, the maintenance dose is administered as a weekly, subcutaneous injection. In some embodiments, the maintenance dose is administered as a biweekly, subcutaneous injection. In some embodiments, the maintenance dose is administered as a monthly, subcutaneous injection. In some embodiments, the maintenance dose is administered as a quarterly, subcutaneous injection. In some embodiments, the maintenance dose is administered weekly or less frequently, e.g., every two weeks (biweekly), every four weeks, monthly, every six weeks, every eight weeks (2 months), every three months (quarterly) or every six monthly (semi-annually). In some embodiments, the maintenance dose is administered as a biweekly, subcutaneous injection of 500 mg, 360 mg, or 250 mg. In some embodiments, the maintenance dose is administered as a biweekly, subcutaneous injection of 500 mg comprising two concurrent, e.g., sequential, injections of 250 mg (e.g., 2 x 1.25 mL of 400 mg/2 mL) of the subcutaneous formulation. In some embodiments, the subcutaneous dose is administered in a single injection of 360 mg (e.g., 1 x 1.8 mL of 400 mg/2 mL) of the subcutaneous formulation. In some embodiments, the subcutaneous dose of 250 mg is administered in a single injection of 250 mg (e.g., 1 x 1.25 mL of 400 mg/2 mL) of the subcutaneous formulation. In some embodiments, the subcutaneous dose is administered by a vial-syringe method or by an auto-injector (Al). In some embodiments, a subcutaneous dose of 500 mg, 360 mg, or 250 mg is administered using an auto-injector.

[547] In some embodiments, the maintenance dose is administered once or multiple times. In some embodiments, the maintenance dose is administered at a lower dose than during an earlier course of treatment and/or is administered less frequently than during the earlier course of treatment.

[548] In some embodiments, after switching to a maintenance dose, a subject’s biomarker levels may indicate increasing levels of amyloid in the brain. In some embodiments, after switching to a maintenance dose, a subject’s biomarker levels may begin to worsen, e.g. an increasing plasma AP42/40 ratio, indicating increasing levels of amyloid in the brain. In some embodiments, a subject on a maintenance dose may have a decrease in the AP42/40 ratio. In some embodiments, a subject is put on a maintenance dose chosen such that the subject may have a decrease in the AP42/40 ratio but the AP42/40 ratio may remain above the threshold for amyloid positivity, e.g. for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[549] In some embodiments, after switching to a maintenance dose, levels of a subject’s biomarker, e.g., MTBR-tau243 from a biofluid sample (e.g., CSF or blood) may increase. In some embodiments, after switching to a maintenance dose, a subject’s biomarker levels may begin to worsen, e.g. an increasing CSF MTBR-tau243. In some embodiments, a subject is put on a maintenance dose chosen such that the subject may have a decrease in the MTBR- tau243 concentration and maintain the concentration at a level comparable to a healthy control for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[550] In some embodiments, after switching to a maintenance dose, a subject’s biomarker levels, e.g. a MTBR-tau243 concentration or a tau PET level, may begin to increase or a rate of increase may increase. In some embodiments, such a subject may be moved back to a treatment regimen. In some embodiments, a subject may remain on a maintenance dose, e.g., if the increase remains below a tau PET level or rate of increase seen in a control subject who has AD but does not receive an anti-Ap protofibril antibody.

[551] As used herein, the term “prevent” refers to obtaining beneficial or desired results including, but not limited to, prophylactic benefit. For prophylactic benefit, the composition may be administered to a subject at risk of developing Alzheimer’s disease, to a subject having one or more preclinical symptoms but not clinical symptoms of Alzheimer’s disease, or to a subject reporting one or more of the physiological symptoms of Alzheimer’s disease, even though a clinical diagnosis of having Alzheimer’s has not been made. As used herein “prevention” may further include therapeutic benefit, by which is meant eradication or amelioration of the underlying condition being treated or of one or more of the physiological symptoms associated therewith.

[552] As used herein, the term “ARIA” refers to amyloid-related imaging abnormality as evaluated using MRI. In some embodiments, ARIA includes amyloid related imaging abnormality edema/effusion (ARIA-E). In some embodiments, ARIA includes amyloid related imaging abnormality hemorrhage (ARIA-H). In some embodiments, subjects with ARIA experience headache, confusion, and/or seizure and these may be used to identify a subject with ARIA or to indicate further evaluation for ARIA. In some embodiments, ARIA is evaluated at specified intervals during treatment. In some embodiments, ARIA is evaluated when the subject experiences symptoms of ARIA. In some embodiments, maximum serum concentration (Cmax) of anti-Ap protofibril antibody can be used as a predictor of the risk of ARIA-E. In some embodiments, the use of a subcutaneous formulation may provide a reduced risk of ARIA-E (e.g., due to a lower Cmax) compared to an IV administration.

[553] As used herein, the term “clinical decline” refers to a worsening of one or more clinical symptoms of AD. Methods for measuring clinical decline may employ the tests and assays specified herein. In some embodiments, clinical decline is determined by a worsening of ADCOMS. In some embodiments, clinical decline is determined by a worsening of MMSE. In some embodiments, clinical decline is determined by a worsening of ADAS-Cog. In some embodiments, clinical decline is determined by a worsening of FAQ. In some embodiments, clinical decline is determined by a worsening of CDR-SB. In some embodiments, clinical decline is determined by a worsening of Wechsler Memory Scale-IV Logical Memory (subscale) I and/or (subscale) II. In some embodiments, clinical decline is determined by a worsening of CDR score. In some embodiments, clinical decline refers to a worsening in one or more biomarkers of AD or brain measurement (e.g., by PET or MRI), e.g., of brain atrophy and/or amyloid accumulation.

[554] As used herein, the term “blood sample” or “blood” refers to a sample of blood, including serum and/or blood plasma from a human subject. In some embodiments, blood will be collected from subjects to evaluate potential biomarkers of AD that may include amyloid fragments and isoforms, tau, and other protein biomarkers (e.g., neurofilament light chain or NfL) for association with AD diagnosis, amyloid or tau load, or disease modification. In some embodiments, subjects are required to fast if possible before collection at Week 96 and Week 216. In other embodiments and/or at other time points, subjects do not require fasting. Pre- AD biomarker levels that may suggest the development of Alzheimer’s disease include, but are not limited to, brain amyloid level, cerebrospinal fluid level of Api- 42, cerebrospinal fluid level of total tau, cerebrospinal fluid level of neurogranin, and cerebrospinal fluid level of neurofilament light chain (NfL). SEQUENCE TABLES

Table 1. Amino acid sequences of monoclonal antibody (mAb) CDRs

Table 2. Amino acid sequences of mAb variable regions

Table 3. Amino acid sequences of mAb heavy and light chains Table 4. Amino acid sequences of mAb constant regions

Table 5. Amino acid sequences of Amyloid P

Table 6. Amino acid sequences of E2814 CDRs

Table 7. Amino acid sequences of E2814 variable regions Table 8. Amino acid sequences of E2814 constant regions

Table 9. Amino acid sequence of Tau

EXAMPLES

Example 1. Purification of MTBR-tau243 forms

[555] CSF samples were analyzed in a subset of early AD participants from the Phase 3 Clarity AD trial (ClinicalTrials.gov number: NCT03887455). Additional CSF and plasma samples will be analyzed. Different peptides of MTBR-tau243 were obtained according to methods described in WO2024044637 (e.g., Figs. 16, 18, 19, 25, 29, 38, 39, and 41), the contents of which are incorporated by reference.

[556] Briefly, in a first method (Method A), samples were immunodepleted and immunoprecipitated in a 2-step process. Four antibodies were used in a first affinity depletion step (antibodies Taul/HJ8.5/HJ8.7/HJ34.8). As noted above, antibodies HJ8.5 and HJ8.7 bind to the N-terminus, while antibody Taul binds to the mid-domain, and HJ34.8 binds to a long form of MTBR. The immunodepleted precipitate from either design 1 or design 2 was washed and subjected to trypsin digestion, desalted, and analyzed by LC-MS. Subsequently, the remaining immunodepleted sample was immunoprecipitated with an antibody that binds to the short form of MTBR (antibody HJ32.11). This second immunodepleted precipitate was washed and subjected to trypsin digestion, desalted, and analyzed by LC-MS. An exemplary form of MTBR-tau detected by this method was MTBR-tau243-254 (tryptic MTBR-tau243).

[557] A second method (Method B) was used for detecting endogenous MTBR-tau peptides, based on digesting peptides with an endopeptidase (a highly selective Arg-C that primarily cleaves at C-terminal Arg sites). Briefly, plasma was immunoprecipitated with an antibody to the short form MTBR (antibody HJ32.11), then washed, digested with Arg, incubated and desalted, and the solution is analyzed by LC-MS. Peptides were sequenced using PEAKS to identify MTBR-tau243 species. Species with endogenous cleavage at the C- terminus and/or post-translational modifications (PTM) were detected. This method detected E-MTBR-tau243. The method may be modified to detect deamidated fragments such as 243- 256 with deamidation at position 255N. MTBR-tau243 species isolated according to this method include, but are not limited to: MTBR-tau243 (243-254); MTBR-tau243 (243-255) MTBR-tau243 (243-255-dN), deamidated; MTBR-tau243 (243-257); MTBR-tau243 (243- 257-dN), deamidated; MTBR-tau243 (243-253); MTBR-tau243 (243-254-dQ), deamidated; MTBR-tau243 (243-252); MTBR-tau243 (243-258-dN), deamidated; MTBR-tau243 (243- 256); MTBR-tau243 (243-256-dN), deamidated. The sequences of these species are listed in Table 9.

Example 2. Lecanemab slows amyloid-induced tau pathology

[558] Lecanemab is a humanized immunoglobulin G1 monoclonal antibody targeting both neurotoxic Ap protofibrils and Ap plaques, which reduces markers of amyloid and significantly slows clinical decline on multiple measures of cognition and function. CSF MTBR-tau243 is an merging tau pathology biomarker that tracks with tangle formation in Alzheimer’s disease (AD) (Horie et al., 2023. Nat Med 29, 1954-1963). In order to evaluate effects of lecanemab on MTBR-tau243, CSF was analyzed in a subset of early AD participants from the Phase 3 Clarity AD trial (ClinicalTrials.gov number: NCT03887455).

[559] In Clarity AD Core Study, the safety and efficacy of lecanemab was evaluated in a double-blind, placebo-controlled, parallel-group, randomized study in patients with Alzheimer’s disease (patients with confirmed presence of amyloid pathology and mild cognitive impairment [62%] and mild cognitive impairment [38%], consistent with Stage 3 and Stage 4 Alzheimer’s disease). Patients could enroll in an optional, long-term extension of the study.

[560] The primary efficacy outcome was change from baseline at 18 months in the Clinical Dementia Rating scale Sum of Boxes (CDR-SB). Key secondary endpoints included change from baseline at 18 months for the following measures: amyloid Positron Emission Tomography (PET) using centiloids, Alzheimer Disease Assessment Scale - Cognitive Subscale 14 (ADAS-cogl4), and Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL).

[561] A total of 1795 patients were enrolled and randomized 1 : 1 to receive lecanemab 10 mg/kg (LEC10-BW) or placebo (PBO) once every 2 weeks. Of the total number of patients randomized, 69% were ApoE s4 carriers and 31% were ApoE s4 non-carriers. Overall median age of patients was 72 years, with a range to 50 to 90 years. Fifty-two percent were women. Of the global population, 1381 (77%) were White, 303 (17%) Asian, and 47 (2.6%) Black; of the 947 patients in the United States, 895 (94.5%) were White, 213 (22.5%) were Hispanic ethnicity, 43 (4.5%) Black, and 7 (0.7%) Asian. [562] Patients with MCI due to Alzheimer’s disease were enrolled with a CDR global score of 0.5, Memory Box score of 0.5 or greater. Patients with mild AD dementia were enrolled with a global CDR score of 0.5 or 1.0, Memory Box score of 0.5 or greater. All patients had a Mini -Mental State Examination (MMSE) score of >22, had objective impairment in episodic memory as indicated by at least 1 standard deviation below age- adjusted mean in the Wechsler-Memory Scale-IV Logical Memory II (subscale) (WMS-IV LMII). The randomization was stratified according to clinical subgroup; the presence or absence of concomitant symptomatic medication for Alzheimer’s disease at baseline (cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine); ApoE s4 carrier status; and region. Enrollment in three longitudinal substudies included 698 participants in the substudy of amyloid burden on PET, 257 in the study of tau pathologic features on PET, and 281 in the substudy of CSF biomarkers of Alzheimer’s disease. The baseline characteristics of the substudy groups were generally similar to those in the main analysis. In the amyloid PET, tau PET, and CSF substudies, amyloid PET scans were performed at baseline, 3, 6, 12 and 18 months; Tau PET scans were performed at baseline, 13 months, and 18 months; and CSF samples were collected at baseline, 12, and 18 months, respectively.

[563] The mean length of treatment was 16 months (range: 0.5 to 19 months).

[564] Lecanemab treatment met the primary endpoint and reduced clinical decline on the global cognitive and functional scale, CDR-SB, compared with placebo at 18 months by 27%, which represents a treatment difference in the score change of -0.45 (p=0.00005).

[565] Highly statistically significant differences (p<0.01) between treatment groups were also seen in the results for ADAS-cogl4 and ADCS MCI-ADL at 18 months.

[566] Starting as early as six months, across all time points, lecanemab treatment showed statistically significant changes in the primary and all key secondary endpoints from baseline compared to placebo (all p-values <0.01). The primary and QOL results of Clarity AD Core Study were reported in the articles, e.g. van Dyck et al., N Engl J Med. 2023 ;388(1) :9-21 ; and Cohen et al,. 2023. J Prev Alzheimers Dis. 2023;10(4):771-777, which are incorporated by reference.

[567] Methods: CSF from n=167 early AD participants from Clarity AD Core Study was analyzed using an IP -MS based method (Horie et al., 2023. Nat Med 29, 1954-1963), Method A disclosed above. Pearson correlation analysis was performed to assess relationships between CSF tryptic MTBR-tau243, AD fluid biomarkers, amyloid PET and tau PET SUVR in multiple regions of interest. Mixed model for repeated measures was used to analyze change from baseline and assess treatment effect over 18 months.

[568] Results are shown in Figures 1-5, in which tryptic MTBR-tau243 is labelled as “MTBR -tau243”. Figure 1 shows that lecanemab slows the rate of increase in CSF tryptic MTBR-tau243. CSF was analyzed from 167 subjects from the Clarity AD Core Study (placebo: n = 83; lecanemab: n = 84). A mixed model for repeated measures (MMRM) was used to analyze change from baseline and assess treatment effect over 18 months in the subjects. While CSF tryptic MTBR-tau243 increased through the Core Study, treatment with lecanemab slowed the rate of increase of tryptic MTBR-tau243 vs. placebo, with a greater separation from placebo observed at 18 month (77 weeks) vs. 12 months (53 weeks). The effect was greater at 18 months than at 12 months. At 18 months lecanemab slowed the rate of increase in CSF tryptic MTBR-tau243 by 44% vs. placebo.

[569] The effect of lecanemab on CSF tryptic MTBR-tau243 parallels the effect of lecanemab on a tau PET response during the same time period. Figure 2 shows the adjusted mean change from baseline tau PET SUVr in 3 regions of interest (ROIs, the temporal lobe, meta temporal lobe, and medial temporal lobe) in subjects who received either lecanemab (N = 135) or placebo (N = 122).

[570] In contrast to lecanemab, gantenerumab treatment had no effect on CSF MTBR- tau243 levels or Tau PET (as reported in McDade, DIAN-TU CTAD presentation 2023 and Graduate Imaging ADPD presentation 2023).

[571] The effect of lecanemab on CSF tryptic MTBR-tau243 was impacted by the subject’s tau PET burden at baseline. Figure 3 shows the change from baseline (CFB) in CSF tryptic MTBR-tau243 over time, as determined in all subjects combined, as well as in subgroups of subjects who were categorized as having low tau PET levels in WCG (SUVr <1.06) or medium-high tau PET levels in WCG (SUVr > 1.06). Lecanemab had the greatest effect on CSF tryptic MTBR-tau243 in the low tau PET group after 77 weeks of treatment. In the low tau PET group, the baseline tryptic MTBR-tau243 level was 355 pg/mL in subjects who received a placebo, and 370 pg/mL in subjects who received lecanemab. In the medium- high tau PET group, the baseline tryptic MTBR-tau243 level was 731 pg/mL in subjects who received a placebo, and 485 pg/mL in subjects who received lecanemab.

[572] Correlation analysis illustrates the relationship of tryptic MTBR-tau243 to tauPET, amyloid PET, and a panel of biomarkers. In Fig. 4, results of a baseline correlation analysis show that CSF tryptic MTBR-tau243 has the highest correlation with Tau PET SUVR across regions of interest (ROI) (Braak 1-6, whole cortical grey matter (WCG) vs. all other fluid biomarkers assessed (CSF markers: ptaul81, total tau, neurogranin, NfL, Ap40 and Ap42; plasma markers: pTau217, pTaul81, AP42/40, NfL and GFAP). CSF tryptic MTBR-tau243 has a higher correlation with Tau PET SUVR (r=0.74, WCGROI) vs. Amyloid PET Centiloids (r=0.39, WCG ROI). Levels of CSF tryptic MTBR-tau243 increased over time in early AD (placebo). Figure 5 shows the correlation of CSF tryptic MTBR-tau243 with amyloid PET centiloids (CL), left graph, and with tau PET SUVr in WCG, right graph.

[573] Taken together, the results indicate that CSF tryptic MTBR-tau243 is a specific biomarker of tau tangle pathology and are consistent with the effects of lecanemab on Tau PET, which similarly showed a slowing of tau accumulation vs. placebo. These results demonstrate that lecanemab-associated amyloid removal slows the formation of tau pathology in the brain.

Example 3. Lecanemab and MTBR-tau243 fragments in CSF

CSF samples were collected from Clarity AD subjects administered lecanemab or placebo at various timepoints during the treatment course. The CSF samples were analyzed according to Methods A and B, as described above, to measure CSF tryptic MTBR-tau243 and CSF E- MTBR-tau243. The data indicate a progression of CSF tryptic MTBR-tau243 levels during lecanemab treatment, but with a slower rate of increase as compared to placebo (Figure 1).

Example 4. Correlation of MTBR-tau243 with amyloid PET and tau PET status

[574] Correlation analysis was performed on baseline data obtained from the CSF of Clarity AD subjects in order to determine the relationship of CSF tryptic MTBR-tau243 and CSF E-MTBR-tau243 to amyloid PET, tauPET, and a panel of biomarkers known to be related to AD pathology. In this example, “MTBR-tau243” refers to tryptic MTBR-tau243, while E-MTBR-tau243 refers to the endogenous form of MTBR-tau243.

[575] Figure 6 shows the association of brain amyloid and tau status with CSF MTBR- tau243, CSF E-MTBR-tau243, CSF biomarkers (AP42/40 ratio, p-taul81, and total tau), and plasma biomarkers (AP42/40 ratio, p-taul81, p-tau217, and the ratio of p-tau217 to total tau (p-tau217R). Each biomarker was evaluated for its ability to distinguish between subjects with and without abnormal tau (T) or amyloid levels (as measured by CL) by comparing biomarker values across predefined binary groupings. These groupings included: CL < 20 vs. CL > 20; CL < 50 vs. CL > 50; tau-negative vs. tau-positive based on PET visual read; tau- negative vs. tau-positive based on SUVR threshold; and CL < 20 vs. CL > 20 stratified by SUVR-based tau-negative and tau-positive subgroups. To assess each biomarker’s discriminative ability, the area under the receiver operating characteristic curve (AUROC) was calculated. The AUROC represents the probability that a randomly selected subject from the positive group (e.g., T+ or CL > threshold) will have a higher biomarker value than a randomly selected subject from the negative group. The columns marked with nl, n2 indicate the sample size of two groups. Results are not provided if n < 5 in any group. CL: Centiloid; T-/T+: tau negative/positive; SUVR T+: SUVR > 1.126.

[576] The data show a strong association of CSF E-MTBR-tau243 with amyloid status, which is also observed within the tau-negative subgroup. Plasma p-tau217R performs at least as well as CSF E-MTBR-tau243 in relation to both amyloid status (CL = 20 and 50) and tau status.

[577] Figure 7 shows that all markers evaluated were significantly associated with amyloid status or subjects having amyloid PET levels at about 20 CL (e.g., amyloid status of 20 CL).

[578] Table 11 shows the Spearman rank correlation between the biomarkers and amyloid status, in subjects who were tau-negative (T-), tau -positive (T+), and the correlation between the biomarkers and tau PET SUVR, both in global cortical white matter (“global”) and in the m-temporal lobe (“MTL”).

Table 11. Correlation of biomarkers with amyloid and tau levels [579] The results show that both E-MTBR-tau243 and tryptic MTBR-tau243 show a correlation with amyloid and tau PET, but with E-MTBR showing a stronger correlation with both, as compared to tryptic MTBR-tau243CSF E-MTBR-tau243 is highly correlated with amyloid PET CL in both tau-negative and tau-positive subgroups. Plasma p-tau217R shows a similar correlation with amyloid CL and tau PET SUVR as CSF E-MTBR-tau243 SUVR. CSF E-MTBR-tau243 and plasma p-tau217R have similar relationships and correlations with amyloid CL and global tau SUVR. CSF MTBR-tau243 shows a relatively lower correlation with amyloid CL and global tau SUVR, which may be due to higher variability in CSF MTBR-tau243 levels.

[580] The association of CSF MTBR-tau243 with amyloid and tau levels was evaluated to determine the relative contribution of amyloid and tau to the association. Table 12 shows the contribution of each of amyloid and tau to the association of CSF MTBR-tau243, CSF E- MTBR-tau243, and plasma p-tau217 ratio to amyloid plus tau.

Table 12. Association of MTBR-tau243 with amyloid and tau levels in different datasets

[581] The association between tau progression, CSF biomarkers, and plasma biomarkers was determined in the placebo arm (untreated subjects) of the Clarity AD data. Progression status was defined using the 99% upper confidence limit of 18-month tau PET SUVR in tau- negative subjects. In brief, tau PET data from a subset of approximately 20 subjects with no or low tau levels were used to derive a 99% upper confidence limit on the change in whole cortical gray matter tau PET SUVR from baseline to month 18. This threshold was then used to define tau progression status, which served as the reference for evaluating the association between each baseline biomarker and future tau accumulation. [582] The data include subjects whose tau did not progress (n = 26) and subjects whose tau progressed (n = 10). Figure 8 shows that all biomarkers measured, except for the plasma AP42/40 ratio, are associated with tau progression. Thus, without being bound by theory, based on these results, CSF tryptic MTBR-tau243, E-MTBR-tau243, and plasma p-tau217 ratio appear to be strongly associated with tau progression.

Claims

1. A method of treating a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and/or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., comparable to a MTBR-tau243 concentration in an individual who has AD, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

2. The method of claim 1, further comprising: in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; and in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a p-tau217 concentration in a control sample, or if the p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample.

3. The method of claim 1 or claim 2, further comprising: c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is elevated as compared to the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration is comparable to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject.

4. The method of claim 1 or claim 2, further comprising c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is less than the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject, wherein the further therapeutically effective dose of the anti-Ap protofibril antibody is administered according to a maintenance dosing regimen.

5. A method of selecting a subject having, suspected of having, or at risk for developing AD for a treatment with an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for treatment if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., compared to a MTBR-tau243 concentration in an individual who has AD, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

6. The method of claim 5, further comprising: in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; in step b), selecting the subject for treatment if the p-tau217 concentration is elevated compared to a p-tau217 concentration in the control sample or if the p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample.

7. A method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD) and/or if the first MTBR-tau243 concentration is comparable to a positive control sample, e.g., compared to a MTBR-tau243 concentration in an individual who has AD; and c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, wherein a decrease in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration, and/or a rate of increase from the first MTBR- tau243 concentration to the first MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

8. The method of claim 7, further comprising: in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample from the subject; in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration is elevated compared to a p-tau217 concentration in the control sample or if the first p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample; and in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample, wherein a decrease in the second p-tau217 concentration as compared to the first p-tau217 concentration or a decrease in the rate of increase from the first p-tau217 concentration to the second p-tau217 concentration as compared to the rate of increase in the positive control indicates a reduction in tau tangles.

9. A method of preventing or treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody; b) comparing the MTBR-tau243 concentration to a control sample, e.g., a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD) and/or comparing the MTBR-tau243 concentration to a positive control, e.g., a MTBR-tau243 concentration in an individual who has AD; and c) adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody if the MTBR-tau243 concentration differs from the control sample or if the MTBR- tau243 concentration differs from the positive control sample, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

10. The method of claim 9, further comprising: in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; in step b), comparing the p-tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the control sample and/or comparing the p-tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample; and in step c), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody, if the p-tau217 concentration and the MTBR-tau243 concentration in the sample differ from the control sample or if the p-tau217 concentration and the MTBR-tau243 concentration in the sample differ from the p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample.

11. The method of any one of claims 1-10, wherein the control is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

12. The method of any one of claims 1-11, wherein the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

13. A method of monitoring treatment efficacy in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second MTBR-tau243 concentration as compared to first MTBR-tau243 concentration is an indicator of treatment efficacy, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

14. The method of claim 13, wherein a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates an effective treatment.

15. The method of claim 13, wherein a lack of a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control, indicates a non-effective treatment.

16. The method of any one of claims 13-15, further comprising: in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p- tau217 concentration is an indicator of treatment efficacy.

17. The method of claim 16, wherein a decrease from the first p-tau217 concentration to the second p-tau217 concentration, or reduction in a rate of increase from the first p-tau217 concentration to the second p-tau217 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first p-tau217 to a second tau217 concentration in an individual who has AD and is not treated, indicates an effective treatment.

18. The method of claim 16, wherein a lack of a decrease from the first p-tau217 concentration to the second p-tau217 concentration and from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in a rate of increase between the first and second p-tau217 concentrations and MTBR-tau243 concentrations, as compared to rates in a placebo control, indicates a non-effective treatment.

19. A method of detecting a decrease in a brain Ap level in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain Ap level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

20. The method of claim 19, further comprising: in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p- tau217 concentration indicates a decrease of the brain Ap level in the subject.

21. A method of detecting a decrease in a brain tau level in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease in the second MTBR-tau243 concentration and the first MTBR-tau243 concentration, or a reduction in a rate of increase between the first and second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain tau level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

22. The method of claim 21, further comprising: in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change from the first p-tau217 concentration to the second p-tau217 concentration indicates a decrease of the brain tau level in the subject

23. The method of claim 21 or claim 22, wherein a decrease in a brain tau level is a reduction in tau tangles.

24. The method of any one of claims 1-23, wherein the treatment with the anti-Ap protofibril antibody comprises administration of a therapeutically effective dose of the anti- Ap protofibril antibody according to an initiation dosing regimen, optionally after which the subject is switched to a maintenance dosing regimen.

25. The method of claim 24, wherein the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject is at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD.

26. The method of claim 24, wherein the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of p-tau217 and a further measurement of MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject are at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD.

27. The method of any one of claims 24-26, wherein the subject is switched to a maintenance dosing regimen when at least one of: a decrease in amyloid or tau positron emission tomography (PET); an increase in cerebrospinal fluid level of AP42 and/or AP42/40 ratio; a decrease in cerebrospinal fluid level of total tau, cerebrospinal fluid level of neurogranin, and/or cerebrospinal fluid level of neurofilament light peptide (NfL); and a change in blood biomarkers as measured in the serum or plasma (e.g. increased levels of Ap42 and/or AP42/40 ratio; decreased plasma levels of plasma total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), glial fibrillary acidic protein (GFAP), and/or neurofilament light (NfL)) is detected in a sample from the subject as compared to a control disease sample, e.g., a sample from an individual who has AD.

28. The method of any one of claims 24-27, wherein the subject is switched to a maintenance dosing regimen when a decrease in tau PET SUVr is measured in the subject as compared to control sample, e.g., a sample from an individual who has AD.

29. The method of any one of claims 24-28, wherein the subject is switched to a maintenance dosing regimen when a low tau PET level as measured by PET SUVr is detected in the subject, e.g., a tau PET SUVr of about 1.1, preferably about 1.06, as measured with a MK6240 PET scan, e.g., of whole cortical gray matter.

30. The method of claim 29, wherein the maintenance dosing regimen comprises administering a maintenance dose that maintains a tau PET SUVr level at or below 1.06.

31. The method of any one of claims 24-30, wherein the subject is switched from an initiation dosing regimen to a maintenance dosing regimen at least 6 months (e.g., 6 months, or 12 months, or 18 months, or 24 months, or 36 months) after the start of the initiation dosing regimen.

32. The method of any one of claims 24-31, wherein the maintenance dosing regimen differs from the initiation dosing regimen in the size of dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody.

33. The method of any one of claims 24-32, wherein the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject.

34. The method of any one of claims24-33, wherein the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 2 weeks.

35. The method of claim 33 or 34, wherein the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks, preferably as an intravenous administration at 10 mg/kg relative to the weight of the subject.

36. The method of any one of claims 24-34, wherein the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg.

37. The method of any one of claims 24-32 or 36, wherein the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose once every week.

38. The method of claim 36 or 37, wherein the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

39. The method of any one of claims 36-38, wherein the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every week.

40. The method of any one of claims 24-39, wherein at least one of the initiation dosing regimen and the maintenance dosing regimen further comprises administration of a therapeutically effective dose of an anti-tau antibody, e.g., E2814, sequentially or simultaneously with administration of the anti-Ap protofibril antibody.

41. The method of claim 40, wherein the anti-tau antibody is E2814.

42. The method of claim 41, wherein the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose once every 4 weeks.

43. The method of claim 40 or claim 41, comprising intravenous administration of E2814 at a therapeutically effective dose between 500-4500 mg (e.g., 500, 750, 1000, 1500, 3000, 4500 mg).

44. The method of any one of claims 40-43, wherein the anti-tau antibody is administered prior to the first administration of the anti-Ap protofibril antibody, optionally wherein the subject has pre- AD (e.g., is asymptomatic for AD).

45. The method of any one of claims 30-43, wherein the anti-Ap antibody is administered prior to the first administration of the anti-tau antibody, optionally wherein the subject has AD (e.g., early AD).

46. The method of any one of claims 1-45, wherein the MTBR-tau243 concentration is quantified by LC/MS.

47. The method of any one of claims 1-46, wherein the biofluid sample is CSF.

48. The method of any one of claims 1-47, wherein the biofluid sample is blood.

49. The method of any one of claims 1-48, wherein the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment.

50. The method of claim 49, wherein the change and/or difference in the measurement is selected from: a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), c) decreased cerebrospinal fluid levels of ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, neurogranin, and/or neurofilament light chain (NfL), and d) decreased blood serum or plasma levels of a ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL).

51. The method of any one of claims 1-50, wherein the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology during and/or after treatment.

52. The method of claim 51, wherein the change and/or difference in the measurement is selected from: a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), c) increased cerebrospinal fluid levels of ratio of Api-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, neurogranin, and/or neurofilament light chain (NfL), and d) increased blood serum or plasma levels of a ratio of Api-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL).

53. The method of claim 52, wherein the decreased amyloid in the brain is an adjusted mean change from baseline in amyloid PET SUVr of at least about 0.10, or 0.15, or 0.20.

54. The method of any one of claims 1-53, wherein the treatment a) delays clinical decline as determined by ADCOMS; b) delays clinical decline as determined by ADAS MCI-ADL; c) delays clinical decline as determined by modified iADRS; d) delays clinical decline as measured by a CDR-SB; or e) delays clinical decline as measured by an ADAS-Cog.

55. The method of any one of claims 1-54, wherein the method further comprises monitoring for ARIA, e.g., ARIA-E and/or ARIA-H, e.g., as observed by MRI.

56. The method of any one of claims 1-55, wherein the subject has a genetic mutation for a dominantly inherited Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP.

57. The method of claim 56, wherein the subject has a mutation in APP.

58. The method of any one of claims 1-57, wherein the subject has a family history of Alzheimer’s disease, e.g., a history of a family member being diagnosed with Alzheimer’s disease before the age of 60.

59. The method of any one of claims 1-58, wherein the subject is ApoE4-positive.

60. The method of any one of claims 1-59, wherein the subject is 65 to 80 years old.

61. The method of any one of claims 1-60, wherein the subject is 55 to 64 years old and has at least one risk factor chosen from:

(i) a first degree relative diagnosed with dementia onset before age 75;

(ii) at least one apolipoprotein E4 variant (APOE4) allele; and

(iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing prior to said administration.

62. The method of any one of claims 1-61, wherein the subject is amyloid positive.

63. The method of claim 62, wherein the subject is amyloid positive based on a PET assessment, a CSF assessment of A0(l-42), a CSF assessment of total tau, a CSF assessment of phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), a CSF assessment of the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np- taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, MRI, retinal amyloid accumulation, and/or a blood biomarker assessment (e.g. a plasma A 1- 42/1-40 ratio, plasma total tau, plasma phosphorylated tau (e.g., p-taul81, p-tau205, p- tau217, and/or p-tau231), and/or the plasma ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np- tau231)).

64. The method of any one of claims 1-63, wherein the subject has Alzheimer’s disease.

65. The method of any one of claims 1-64, wherein the subject has early Alzheimer’s disease.

66. The method of any one of claims 1-65, wherein the subject has been diagnosed with a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and/or has been diagnosed as having mild Alzheimer’s disease dementia; b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging - Alzheimer’s Association (NIA-AA) core clinical criteria; c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last

1 year before treatment, e.g., as corroborated by an informant; e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.

67. The method of any one of claims 1-66, wherein the subject is suspected of having AD.

68. The method of any one of claims 1-67, wherein the subject is a subject at risk for developing AD.

69. The method of claim 68, wherein the subject at risk for developing AD has preAlzheimer’s disease (pre- AD).

70. The method of claim 68 or claim 69, wherein the subject does not have cognitive impairment.

71. The method of any one of claims 1-70, wherein the anti-Ap protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

72. The method of claim 71, wherein the anti-Ap protofibril antibody is lecanemab.

73. The method of any one of claims 40-72, wherein the anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

74. The method of claim 73, wherein the anti-tau antibody is E2814.

75. The method of any one of claims 1-74, wherein the MTBR-tau243 is MTBR-tau243- 254, MTBR-tau243-256, or MTBR-tau243-256 (deamidation on 255N).

76. The method of any one of claims 1-74, wherein the MTBR-tau243 is MTBR-tau243- 254.

77. The method of any one of claims 1-74, wherein the MTBR-tau243 is MTBR-tau243- 256.

78. The method of any one of claims 1-74, wherein the MTBR-tau243 MTBR-tau243-256 (deamidation on 255N).

79. A method of treating or preventing Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration and/or the first MTBR-tau243 concentration are elevated compared to a first control sample, e.g., a sample from an individual who does not have AD; c) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p- tau217 concentration and the second MTBR-tau243 concentration are elevated compared to the first p-tau217 concentration and the second MTBR-tau243 concentration, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

80. A method of treating or preventing Alzheimer’s disease (AD) in a subject having, suspected of having AD, or at risk for developing AD, comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., a p-tau217 concentration in an individual who does not have AD; c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., a MTBR-tau243 concentration in an individual who does not have AD; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

81. The method of claim 80, further comprising: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

82. The method of claim 80 or claim 81, further comprising: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 and the MTBR- tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

83. A method of selecting a subject having, suspected of having, or at risk for developing AD for treatment with an anti-Ap protofibril antibody and an anti-tau antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the first p-tau217 concentration and/or the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

84. A method of selecting a subject having, suspected of having, or at risk for developing AD for a treatment with an anti-Ap protofibril antibody and an anti-tau antibody, comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

85. The method of claim 84, further comprising: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample; and in step b), selecting the subject for the first treatment with the anti-Ap protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

86. The method of claim 84 or claim 85, further comprising: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step d), selecting the subject for a second treatment with the anti-tau antibody if the second p-tau217 concentration and the MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

87. A method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a first p-tau217 concentration and a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the first p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p- tau217 concentration and the second MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD; e) optionally obtaining a measurement of a third p-tau217 concentration and a third MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the third p-tau217 concentration as compared to the second p-tau217 concentration and in the third MTBR-tau243 concentration as compared to the second MTBR-tau243 concentration, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

88. A method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the MTBR- tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD); e) obtaining a measurement of a second MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the second MTBR-tau243 concentration after the second treatment as compared to the MTBR-tau243 concentration after the first treatment, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

89. The method of claim 88, further comprising: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

90. The method of claim 88 or claim 89, further comprising: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample e.g., a p- tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

91. The method of any one of claims 83-90, wherein the first control sample and/or the second control sample are obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

92. The method of any one of claims 83-90, wherein the second control sample is obtained from the subject after the first treatment and prior to the second treatment.

93. A method of preventing or treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody; b) comparing the first p-tau217 concentration and the first MTBR-tau243 to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) adjusting the treatment regimen to further administer a therapeutically effective amount of an anti-tau antibody if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

94. The method of claim 93, further comprising d) obtaining a measurement of a third p-tau217 concentration and a third MTBR- tau243 concentration in a third biofluid sample, e.g., a CSF or blood sample, from the subject; e) comparing the third p-tau217 concentration and the third MTBR-tau243 concentration to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); and f), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody and/or the anti-tau antibody, if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample.

95. The method of claim 93 and claim 94, wherein the control sample is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

96. The method of any one of claims 93-95, wherein the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

97. A method of monitoring treatment efficacy in a subject having, suspected of having AD, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second p-tau217 concentration and a change in the second MTBR-tau243 concentration, as compared to the first p-tau217 concentration and the first MTBR-tau243 concentration, is an indicator of treatment efficacy, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

98. The method of claim 97, wherein a decrease or reduction in increase in the second p- tau217 concentration as compared to the first p-tau217 concentration and/or in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration indicates an effective treatment.

99. The method of claim 97, wherein a lack of a decrease or lack of a reduction in increase in the second p-tau217 concentration as compared to the first p-tau217 concentration and/or in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration indicates a non-effective treatment.

100. A method of detecting a decrease in a brain Ap level in a subject having, suspected of having AD, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a decrease between the second p-tau217 concentration and the first p- tau217 concentration and a decrease between the second MTBR-tau243 concentration and the first MTBR-tau243 concentration indicates a decrease of a brain Ap level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

101. A method of detecting a decrease in a brain tau level in a subject receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a decrease between the second p-tau217 concentration and the first p- tau217 concentration and a decrease between the second MTBR-tau243 concentration and the first MTBR-tau243 concentration, indicates a decrease of a brain tau level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

102. The method of claim 101, wherein a decrease in a brain tau level is a reduction in tau tangles.

103. The method of any one of claims 79-102, wherein the treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody is administered according to an initiation dosing regimen if the subject receives treatment with an anti -tau antibody.

104. The method of any one of claims 79-103, wherein the treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody is administered according to an initiation dosing regimen, optionally after which the subject is switched to a maintenance dosing regimen of the anti-Ap protofibril antibody.

105. The method of claim 104, wherein the maintenance dosing regimen of the anti-Ap protofibril antibody is administered if a subject receives a treatment with an anti -tau antibody.

106. The method of claim 104 or claim 105, wherein the subject is switched from an initiation dosing regimen to a maintenance dosing regimen of the anti-Ap protofibril antibody at least 6 months (e.g., 6 months, or 12 months, or 18 months, or 24 months, or 36 months) after the start of the initiation dosing regimen.

107. The method of any one of claims 104-106, wherein the maintenance dosing regimen differs from the initiation dosing regimen in the size of dose, the frequency of administration, and/or the route of administration of the anti-Ap protofibril antibody.

108. The method of any one of claims 104-107, wherein the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg/kg relative to the weight of the subject.

109. The method of any one of claims 104-108, wherein the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 2 weeks.

110. The method of claim 108 or 109, wherein the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks, preferably as an intravenous administration at 10 mg/kg relative to the weight of the subject.

111. The method of any one of claims 104-107, wherein the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg.

112. The method of any one of claims 104-107 or 111, wherein the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose once every week.

113. The method of claim 111 or claim 112, wherein the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

114. The method of any one of claims 111-113, wherein the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every week.

115. The method of any one of claims 79-96, wherein the second treatment comprises administration of a therapeutically effective dose of the anti-tau antibody E2814.

116. The method of claim 115, wherein the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose once every 4 weeks.

117. The method of claim 115 or claim 116, comprising intravenous administration of E2814 at a therapeutically effective dose between 500-4500 mg (e.g., 500, 750, 1000, 1500, 3000, or 4500 mg).

118. The method of any one of claims 1-117, wherein the MTBR-tau243 concentration is quantified by LC/MS.

119. The method of any one of claims 1-118, wherein the biofluid sample is CSF.

120. The method of any one of claims 1-119, wherein the biofluid sample is blood.

121. The method of any one of claims 1-120, wherein the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment with the anti-Ap protofibril antibody.

122. The method of claim 121, wherein the change and/or difference in the measurement is selected from: a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), c) decreased cerebrospinal fluid levels of ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, neurogranin, and/or neurofilament light chain (NfL), and d) decreased blood serum or plasma levels of a ratio of Api-42/1-40 and/or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL).

123. The method of any one of claims 1-122, wherein the subject shows a change and/or difference in a measurement of one or more biomarkers associated with AD pathology during and/or after treatment with the anti-tau antibody.

124. The method of claim 123, wherein the change and/or difference in the measurement is selected from: a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), c) increased cerebrospinal fluid levels of ratio of Api-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p- tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, neurogranin, and/or neurofilament light chain (NfL), and d) increased blood serum or plasma levels of a ratio of Api-42/1-40 and/or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and/or neurofilament light chain (NfL).

125. The method of claim 124, wherein the decreased amyloid in the brain is an adjusted mean change from baseline in amyloid PET SUVr of at least about 0.10, or 0.15, or 0.20.

126. The method of any one of claims 1-125, wherein the treatment a) delays clinical decline as determined by ADCOMS; b) delays clinical decline as determined by ADAS MCI-ADL; c) delays clinical decline as determined by modified iADRS; d) delays clinical decline as measured by a CDR-SB; or e) delays clinical decline as measured by an ADAS-Cog.

127. The method of any one of claims 1-126, wherein the method further comprises monitoring for ARIA, e.g., ARIA-E and/or ARIA-H, e.g., as observed by MRI.

128. The method of any one of claims 1-127, wherein the subject has a genetic mutation for a dominantly inherited Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP.

129. The method of claim 128, wherein the subject has a mutation in APP.

130. The method of any one of claims 1-129, wherein the subject has a family history of Alzheimer’s disease, e.g., a history of a family member being diagnosed with Alzheimer’s disease before the age of 60.

131. The method of any one of claims 1-130, wherein the subject is ApoE4-positive.

132. The method of any one of claims 1-131, wherein the subject is 65 to 80 years old.

133. The method of any one of claims 1-132, wherein the subject is 55 to 64 years old and has at least one risk factor chosen from:

(i) a first degree relative diagnosed with dementia onset before age 75;

(ii) at least one apolipoprotein E4 variant (APOE4) allele; and

134. The method of any one of claims 1-133, wherein the subject is amyloid positive.

135. The method of claim 134, wherein the subject is amyloid positive based on a PET assessment, a CSF assessment of A0(l-42), a CSF assessment of total tau, a CSF assessment of phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and/or p-tau231), a CSF assessment of the ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np- taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np-tau231), MTBR-tau243, MRI, retinal amyloid accumulation, and/or a blood biomarker assessment (e.g. a plasma A 1- 42/1-40 ratio, plasma total tau, plasma phosphorylated tau (e.g., p-taul81, p-tau205, p- tau217, and/or p-tau231), and/or the plasma ratio of phosphorylated tau/non-phosphorylated tau (e.g., p-taul81/np-taul81, tau205/np-tau205, p-tau217/np-tau217 and/or tau231/np- tau231)).

136. The method of any one of claims 1-135, wherein the subject has Alzheimer’s disease.

137. The method of any one of claims 1-136, wherein the subject has early Alzheimer’s disease.

138. The method of any one of claims 1-137, wherein the subject has been diagnosed with a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and/or has been diagnosed as having mild Alzheimer’s disease dementia; b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging - Alzheimer’s Association (NIA-AA) core clinical criteria; c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last

139. The method of any one of claims 1-135, wherein the subject is suspected of having AD.

140. The method of any one of claims 1-135, wherein the subject is a subject at risk for developing AD.

141. The method of claim 140, wherein the subject at risk for developing AD has preAlzheimer’s disease (pre- AD).

142. The method of claim 140 or claim 141, wherein the subject does not have cognitive impairment.

143. The method of any one of claims 1-142, wherein the anti-Ap protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

144. The method of claim 143, wherein the anti-Ap protofibril antibody is lecanemab.

145. The method of any one of claims 79-96, wherein the anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

146. The method of claim 145, wherein the anti-tau antibody is E2814.

147. The method of any one of claims 79-146, wherein the MTBR-tau243 is MTBR- tau243-254, MTBR-tau243-256, or MTBR-tau243-256 (deamidation on 255N).

148. The method of any one of claims 79-146, wherein the MTBR-tau243 is MTBR- tau243-254.

149. The method of any one of claims 79-146, wherein the MTBR-tau243 is MTBR- tau243-256.

150. The method of claim any one of claims 79-146, wherein the MTBR-tau243 is MTBR- tau243-256 (deamidation on 255N).