NZ788486A - Methods for treating Alzheimer's disease - Google Patents

Abstract

Provided are methods for treating Alzheimer's disease in a human subject in need thereof when the subject develops an Amyloid Related Imaging Abnormality (ARIA) during a treatment regimen comprising administration of multiple doses of an anti-beta-amyloid antibody (e.g., BIIB037) to the subject.

Description

METHODS FOR TREATING ALZHEIMER'S DISEASE Cross-Reference to Related Applications This application is a divisional of New Zealand Patent Application No. 748824 (the national phase application of ) and claims the t of priority of U.S.

Provisional Application Nos. 62/346,818, filed 7 June 2016, and ,531 filed 16 December 2016, the entire content of each of which is incorporated herein by reference. cal Field This disclosure relates generally to methods for treating Alzheimer's disease.

Background Alzheimer's disease (AD) is a progressive neurodegenerative disorder clinically characterized by cognitive impairment, behavioral disturbances, psychiatric ms, and disability in activities of daily living. These al manifestations constitute AD ia.

AD International estimates that the number of people living with dementia worldwide will increase from the current value of 35.6 million to 1 15.4 million by 2050. Being the most common cause of ia, AD accounts for 60 to 80% of dementia cases. In the United States, it is estimated that 5.3 million Americans suffer from dementia caused by AD, and that by 2050 the prevalence will double or triple unless an effective treatment is found.

Clinical research criteria for dementia due to AD have been recently updated and conforming to the current concept of the disease, a diagnostic framework was developed to embrace mentia stages of AD (e.g., prodromal AD). The main neuropathological hallmarks of the disease are (i) ellular senile (neuritic) plaques containing aggregated βamyloid (Αβ) peptides and (ii) intraneuronal ibrillary tangles ( FTs) composed of abnormal hyperphosphorylated Tau protein. Although the pathogenesis of these plaques and tangles and how they contribute to the clinical me remain to be fully elucidated, the leading hypothesis the "amyloid cascade" proposes that the driving force behind the disease s is the accumulation of Αβ resulting from an imbalance between Αβ production and Αβ clearance in the brain. Αβ is a e generated from the metabolism of amyloid precursor protein. Several Αβ peptide alloforms exist (e.g., Αβ40, Αβ42). These ric peptides have a variable tendency to aggregate into higher order dimers and oligomers. Through a process of fibrillogenesis, soluble oligomers may transition into insoluble deposits having a β pleated sheet structure. These deposits are also ed to as amyloid plaques and hence are ed of predominantly lar amyloid. Both e and fibrillar forms of A� appear to contribute to the disease process.

Biomarker, clinicopathologic, and cohort studies suggest that the disease process commences 10 to 20 years before the clinical onset of symptoms, and some of the early pathological findings include the deposition of neocortical neuritic s and mesial temporal NFTs followed years later by neocortical NFTs.

There are currently no therapies that modify the course of Alzheimer's disease.

Currently approved therapies provide only modest symptomatic benefit and do not attenuate the course of the disease. l potential disease-modifying drug candidates are currently under investigation. These candidates include small molecules and immunotherapy (active and passive) that target the A� pathway and aim to e therapeutic benefit by ng either soluble or insoluble forms of A� in the brain and cerebrospinal fluid (CSF).

In se to guidance issued by the U.S. Food and Drug Administration (FDA) to various sponsors on the conduct of clinical trials of amyloid-modifying agents for the treatment of AD, the Alzheimer's Association Research Roundtable convened a Workgroup in July 2010. The W orkgroup was composed of academic and industry representatives identified on the basis of their expertise and interest in this area. It was tasked with the objective of providing expert advice regarding the FDA's concerns related to magnetic resonance imaging (MRI) abnormalities, including signal changes thought to represent vasogenic edema (VE) and microhemorrhages (mH). MRI signal changes were first observed in trials of a monoclonal antibody against �-amyloid, and have since been associated with other amyloid-modifying ies.

While the exact pathophysiologic mechanisms of these MRI abnormalities have not been determined, VE and mH are typically detected on different MRI sequences. They appear to represent a spectrum of image alities which may share some common underlying pathophysiological mechanism, both in the natural history of AD and in the setting of amyloid-modifying therapeutic approaches. The Workgroup suggested referring to this spectrum as Amyloid d g Abnormalities (ARIA).

Despite the likelihood of shared underlying mechanisms, there may be instances in which it is useful to describe specific phenomena. Thus, the Workgroup further refined the terminology: ARIA-E refers to the MR signal alterations t to represent VE and d extravasated fluid phenomena. ARIA-H refers to the MR signal alterations attributable to mH and hemosiderosis.

ARIA-E most commonly manifests as increased MR signal intensity on FLAIR or other T2-weighted sequences in the parenchyma and/or leptomeninges in the parietal, occipital, and frontal lobes, but has also been observed in the cerebellum and brainstem. The presence of Apolipoprotein E £4 allele, ApoE £4, has been found to be a significant risk factor for the development of ARIA-E.

There are currently very limited publicly available data regarding the clinical course associated with ARIA-E occurring in the g of clinical trials of amyloid modifying therapies. The Workgroup reviewed the data from bapineuzumab trials, but it noted that it was unknown whether ARIA seen in other amyloid-modifying therapies will have similar clinical course. In any event, the pathophysiological isms underlying vasogenic edema remain to be elucidated. mH are generally attributed to one of two etiologies: small vessel angiopathy and al amyloid angiopathy (CAA). The prevalence of mH is significantly increased in y individuals with cardiovascular risk factors and/or evidence of a previous cerebrovascular event. In AD, mH and superficial sis are uted to leakage of blood from CAA vessels. CAA is believed to weaken the vessel wall, increasing the risk of micro leaks of blood into adjacent brain, forming mH. Moreover, there are limited publicly available data on incident mH in the setting of ARIA-E associated with amyloid-modifying therapies.

Preliminary reports of ARIA occurrence in therapeutic strategies aimed at sing tion of specific A� peptides suggest that decreasing A�1-42 or altering the ratio of various A� species might change the dynamics of amyloid tion and clearance, resulting in ARIA. It is possible that direct removal of d from the vessel wall would be ated with compromise in the vascular integrity. Alternatively, there may be amyloid related endothelial cell dysfunction resulting in increased vascular permeability, which might explain the similarity to increased permeability. It is also possible that there is a focal inflammatory component that would result in both ARIA-E and ARIA-H, as suggested by the pathology reports from patients with CAA. Normal CSF has also been reported in inflammatory CAA, and it is possible that focal amyloid-related vascular inflammation may play a role in some cases of ARIA. It also remains unknown r different forms of immunotherapy or specific antibodies are more or less likely to be associated with ARIA.

The incidence of ARIA in patients undergoing treatment for Alzheimer's disease ues to be a persistent problem. While there are a number of potential isms of action to target, solutions to the problem have not been found.

Thus, there is a need in the art for methods to reduce the incidence ofARIA in susceptible mer's disease patients during AD treatment protocols.

Summary This disclosure fulfills the need in the art for methods to reduce the incidence of ARIA in Alzheimer's disease patients during Alzheimer's disease (AD) treatment protocols.

In one aspect, the disclosure es a method for treating AD in a human subject in need f. The method involves administering to the human subject multiple doses of an anti-beta-amyloid antibody, wherein the subject develops an Amyloid d Imaging ality (ARIA) during ent with the anti-beta-amyloid antibody. The ARIA can be, for example: (i) ARIA-E that is moderate or severe and is accompanied by no clinical symptoms; (ii) ARIA-E that is mild, te, or severe and is accompanied by mild, moderate, or severe clinical symptoms, or clinical symptoms meeting the "other medically important" serious criteria; (iii) ARIA-H with 5 to 9 cumulative microhemorrhages and accompanied by no clinical symptoms; (iv) ARIA-H with 1 to 9 cumulative microhemorrhages and accompanied by mild, moderate, or severe clinical symptoms, or clinical symptoms meeting the "other medically ant" serious criteria; (v) ARIA-H with 2 cumulative areas of superficial sis and accompanied by no clinical symptoms; or (vi) ARIA-H with 1 or 2 cumulative areas of superficial siderosis and accompanied by mild, moderate, or severe clinical symptoms, or al symptoms meeting the "other medically important" serious criteria. After the onset ofARIA in the subject, administration of the antibeta-amyloid antibody to the subject is suspended until the ARIA resolves (and if there are clinical symptoms, until they also resolve). The method further involves resuming stration to the subject of the same dose of the anti-beta-amyloid antibody that was administered immediately prior to the subject ping the ARIA.

In some embodiments, the multiple doses of the anti-beta-amyloid antibody are doses of the same amount. In certain instances, the multiple doses are each 1 mg/kg of body weight of the subject. In certain instances, the multiple doses are each 3 mg/kg of body weight of the subject. In certain instances, the multiple doses are each 6 mg/kg of body weight of the subject. In certain instances, the multiple doses are each 10 mg/kg of body weight of the subject. In certain instances, the multiple doses are each 12 mg/kg of body weight of the subject. In certain instances, the multiple doses are each15 mg/kg of body weight of the subject. In n instances, the multiple doses are each 18 mg/kg of body weight of the subject. In certain instances, the multiple doses are each 20 mg/kg of body weight of the subject. In certain instances, the multiple doses are each 24 mg/kg of body weight of the subject. In certain instances, the multiple doses are each 30 mg/kg of body weight of the subject.

In other embodiments, the multiple doses of the anti-beta-amyloid antibody se doses of different amounts. In certain instances, the multiple doses comprise 1 mg/kg and 3 mg/kg of body weight of the subject. In certain instances, the multiple doses comprise 1 mg/kg, 3 mg/kg, and 6 mg/kg of body weight of the t. In certain instances, the multiple doses comprise 3 mg/kg and 6 mg/kg of body weight of the subject. In certain instances, the multiple doses comprise 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg of body weight of the t. In certain instances, the le doses comprise 3 mg/kg, 6 mg/kg, and 10 mg/kg of body weight of the subject. In certain instances, the multiple doses comprise 3 mg/kg, 6 mg/kg, 10 mg/kg and 12 mg/kg of body weight of the subject. In certain instances, the multiple doses comprise 3 mg/kg, 6 mg/kg, 10 mg/kg and 15 mg/kg of body weight of the In some embodiments, wherein the subject is an ApoE4 carrier, the multiple doses comprise two or more of the doses 1 mg/kg, 3 mg/kg, 6 mg/kg, or 10 mg/kg of body weight of the subject. In some ments, wherein the subject is an ApoE4 non-carrier, the multiple doses comprise two or more of the doses 1 mg/kg, 3 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg, or 30 mg/kg of body weight of the t.

In certain embodiments, the method further involves subsequently administering the anti-beta-amyloid antibody at a dose that is higher than the dose that is administered upon resumption of stration after resolution of the ARIA.

In some embodiments, the multiple doses are administered at intervals of 4 weeks.

In some embodiments, the number of multiple doses administered to the subject prior to the onset of the ARIA is 2 to 14 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 doses). In other embodiments, the number of multiple doses administered to the subject prior to the onset of the ARIA is 2 to 5. In one embodiment, the number of multiple doses administered to the subject prior to the onset of the ARIA is 2. In one embodiment, the number of multiple doses stered to the subject prior to the onset of the ARIA is 3. In one embodiment, the number of multiple doses administered to the subject prior to the onset of the ARIA is 4. In one embodiment, the number of le doses administered to the subject prior to the onset of the ARIA is 5.

In certain embodiments, the administering to the human subject multiple doses of the anti-beta-amyloid antibody comprises, in order, beginning with step (a) performing two or more of the ing administering steps prior to the onset of the ARIA: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the t; ( c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the t in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (f) 4 weeks after step ( e ), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (h) in consecutive intervals of 4 weeks after step (g), stering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject.

In certain embodiments, the method involves, after resolution of the ARIA (and resolution of any clinical symptoms), ming from the following administering steps, in order, those steps that were not performed prior to the onset of the ARIA: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; ( c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the t; (f) 4 weeks after step ( e ), administering the antibody to the t in an amount of 3 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (h) in utive intervals of 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject.

In certain embodiments, the method involves administering to the human subject (wherein the subject is an ApoE4 rrier or an ApoE4 carrier), multiple doses of the antibeta-amyloid antibody, in order, beginning with step (a) performing two or more of the following administering steps prior to the onset of the ARIA: (a) administering the anti-beta-amyloid antibody to the t in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the t; ( c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), stering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step ( e ), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (g) in consecutive intervals of 4 weeks after step (f), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject.

In certain embodiments, the method comprises, after resolution of the ARIA, performing from the ing administering steps, in order, those steps that were not performed prior to the onset of the ARIA: (a) administering the anti-beta-amyloid antibody to the t in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; ( c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), stering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the dy to the subject in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step ( e ), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (g) in consecutive intervals of 4 weeks after step (f), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject.

In certain embodiments, administering to the human subject (wherein the subject is an ApoE4 carrier), multiple doses of the anti-beta-amyloid antibody comprises: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; and ( c) in consecutive intervals of 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject.

In some embodiments, wherein, after resuming administration of the anti-betaamyloid antibody, the human t develops a second ARIA. The second ARIA, can be, e.g., : (i) ARIA-E that is moderate or severe and is accompanied by no clinical symptoms; (ii) ARIA-E that is mild, moderate, or severe and is anied by mild, moderate, or severe clinical ms, or clinical symptoms meeting the "other medically important" serious criteria; (iii) ARIA-H with 5 to 9 cumulative microhemorrhages and accompanied by no clinical ms; (iv) ARIA-H with 1 to 9 cumulative microhemorrhages and accompanied by mild, moderate, or severe clinical symptoms, or clinical symptoms meeting the "other medically important" serious criteria; (v) ARIA-H with 2 cumulative areas of superficial siderosis and accompanied by no al symptoms; or (vi) ARIA-H with 1 or 2 cumulative areas of superficial siderosis and anied by mild, moderate, or severe al symptoms, or al symptoms meeting the "other medically important" serious criteria.

The method further ses suspending administration of the anti-beta-amyloid antibody to the subject until the second ARIA resolves (and clinical symptoms, if any, resolve). The method further involves resuming administration of the anti-beta-amyloid antibody to the subject at a dose that is lower than the dose that was administered to the t immediately prior to the t developing the second ARIA.

In some embodiments, the ARIA is accompanied by no clinical symptoms. In other embodiments, the ARIA is accompanied by mild clinical symptoms. In yet other embodiments, the ARIA is accompanied by moderate clinical symptoms. In still other embodiments, the ARIA is accompanied by clinical symptoms meeting the "other medically important" serious criteria.

In another aspect, this disclosure es a method for ng AD in a human subject in need thereof. The method involves administering to the human subject (wherein the subject is an ApoE4 carrier or ApoE4 non-carrier), multiple doses of an eta-amyloid antibody (e.g., aducanumab). The method comprises: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the dy to the subject in an amount of 1 mg/kg of body weight of the subject; ( c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (f) 4 weeks after step ( e ), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the t; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (h) 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the t; (i) 4 weeks after step (h), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; G) 4 weeks after step (i), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (k) 4 weeks after step G), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (1) in utive intervals of 4 weeks after step (k), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject.

In certain ments, the subject is administered the antibody in an amount of 10 mg/kg of body weight of the subject for at least two, three, four, five, six, seven, or eight consecutive intervals of 4 weeks.

In another aspect, this disclosure features a method for ng AD in a human subject in need thereof. The method involves administering to the human subject (wherein the subject is an ApoE4 r or ApoE4 non-carrier), multiple doses of an eta-amyloid antibody (e.g., aducanumab). The method comprises: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the dy to the subject in an amount of 3 mg/kg of body weight of the subject; ( c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step ( e ), stering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (h) 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (i) 4 weeks after step (h), administering the dy to the subject in an amount of 6 mg/kg of body weight of the subject; and G) in consecutive intervals of 4 weeks after step (i), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject.

In certain embodiments, the subject is administered the dy in an amount of 10 mg/kg of body weight of the subject for at least two, three, four, five, six, seven, or eight consecutive intervals of 4 weeks.

In another aspect, this disclosure features a method for treating AD in a human subject in need f. The method involves administering to the human subject (wherein the subject is an ApoE4 carrier or ApoE4 non-carrier), multiple doses of an anti-beta-amyloid antibody (e.g., aducanumab). The method comprises: (a) administering the anti-beta-amyloid antibody to the t in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; ( c) 4 weeks after step (b), administering the dy to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step ( e ), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (g) in consecutive intervals of 4 weeks after step (f), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject.

In certain embodiments, the subject is administered the antibody in an amount of 10 mg/kg of body weight of the subject for at least two, three, four, five, six, seven, or eight consecutive intervals of 4 weeks.

In r aspect, this sure features a method for treating AD in a human t in need f. The method es administering to the human subject in the subject is an ApoE4 carrier or ApoE4 non-carrier), multiple doses of an anti-beta-amyloid antibody (e.g., aducanumab). The method comprises: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; ( c) 4 weeks after step(b ), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (e) in consecutive intervals of 4 weeks after step (d), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject.

In certain embodiments, the subject is administered the dy in an amount of 10 mg/kg of body weight of the subject for at least two, three, four, five, six, seven, or eight consecutive intervals of 4 weeks.

The following embodiments apply to all of the above aspects: In certain embodiments, the eta-amyloid antibody is administered to the human subject intravenously.

In some embodiments, the anti-beta-amyloid antibody comprises a heavy chain le region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDRI) with the amino acid sequence of SEQ ID NO:3, a VHCDR2 with the amino acid sequence of SEQ ID NO:4, and a VHCDR3 with the amino acid sequence of SEQ ID NO:5, and wherein the VL comprises a VLCDRl with the amino acid ce of SEQ ID NO:6, a VLCDR2 with the amino acid sequence of SEQ ID NO:7, and a VLCDR3 with the amino acid sequence of SEQ ID NO:8. In certain instances, the antibody comprises a human IgG1 constant region.

In some embodiments, the anti-beta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH consists of SEQ ID NO:1 and the VL consists of SEQ ID NO:2. In certain instances, the antibody comprises a human IgG1 constant region.

In certain embodiments, the anti-beta-amyloid antibody comprises a heavy chain and a light chain, wherein the heavy chain consists of SEQ ID NO:10 and the light chain consists of SEQ ID NO:11.

Unless otherwise defined, all technical and scientific terms used herein have the same g as commonly understood by one of ordinary skill in the art to which this invention belongs. Although s and materials similar or equivalent to those described herein can be used in the practice or testing of the present ion, the exemplary methods and materials are described below. All publications, patent applications, patents, and other references ned herein are orated by reference in their entirety. In case of conflict, the present application, including definitions, will control. The als, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be nt from the following detailed description and from the claims.

BriefDescription of the gs shows the mean positron emission tomography (PET) composite standardized uptake ratio values (SUVR) by time point as determined by PET scans in a study of subjects treated with antibody BIIB037. shows the ed mean change from baseline PET composite SUVR ofthe subjects by baseline al stage, namely, mal or mild AD. shows the adjusted mean change from baseline PET composite SUVR by baseline ApoE4 status of the subjects. reports the estimated incidence ofARIA-E and/or ARIA-Hin a study ofAD subjects treated with antibody BIIB037. shows the adjusted mean change from baseline Clinical Dementia Rating Sum of Boxes (CDR-SB) for patients dosed every 4 weeks for 54 weeks with placebo, or 1 mg/kg, 3 mg/kg, or 10 mg/kg of antibody BIIB037. shows the adjusted mean change from baseline Mini Mental State Examination (MMSE) + standard error (SE) for patients dosed every 4 weeks for 54 weeks with o, or 1 mg/kg, 3 mg/kg, or 10 mg/kg body BIIB037.

FIGs. 7 A-7F show amyloid plaque reduction with aducanumab. A shows mean composite SUVR over time for PD analysis population. The dashed line tes the SUVR cut-point for florbetapir. FIGs. 7B-7F show adjusted mean (±SE) change from baseline in composite SUVR at 26 and 54 weeks among () the overall PD analysis population, () ApoE £4 rs, () non-carriers, and patients with () prodromal, and () mild AD. shows the effect ofaducanumab on MMSE. shows the effect ofaducanumab on CDR-SB. depicts selected dosing schedules for ApoE4 carriers and rriers. demonstrates the ability of umab to reduce amyloid plaque. demonstrates a slowing of decline on CDR-SB with aducanumab. demonstrates a slowing of decline on MMSE with aducanumab. depicts the study design for PRIME, a multicenter, randomized, double­ blind, placebo-controlled, multidose study. ts (planned N 188) were randomized to 1 of 9 treatment arms (target enrollment: n 30 per active treatment arm) in a staggered, ascending dose design at a ratio of 3: 1 active vs. placebo. depicts primary and secondary endpoints for the PRIME study. provides the PRIME assessment timeline. Data were analyzed to Week 54 for the 1, 3, and 10 mg/kg arms and to Week 30 for the 6 mg/kg arm. depicts patient disposition in the PRIME study. Of the 166 patients randomized, 165 were dosed; 107 ( 65%) were ApoE £4 carriers, and 68 ( 41 % ) had mal depicts baseline demographic and disease characteristics for the PRIME study. es a summary ofARIA findings and patient disposition following ARIA-E.

Detailed Description mer's Disease Alzheimer's disease, abbreviated herein as AD, is a dementia that is primarily identified by clinical diagnosis and established by markers ofthe disease.

AD is a uum having certain operationally defined stages of disease progression.

AD pathology begins prior to the onset of al symptoms. For example, amyloid plaques, one marker ofAD pathology, form 10-20 years prior to the onset ofAD dementia. The currently recognized stages ofAD include preclinical, prodromal, mild, te, and severe.

These stages may be further divided into subcategories based on the severity of symptoms and measures ofAD progression.

Because AD does not occur in discrete stages, those skilled in the art will recognize that the differences between patient groups may not be distinct in a particular clinical setting.

Nevertheless, the clinical disease stage can be characterized by measures, and changes in these measures over time, such as A� lation (CSF/PET), synaptic dysfunction (FDGPET /fMRI), tau-mediated neuronal injury (CSF), brain structure (volumetric MRI), cognition, and clinical function. (Jack CR, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neural., 20 IO; 9(1):119-28). t core clinical criteria for all ia, referred to as the NINCDS-AD RDA criteria (McKhann GM, V. diagnosis ofdementia due to mer's e: Recommendations from the al Inst. on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia, 7 (2011) 9), are known in the art and can be employed in practicing this invention. They include cognitive or behavioral impairment involving impaired ability to acquire and remember new information, impaired reasoning and handling of complex tasks, impaired visuospatial abilities, impaired language functions (speaking, reading, writing), and changes in personality, behavior, or comportment. mer's disease is currently diagnosed using the core criteria and is typically characterized by symptoms which have a gradual onset over months to years, not sudden over hours or days (insidious onset). There is usually a clear-cut history ofworsening of cognition by report or observation in Alzheimer's e subjects.

Other diagnostic classification systems have evolved as new information on AD has become available. These systems include the International Working Group (IWG) new research criteria for diagnosis ofAD s B et al., Lancet Neural., 2007; 6(8):734-736), IWG ch criteria, (Dubois et al., Lancet ., 2010;9(11): 1118-27), NIA/AA ia (Jack CR et al. Alzheimer's ., 2011;7(3):257-62), and DSM-5 criteria (American Psychiatric Association, DSM-5, 2013). These classification systems can also be ed in diagnosing AD subjects for treatment according to the methods of this disclosure.

Patients The term "patient" is meant to include any human subject for whom diagnosis, sis, prevention, or therapy for Alzheimer's disease is desired, and includes a human subject in need oftreatment. Those in need oftreatment include those already with AD, as well as those prone to have AD, or those in which the manifestation ofAD is to be prevented.

Typical ts will be men or women aged 40 to 90 (e.g., 45 to 90, 50 to 90, 55 to 90, 60 to 90). In one embodiment, the disclosure provides a method of treating a patient with AD (including, without limitation, patients with preclinical, mal, mild, moderate, or severe AD). In a further embodiment, the patient has amyloid pathology confirmed, e.g., by positron emission tomography (PET) imaging.

AD patients in need oftreatment range from subjects with amyloid pathology and early neuronal degeneration to subjects with widespread neurodegeneration and irreversible neuronal loss with ssive cognitive and functional impairment to subjects with dementia.

Patients with preclinical AD can be identified by asymptomatic stages with or without memory complaints and emerging ic memory and executive function deficits. This stage is typically characterized by the appearance of in vivo lar biomarkers ofAD and the absence clinical symptoms.

Prodromal AD patients are pre-dementia stage characterized predominantly by cognitive deficits and emerging functional impairment with disease ssion. Prodromal AD patients typically have mini-mental state examination (MMSE) scores between 24-30 sive), a spontaneous memory complaint, objective memory loss defined as a free recall score of<27 on the Free and Cued Selective Reminding Test (FCSRT), a global Clinical Dementia Rating (CDR) score of0.5, absence ofsignificant levels irment in other cognitive domains, and essentially preserved ties ofdaily living, and an e of dementia.

Patients with mild AD typically have MMSE scores between 20-26 sive), a global CDR of0.5 or 1.0, and meet the National Institute on Alzheimer's Association core clinical criteria for probable AD (see Section 22).

Basing AD diagnosis on clinical symptoms, mild stage AD patients will exhibit conspicuous behavior at work, forgetfulness, mood swings, and attention disturbances.

Moderate stage AD patients will exhibit cognitive deficits, restricted everyday activities, orientation disturbance, apraxia, agnosia, aphasia, and behavioral abnormalities. Severe stage AD patients are characterized by loss ofindependence, decay ofmemory and speech, and incontinence, In certain embodiments, treatment is ofearlier-stage patients who are amyloid positive as assessed by 18F-AV-45 PET scans. The patient may be omatic for, or exhibit only transient symptoms of, headache, confusion, gait ulties, or visual disturbances. The patient may or may not be an ApoE4 carrier as ined by ApoE ping.

In other embodiments, ent is ofpatients having any medical or neurological condition (other than AD) that might be a contributing cause ofthe subject's ive impairment, such as stroke or other cerebrovascular condition, other neurodegenerative disease, a history ofclinically icant psychiatric illness, acute or sub-acute micro- or macro hemorrhage, prior macrohemorrhage, or superficial siderosis. These patients can be treated following screening and selection by a qualified clinician.

Treatment As used herein, the terms "treat" or "treatment" generally mean obtaining a desired pharmacological and/or physiological effect. The effect can be prophylactic in terms of completely or partially preventing AD or symptoms thereofand/or can be therapeutic in terms ofpartially or completely curing AD and/or one or more adverse effects attributed to AD. Hence, the term ment" as used herein includes: (a) preventing AD from occurring in a subject who may be predisposed to AD, but has not yet been diagnosed as having it; (b) ting AD, e.g. arresting its development; (c) relieving AD, e.g. causing regression of AD; or (d) ging survival as compared to expected survival if not receiving treatment.

In one embodiment, the treatment is prophylactic for completely or partially preventing AD or symptoms thereof in the patient, or the treatment is therapeutic for partially or completely curing AD or ms attributed to AD in the patient.

In another embodiment, treatment has a disease modifying effect. This means that the treatment slows or delays the underling pathological or pathophysiological disease processes and there is an improvement in clinical signs and symptoms of AD relative to placebo.

In a further embodiment, treatment results in matic improvement. This may consist of enhanced cognition, more autonomy, and/or improvement in sychiatric and behavioral dysfunction, even if for only a limited duration.

While the goal of any therapy is the prevention or cure of e, it will be understood that this disclosure contemplates a delay of clinical decline or progression of disease or relief of symptoms. Delaying clinical decline or e progression directly impacts the patient and care-givers. It delays disability, maintains independence, and allows the patient to live a normal life for a longer period of time. Relief of symptoms to the best degree possible can incrementally improve cognition, function, and behavioral symptoms, as well as mood.

In the method of treatment of AD according to this disclosure, an anti-beta amyloid antibody is administered to the human patient. In one embodiment, the anti-beta amyloid dy is a monoclonal antibody. In another embodiment, the anti-beta d antibody is a fully human antibody. In a further embodiment, the anti-beta amyloid antibody is a recombinant antibody. In r embodiment, the anti-beta amyloid dy is a recombinant, fully human, onal antibody. In certain embodiments, the anti-beta amyloid antibody is selective for soluble A� oligomer and fibril binding without substantial monomer binding. These ties improve pharmacokinetics (PK), reduce antibody sink, and minimize off-target cross-reactivity with APP-expressing tissues. An exemplary monoclonal antibody meeting these ia is antibody BIIB037.

Antibody BIIB037, also known as aducanumab, is a biologic treatment for Alzheimer's disease. It is an anti-A� antibody that recognizes aggregated forms of A�, including plaques. BIIB037 ns a human kappa light chain. BIIB037 consists of 2 heavy and 2 human kappa light chains ted by inter-chain disulfide bonds. By "BIIB037" or numab" is meant an anti-A� antibody sing the amino acid sequences set forth in SEQ ID NOs.: 10 and 11.

In vitro characterization studies have established that antibody BIIB037 recognizes a conformational epitope present in A� aggregates, the accumulation ofwhich is believed to underlie the development and progression ofAD.

In vivo pharmacology s indicate that a murine IgG2a chimeric version of the antibody (ch 12F6A) with similar properties significantly reduces amyloid plaque burden in the brains of aged Tg2576 mice, a mouse model of AD. The reduction in parenchymal amyloid was not anied by a change in vascular amyloid, as has been reported for certain anti-A� antibodies (Wilcock OM, Colton CA. Immunotherapy, vascular pathology, and microhemorrhages in transgenic mice. CNS & Neurological Disorders Drug Targets, 2009 Mar;8(1):50-64).

The VH and VL of antibody BIIB037 have amino acid sequences that are identical to the amino acid sequence of the VH and VL of antibody NI-IO1.12F6A described in US Patent No. 8,906,367 (see, Tables 2-4; incorporated by reference in its entirety herein).

Specifically, antibody BIIB037 has an antigen binding domain comprising VH and VL variable regions depicted in Table 1 (VH) and Table 2 (VL), corresponding complementarity determining regions (CDRs) ed in Table 3, and heavy and light chains depicted in Table 4 (H) and Table 5 (L).

Table 1: Amino acid sequences of the VH region of anti-A� antibody 7 (VH CDRs (Kabat definition) underlined).

Variable heavy chain sequence QVQLVESGGG VVQPGRSLRL SCAASGFAFS SYGMHWVRQA PGKGLEWVAY IWFDGTKKYY RFTI NTLY RAED ARDR GIGARRGPYY MDVWGKGTTV TVSS (SEQ ID NO:l) Table 2: Amino acid sequences of the VL region of anti-A� antibody 7 (VL CDRs (Kabat definition) underlined).

Variable light chain sequence (kappa or lambda) DIQMTQSPSS LSASVGDRVT ITCRASOSIS SYLNWYQQKP GKAPKLLIYb ASSLOSGVPS RFSGSGSGTD FTLTISSLQP YCOO SYSTPLTFGG GTKVEIKR (SEQ ID N0:2) Table 3: Denomination of CDR protein sequences in Kabat Nomenclature of VH and VL regions of anti-A� antibody BIIB037.

CDR Variable heavy chain Variable light chain CDRI SYGMH (SEQ ID NO:3) RASQSISSYLN (SEQ ID NO:6) CDR2 VIWFDGTKKYYTDSVKG (SEQ ID NO:4) AASSLQS (SEQ ID NO:7) CDR3 DRGIGARRGPYYMDV (SEQ ID NO:5) PLT (SEQ ID NO:8) The amino acid sequence of the mature heavy chain ofBIIB037 is provided in Table 4 below.

Table 4: Amino acid sequences of the heavy chain ofanti-A� antibody BIIB037 (heavy chain CDRs (Kabat definition) underlined).

Heavy chain sequence QVQLVESGGG VVQPGRSLRL SCAASGFAFS VRQA PGKGLEWVAY IWFDGTKKYY TDSVKGRFTI SRDNSKNTLY LQMNTLRAED TAVYYCARDR GIGARRGPYY MDVWGKGTTV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK CDKT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE YRVV SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KGQP REPQVYTLPP KNQV KGFY PSDIAVEWES NGQPENNYKT TPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPG (SEQ ID NO:10) The amino acid sequence of the mature light chain of BIIB037 is provided in Table 5 below.

Table 5: Amino acid sequences ofthe light chain ofanti-A� antibody BIIB037 (light chain CDRs (Kabat definition) ined).

Light chain sequence DIQMTQSPSS LSASVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ SYSTPLTFGG GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY QWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC(SEQ ID NO:11) In addition to antibody BIIB037, this disclosure contemplates the use of the other anti-beta-amyloid antibodies, such as antibodies comprising either the VH region comprising or consisting of SEQ ID NO: 1 or the VL region comprising or consisting of SEQ ID NO:2, or antibodies comprising the VH region sing or consisting of SEQ ID NO: 1 and the VL region comprising or consisting of SEQ ID NO:2, wherein the VH and/or VL regions have one or more substitutions,deletions,and/or ions. In some embodiments,these VH and VL regions may have up to 25,up to 20,up to 15, up to 10,up to 5,or 1,2,3,4,5,6,7,8,9, ,11,12,13,14, 15, 16, 17,18,19,or 20 amino acid substitutions and still bind betaamyloid.

In specific embodiments,these amino acid substitutions occur only in the framework region. In some embodiments,the amino acid substitution(s) is/are conservative amino acid tutions. In certain embodiments,the VH and VL regions may include 1 to 5 (1,2,3,4,5) amino acid ons and/or additions and still bind beta-amyloid. In certain embodiments,these deletions and/or ons are made at the N- and/or C-terminus ofthe VH and/or VL regions. In one embodiment,one amino acid is deleted and/or added at the N and/or C-terminus ofthe VH region. In one embodiment,one amino acid is deleted and/or added at the N and/or C-terminus ofthe VL .

Other antibodies contemplated for use in the disclosure include antibodies comprising the variable heavy chain (VH) CDRs and the variable light chain (VL) CDRs in Table 3.

Thus,the anti-beta amyloid antibodies comprise the CDRs comprising or consisting ofthe amino acid sequences ofSEQ ID NOs.: 3-8. In one embodiment,the anti-beta amyloid antibodies comprise the CDRs comprising or consisting ofthe amino acid sequences ofSEQ ID NOs.: 4-8 and include as VH CDRl an amino acid ce sing or consisting of GFAFSSYGMH (SEQ ID N0:9). In some instances,the disclosure encompasses anti-betaamyloid antibodies comprising the VH and VL CDRs ofBIIB037 based on any CDR definition (e.g.,Kabat,Chothia,enhanced Chothia,AbM,or contact definition). See,e.g., /www.bioinf.org.uk/abs/index.html. In one embodiment,the disclosure encompasses anti-beta-amyloid antibodies comprising the VH and VL CDRs 037 based on the Chothia definition. In one embodiment, the disclosure encompasses anti-beta-amyloid antibodies comprising the VH and VL CDRs ofBIIB037 based on the enhanced Chothia definition. In another embodiment,the disclosure encompasses eta-amyloid antibodies comprising the VH and VL CDRs ofBIIB037 based on the AbM definition. In yet r embodiment,the disclosure encompasses anti-beta-amyloid antibodies comprising the VH and VL CDRs ofBIIB037 based on the contact definition.

Antibody BIIB037 and other dies employed in the invention can be prepared using known methods. In some embodiments,the antibody is expressed in a Chinese hamster ovary (CHO) cell line.

The patient's response to treatment according to the invention is generally dosedependent.

One ment ofthe invention comprises administering at least one dose ofthe anti-A� antibody to the patient in an amount that is less than the minimum therapeutic amount required to treat the patient for AD. This is ed by at least one dose of the anti­ A� antibody administered to the patient in an amount that is about equal to the minimum therapeutic amount required to treat the patient for AD. And then at least one dose of the anti-A� antibody is administered to the patient in an effective amount that is more than the minimum therapeutic amount, but less than the maximum tolerated amount required to treat the patient for AD. In a preferred embodiment, cerebral amyloid burden is d. In a further preferred embodiment, the susceptibility of the patient to ARIA is reduced.

A therapeutically effective amount refers to the amount of the anti-A� antibody sufficient to ameliorate a symptom or condition associated with mer's disease.

Therapeutic efficacy and ty of the anti-A� antibody can be determined by standard pharmaceutical procedures. Ideally, the anti-A� dy is employed in an amount sufficient to restore normal behavior and/or cognitive properties in case of Alzheimer's disease, or at least delay or prevent the ssion of AD in the patient.

In Tg2576 mice, a dose-dependent reduction in cerebral amyloid was observed after chronic dosing with monoclonal antibody 7 (0.3 mg/kg to 30 mg/kg). A significant amyloid reduction was observed at 3 mg/kg, deemed the minimum therapeutic dose for antibody BIIB037 in this animal model.

An effective amount of the anti-A� antibody is that quantity of the antibody that will produce a clinically significant se in the treatment of mer's disease. Effective amounts of about 1 to 30 mg/kg per month (e.g., 1 mg/kg, 3 mg/kg, 6 mg/kg, 10 mg/kg, 12 mg/kg, 15 mg/kg, 18 mg/kg, 20 mg/kg, 24 mg/kg, 25 mg/kg, 28 mg/kg, 30 mg/kg) can be employed. Efficacy of antibody BIIB037 can reach a plateau at effective amounts between about 10 mg/kg and about 30 mg/kg of the patient's body weight, consistent with safety. In certain embodiments, an effective amount of about 3 mg/kg to about 10 mg/kg of the patient's body weight is contemplated. In other embodiments, effective amounts are about 3 mg/kg, about 6 mg/kg, and about 10 mg/kg of the patient's body weight.

The maximum tolerated amount of the anti-A� antibody is that quantity of the antibody which will e a clinically significant response in the treatment of Alzheimer's disease consistent with safety. A principal safety concern in treating patients according to the method of the invention is the occurrence of ARIA, especially ARIA-E or ARIA-H. The s of the invention make it possible to employ higher doses of antibody BIIB037 for the treatment of patients for AD than was feasible using previously known protocols.

It will be understood that dose adjustments can be implemented during the ent protocol. For example, for s of safety or cy, doses can be increased so that the effects of the anti-A� antibody on AD can be enhanced or doses can be decreased so that the ARIA rate and ty can be mitigated. If a dose is missed, the patient should preferably resume dosing by receiving the missed dose and uing thereafter according to the described regimen.

In certain embodiments, the anti-A� antibody is stered to the patient by intravenous infusion following dilution into saline. When using this mode nistration, each infusion step in the titration regime ofthe invention will typically take about 1 hour.

The dose ranges and other numerical values herein e a quantity that has the same effect as the numerically stated amount as indicated by ent ofAlzheimer's disease in the t and a reduction in the incidence or susceptibility of the patient to ARIA when compared to an individual not treated by the method of the invention. At the very least, each numerical parameter should be construed in light ofthe number of icant digits, applying ordinary rounding techniques. In addition, any numerical value inherently ns certain errors from the standard deviation of its measurement and such values are within the scope ofthe invention.

Compositions An anti-A� antibody described herein (e.g., BIIB037) can be formulated as a pharmaceutical composition. The pharmaceutical compositions employed in the present invention can be formulated according to methods well known in the art; see, for example, Remington: The Science and Practice of Pharmacy (2000) by the University of Sciences in Philadelphia, ISBN 683-306472. The compositions can r comprise a pharmaceutically acceptable carrier. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions, such as oil/water ons, various types of wetting , sterile solutions, etc.

Furthermore, the pharmaceutical ition may comprise additional agents. For example, for use in the treatment of Alzheimer's disease the additional agent can be selected from the group consisting ofa small organic molecule, another anti-A� antibody, an anti-Tau antibody, and combinations thereof. Non-limiting es ofanti-A� antibodies can be found in US Patent No. 8,906,367. Non-limiting examples of anti-Tau antibodies can be found in US Patent No. 8,940,272 and US Patent Application Publication US 2015/0344553. stration of the itions can be effected in different ways, e.g., by intravenous, intraperitoneal, subcutaneous, intramuscular, topical, or intradermal administration.

Standard Doses In one method of ent of Alzheimer's disease, an anti-beta amyloid antibody (e.g., BIIB037) is administered to a human patient in multiple doses (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) of the same amount of antibody (i.e., a standard dose) over a period of time.

For example, the human patient may be administered 3 mg/kg of the t's body weight of the eta amyloid antibody on multiple occasions over a period of time.

In r example, the human patient may be stered 6 mg/kg of the patient's body weight of the anti-beta d antibody on multiple occasions over a period of time.

In r example, the human patient may be administered 10 mg/kg of the patient's body weight of the anti-beta amyloid antibody on multiple occasions over a period of time.

In yet another example, the human patient may be administered 15 mg/kg of the patient's body weight of the anti-beta amyloid antibody on multiple occasions over a period of time.

In a r example, the human patient may be administered 20 mg/kg of the patient's body weight of the anti-beta amyloid antibody on multiple occasions over a period of time.

In another example, the human patient may be administered 30 mg/kg of the patient's body weight of the anti-beta amyloid antibody on multiple occasions over a period of time.

The period of time for each of these methods can be, e.g., once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. The ent can proceed until such time as deemed beneficial by a health care practitioner.

In certain ments, the anti-A� antibody is administered to the patient by intravenous infusion following dilution into saline.

In any of the above embodiments, the anti-A� antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDRl) with the amino acid sequence SEQ ID NO:3 or SEQ ID NO:9, a VHCDR2 with the amino acid ce SEQ ID NO:4, and a VHCDR3 with the amino acid sequences SEQ ID NO:5, and wherein the VL comprises a VLCDRl with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8.

In some embodiments, the anti-A� antibody comprises a VH and a VL, wherein the VH comprises VH CDRl, VH CDR2, and VH CDR3 of SEQ ID NO:1; and wherein the VL comprises VL CDRl, VL CDR2, and VLCDR3 of SEQ ID NO:2, wherein the CDRs are defined based on Chothia, enhanced Chothia, AbM, or the contact definition.

In some embodiments, the anti-A� antibody comprises a VH and a VL, wherein the VH comprises or consists of SEQ ID NO:1 and the VL comprises or consists of SEQ ID N0:2.

In n embodiments, the anti-A� antibody bed above further comprises a human IgG1 constant region.

In a particular embodiment, the anti-A� antibody comprises a heavy chain comprising or consisting of SEQ ID NO: IO and a light chain comprising or consisting of SEQ ID NO:11.

Titration (Sequential Administration ofIncreasing Doses) ence of the ARIA in AD patients treated with anti-beta-amyloid antibodies (e.g., BIIB037) is dose-dependent. ARIA has been observed in ts receiving 1 mg/kg and 3 mg/kg of the antibody after the third and fifth doses. At doses of 6 mg/kg and 10 mg/kg of body weight, ARIA has been observed after the second dose. The methods of the disclosure include treatment regimens selected to decrease the incidence of ARIA.

In one method of treatment of Alzheimer's disease, the anti-beta amyloid antibody is administered to a human t in increasing amounts over a period of time. This ure of sequentially administering the antibody to the patient is referred to herein as "titration" because it es administering a standardized pharmaceutical of known trations in carefully measured amounts until completion of the procedure as evidenced by specific endpoints. In the present invention, the endpoints include the effect of the treatment on Alzheimer's disease in the patient and the effect of the treatment in reducing the incidence of ARIA, especially ARIA-E or ARIA-H, in the treated patient population.

One of the advantages of the titration regime of the invention is that it makes it possible to administer higher doses of the monoclonal dy to AD patients, especially apolipoprotein E4 (ApoE4) carriers, without incurring the same extent of ARIA observed with a standard dose regimen. In certain embodiments, the higher dose comprises a dose or doses of the anti-A� antibody of 10 mg/kg of the body weight of the subject. Without intending to be d to any particular mechanism, it is believed that titration results in lower initial amyloid removal and slower removal during the overall treatment.

Titration of the anti-A� dy (e.g., BIIB037) is carried out in multiple doses. For example, two doses of the antibody can be administered to the t in an amount per dose that is less than the minimum eutic amount, followed by 4 doses of the antibody in an amount per dose that is about equal to the m therapeutic amount. This regime can then be ed by multiple doses in an amount per dose that is more than the minimum therapeutic amount, but less than the m tolerated amount until there is an acceptable change in AD in the patient. For e, doses can be administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Progress can be monitored by periodic assessment.

One protocol of the disclosure, designated Protocol ( 1), comprises: (A) administering the anti-beta amyloid antibody to the patient in an amount of 1 mg/kg of body weight of the patient; (B) 4 weeks after step (A), administering the antibody to the patient in an amount of 1 mg/kg of body weight of the patient; (C) 4 weeks after step (B), stering the dy to the patient in an amount of 3 mg/kg of body weight of the patient; (D) 4 weeks after step (C), administering the antibody to the patient in an amount of 3 mg/kg of body weight of the patient; (E) 4 weeks after step (D), administering the antibody to the patient in an amount of 3 mg/kg of body weight of the patient; (F) 4 weeks after step (E), administering the antibody to the patient in an amount of 3 mg/kg of body weight of the patient; (G) 4 weeks after step (F), administering the antibody to the patient in an amount of 6 mg/kg of body weight of the patient; and (H) in consecutive intervals of 4 weeks after step (G), administering the antibody to the patient in an amount of 6 mg/kg of body weight of the patient.

In other words, Protocol (1) comprises administering a first dose of anti-beta d antibody to the patient in an amount of 1 mg/kg of body weight of the patient, followed by a second dose in an amount of 1 mg/kg of body weight four weeks after the first dose. In four week intervals after the second dose, doses 3, 4, 5, and 6 of the antibody are administered to the patient in an amount of 3 mg/kg of body weight. And then, in four week intervals after administration of dose 6, doses 7 and 8 of the antibody are administered to the t in an amount of 6 mg/kg of body weight.

Protocol (1) may comprise a total of 14 doses stered about 4 weeks apart over about 52 weeks, ally continuing to dose about every 4 weeks thereafter, to thereby treat AD with reduced tibility of the patient to ARIA. In other words, four weeks after the administration of dose 8, doses 9-14 may be administered to the patient in an amount of 6 mg/kg body weight in four week intervals. In some embodiments, the antibody continues to be administered to the patient in an amount of 6 mg/kg of body weight every 4 weeks to at least week 76. In other words, in some ments, the method comprises administering doses 9-20 to the t in an amount of 6 mg/kg body weight in four week intervals ing dose 8. In some embodiments, after dose 8, the antibody is administered to the patient in an amount of 6 mg/kg of body weight every 4 weeks indefinitely. In some embodiments, in 12 week intervals following the last dose at 6 mg/kg body weight, the amount of antibody administered to the patient is 3 mg/kg body weight. In some embodiments, this reduced dose is initially administered to the t 12 weeks after week 52 (i.e., 12 weeks after dose 14); in other embodiments, this reduced dose is administered to the patient 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, in four week intervals after the last dose at 6 mg/kg body weight, the amount of antibody administered to the patient is 1mg/kg body weight. In some embodiments, this reduced dose is initially administered to the patient four weeks after week 52 (i.e., four weeks after dose 14); in other embodiments, this reduced dose is initially administered to the patient four weeks after week 76 (i.e., four weeks after dose 20).

Protocol (1) may be employed with patients designated as an ApoE4 r or an ApoE4 non-carrier as determined by ApoEgenotyping. In any of the alternative embodiments of Protocol (1), the anti-A� antibody may comprise a heavy chain variable region (VH ) and a light chain variable region (VL), wherein the VH comprises a first complementarity ining region (VHCDRl ) with the amino acid sequence SEQ ID NO:3 or SEQ ID NO:9, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequences SEQ ID NO:5, and wherein the VL comprises a VLCDRl with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8. In some embodiments of Protocol (1), the anti-A� antibody comprises a VH and a VL, wherein the VH comprises VH CDRl , VH CDR2, and VH CDR3 of SEQ ID NO:1; and wherein the VL ses VL CDRl, VL CDR2, and VLCDR3 of SEQ ID NO:2, wherein the CDRs are defined based on Chothia, enhanced Chothia, AbM, or the contact definition. In some embodiments of Protocol (1), the anti-A� antibody comprises a VH and a VL, wherein the VH comprises or ts of SEQ ID NO:1and the VL comprises or consists of SEQ ID NO:2. In certain embodiments of ol (1), the anti-A� antibody comprises a human IgG1constant region. In a particular ment, the � antibody comprises a heavy chain comprising or consisting of SEQ ID NO:10 and a light chain sing or consisting of SEQ ID NO:11.

Another protocol according to the disclosure, designated Protocol (2), comprises: (A) administering the anti-beta amyloid antibody to the patient in an amount of 1 mg/kg of body weight of the patient; (B) 4 weeks after step (A), stering the antibody to the patient in an amount of 1 mg/kg of body weight of the patient; (C) 4 weeks after step (B), administering the antibody to the patient in an amount of 3 mg/kg of body weight of the patient; (D) 4 weeks after step (C), administering the antibody to the patient in an amount of 3 mg/kg of body weight of the patient; (E) 4 weeks after step (D), administering the antibody to the t in an amount of 6 mg/kg of body weight of the patient; (F) 4 weeks after step (E), administering the antibody to the patient in an amount of 6 mg/kg of body weight of the patient; and (G) in consecutive intervals of 4 weeks after step (F), administering the dy to the patient in an amount of 10 mg/kg of body weight of the patient.

In other words, Protocol (2) comprises administering a first dose of anti-beta amyloid antibody to the patient in an amount of 1 mg/kg of body weight of the patient, followed by a second dose in an amount of 1 mg/kg of body weight four weeks after the first dose. In four week intervals after the second dose, antibody doses 3 and 4 are administered to the patient in an amount of 3 mg/kg of body weight. In four week intervals after administration of dose 4, doses 5 and 6 of the antibody are administered to the patient in an amount of 6 mg/kg of body weight. And then, four weeks after administration of dose 6, antibody dose 7 is administered to the patient in an amount of 10 mg/kg of body .

Protocol (2) may comprise a total of 14 doses administered about 4 weeks apart over about 52 weeks, optionally continuing to dose about every 4 weeks thereafter, to thereby treat AD with reduced tibility of the patient to ARIA. In other words, four weeks after the administration of dose 7, doses 8-14 may be administered to the patient in an amount of 10 mg/kg body weight in four week intervals. In some embodiments, the anti-A� antibody continues to be administered to the patient in an amount of 10 mg/kg of body weight every 4 weeks to at least week 76. In other words, in some ments, the method comprises stering doses 8-20 to the patient in an amount of 10 mg/kg body weight in four week intervals following dose 7. In some embodiments, following dose 7, the anti-A� dy is administered to the patient in an amount of 10 mg/kg of body weight every 4 weeks indefinitely. In some embodiments, after the last dose at 10 mg/kg body weight, the amount of anti-A� antibody is d to 3 mg/kg body weight and is administered to the patient in 12 week intervals. In some embodiments, this reduced dose is initially stered to the patient 12 weeks after week 52 (i.e., 12 weeks after dose 14); in other embodiments, this reduced dose is initially administered to the patient 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, four weeks after the last dose at 10 mg/kg body weight, the amount of antibody administered to the patient is reduced to 1 mg/kg body weight every 4 weeks. In some embodiments, this reduced dose begins four weeks after week 52 (i.e., four weeks after dose 14); in other embodiments, this reduced dose begins four weeks after week 76 (i.e., four weeks after dose 20).

Protocol (2) can be employed for the treatment of both ApoE4 carriers and ApoE4 non-carriers. In any of the alternative embodiments of Protocol (2), the anti-A� antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH ses a first complementarity determining region (VHCDRl) with the amino acid sequence SEQ ID NO:3 or SEQ ID NO:9, a VHCDR2 with the amino acid ce SEQ ID NO:4, and a VHCDR3 with the amino acid sequences SEQ ID NO:5, and wherein the VL comprises a VLCDRl with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8. In some ments of Protocol (2), the � antibody comprises a VH and a VL, wherein the VH comprises VH CDRl, VH CDR2, and VH CDR3 of SEQ ID NO:1; and wherein the VL comprises VL CDRl, VL CDR2, and VLCDR3 of SEQ ID NO:2, n the CDRs are d based on Chothia, enhanced Chothia, AbM, or the contact definition. In certain embodiments of Protocol (2), the � antibody may comprise a heavy chain le region (VH) and a light chain variable region (VL), wherein the VH comprises or consists of SEQ ID NO:1 and the VL comprises or consists of SEQ ID NO:2. In some embodiments of Protocol (2), the anti-A� antibody comprises a human IgG 1 constant region. In a particular embodiment, the anti-A� antibody comprises a heavy chain comprising or consisting of SEQ ID NO:10 and a light chain comprising or consisting of SEQ ID NO:11.

This disclosure provides another protocol, ated Protocol (3), for the treatment of ApoE4 rs. This embodiment comprises: (A) administering the anti-beta amyloid antibody to the patient in an amount of 1 mg/kg of body weight of the patient; (B) 4 weeks after step (A), administering the antibody to the patient in an amount of 1 mg/kg of body weight of the patient; and (C) in consecutive intervals of 4 weeks after step (B), administering the antibody to the t in an amount of 3 mg/kg of body weight of the patient.

In other words, Protocol (3) comprises administering a first dose of an anti-beta amyloid antibody to the patient in an amount of 1 mg/kg of body weight of the patient. Four weeks after the first dose, a second dose of the antibody is administered to the patient in an amount of 1 mg/kg of body weight. And then, 4 weeks after the second dose, dose 3 of the antibody is administered to the patient in an amount of 3 mg/kg of body weight.

Protocol (3) may comprise a total of 14 doses stered about 4 weeks apart over about 52 weeks, optionally uing to dose about every 4 weeks thereafter, to thereby treat AD with reduced susceptibility of the patient to ARIA. In other words, four weeks after the administration of dose 3, doses 4-14 may be stered to the patient in an amount of 3 mg/kg body weight in four week intervals. In some embodiments, the antibody continues to be administered to the patient in an amount of 3 mg/kg of body weight every 4 weeks to at least week 76. In other words, in some embodiments, the method ses administering doses 4-20 to the patient in an amount of 3 mg/kg body in four week intervals following dose 3. In some embodiments, following dose 3, the antibody is administered to the patient in an amount of 3 mg/kg of body weight every 4 weeks indefinitely. In some embodiments, after a prescribed period, the amount of antibody administered to the t may be d to 3 mg/kg body weight every 12 weeks. In some embodiments, the 12 week dosing intervals begin after week 52 (i.e., after dose 14); in other embodiments, the 12 week dosing intervals begin after week 76 (i.e., after dose 20). In some embodiments, after a prescribed period, the amount of antibody administered to the patient may be reduced to 1 mg/kg body weight every 4 weeks. In some embodiments, this reduced dose begins four weeks after week 52 (i.e., four weeks after dose 14); in other embodiments, this reduced dose begins four weeks after week 76 (i.e., four weeks after dose 20).

Protocol (3) may be used with ApoE4 carriers as determined by ApoE genotyping. In any of the alternative embodiments of Protocol (3), the anti-A� antibody may comprise a heavy chain le region (VH) and a light chain variable region (VL), wherein the VH comprises a first mentarity determining region (VHCDRl) with the amino acid sequence SEQ ID NO:3 or SEQ ID NO:9, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequences SEQ ID NO:5, and wherein the VL comprises a VLCDRl with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8. In some embodiments of Protocol (3), the � antibody comprises a VH and a VL, wherein the VH comprises VH CDRl, VH CDR2, and VH CDR3 of SEQ ID NO:1; and n the VL comprises VL CDRl , VL CDR2, and VLCDR3 of SEQ ID NO:2, wherein the CDRs are defined based on Chothia, enhanced Chothia, AbM, or the contact definition.

In some embodiments of ol (3), the anti-A� antibody ses a VH and a VL, wherein the VH comprises or consists of SEQ ID NO: 1and the VL comprises or ts of SEQ ID NO:2. In certain embodiments of Protocol (3), the anti-A� antibody comprises a human IgG1 constant region. In a particular embodiment, the anti-A� antibody comprises a heavy chain comprising or consisting of SEQ ID NO:10 and a light chain comprising or consisting of SEQ ID NO:11.

Another protocol of the sure, designated Protocol ( 4), comprises: (A) administering the anti-beta amyloid dy to the patient in an amount of 1 mg/kg of body weight of the patient; (B) 4 weeks after step (A), stering the antibody to the patient in an amount of 1 mg/kg of body weight of the patient; (C) 4 weeks after step (B), administering the antibody to the patient in an amount of 3 mg/kg of body weight of the patient; (D) 4 weeks after step (C), administering the antibody to the t in an amount of 3 mg/kg of body weight of the patient; and (E) 4 weeks after step (D), administering the antibody to the patient in an amount of 6 mg/kg of body weight of the patient.

In other words, Protocol ( 4) comprises administering a first dose of anti-beta amyloid antibody to the patient in an amount of 1 mg/kg of body weight of the patient, followed by a second dose in an amount of 1 mg/kg of body weight four weeks after the first dose. In four week intervals after the second dose, doses 3 and 4 are administered to the patient in an amount of 3 mg/kg of body weight. And then, four weeks after administration of dose 4, dose 5 of the antibody is administered to the patient in an amount of 6 mg/kg of body weight.

Protocol (4) may comprise a total of 14 doses administered about 4 weeks apart over about 52 weeks, optionally continuing to dose about every 4 weeks thereafter, to thereby treat AD with reduced susceptibility of the t to ARIA. In other words, four weeks after the administration of dose 5, doses 6-14 may be administered to the patient in an amount of 6 mg/kg body weight in four week intervals. In some embodiments, the antibody continues to be administered to the patient in an amount of 6 mg/kg of body weight every 4 weeks to at least week 76. In other words, in some embodiments, the method comprises administering doses 6-20 to the patient in an amount of 6 mg/kg body weight in four week intervals following dose 5. In some ments, following dose 5, the antibody is stered to the t in an amount of 6 mg/kg of body weight every 4 weeks indefinitely. In some embodiments, after the last dose at 6 mg/kg body weight, the amount of antibody administered to the patient is reduced to 3 mg/kg body weight every 12 weeks. In some embodiments, this reduced dose is initially administered to the patient 12 weeks after week 52 (i.e., 12 weeks after dose 14); in other embodiments, this reduced dose is lly administered to the patient 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, after the last dose at 10 mg/kg body weight, the amount of antibody administered to the patient is reduced to 1mg/kg body weight every 4 weeks. In some embodiments, this reduced dose begins four weeks after week 52 (i.e., four weeks after dose 14); in other ments, this reduced dose begins four weeks after week 76 (i.e., four weeks after dose 20).

In any of the alternative embodiments of Protocol (4), the anti-A� antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDRl ) with the amino acid sequence SEQ ID NO:3 or SEQ ID NO:9, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequences SEQ ID NO:5, and wherein the VL comprises a VLCDRl with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8. In some embodiments of Protocol (4), the anti-A� antibody comprises a VH and a VL, wherein the VH comprises VH CDRl, VH CDR2, and VH CDR3 of SEQ ID NO:1; and n the VL comprises VL CDRl, VL CDR2, and VLCDR3 of SEQ ID NO:2, wherein the CDRs are defined based on Chothia, enhanced Chothia, AbM, or the contact definition.

In some embodiments of Protocol (4), the anti-A� antibody comprises a VH and a VL, wherein the VH comprises or consists of SEQ ID NO: 1and the VL comprises or consists of SEQ ID NO:2. In certain embodiments of Protocol (4), the anti-A� antibody comprises a human IgG 1 constant . In a particular embodiment, the anti-A� antibody comprises a heavy chain sing or consisting of SEQ ID NO:10 and a light chain comprising or consisting of SEQ ID NO:11.

Yet another ol of the disclosure, designated as Protocol ( 5), comprises: (A) administering the anti-beta amyloid dy to the patient in an amount of 1 mg/kg of body weight of the patient; (B) 4 weeks after step (A), administering the antibody to the patient in an amount of 1 mg/kg of body weight of the patient; (C) 4 weeks after step (B), administering the antibody to the patient in an amount of 3 mg/kg of body weight of the patient; (D) 4 weeks after step (C), stering the antibody to the patient in an amount of 3 mg/kg of body weight of the patient; (E) 4 weeks after step (D), administering the antibody to the t in an amount of 3 mg/kg of body weight of the patient; (F) 4 weeks after step (E), administering the antibody to the patient in an amount of 3 mg/kg of body weight of the patient; (G) in consecutive intervals of 4 weeks after step (F), administering the antibody to the t in an amount of 6 mg/kg of body weight of the patient; (H) in consecutive intervals of 4 weeks after step (G), stering the antibody to the patient in an amount of 6 mg/kg of body weight of the patient; (I) in consecutive intervals of 4 weeks after step (H), administering the antibody to the patient in an amount of 6 mg/kg of body weight of the patient; (J) in utive intervals of 4 weeks after step (I), administering the antibody to the patient in an amount of 6 mg/kg of body weight of the patient; (K) in consecutive intervals of 4 weeks after step (J), administering the antibody to the patient in an amount of 6 mg/kg of body weight of the patient; and (L) in consecutive intervals of 4 weeks after step (K), administering the antibody to the patient in an amount of 10 mg/kg of body weight of the patient.

In other words, Protocol ( 5) comprises administering a first dose of anti-beta amyloid antibody to the patient in an amount of 1 mg/kg of body weight of the patient, followed by a second dose in an amount of 1 mg/kg of body weight four weeks after the first dose. In four week als after the second dose, antibody doses 3, 4, 5, and 6 are administered to the patient in an amount of 3 mg/kg of body weight. In four week intervals after administration of dose 6, doses 7, 8, 9, 10, and 11 are administered to the patient in an amount of 6 mg/kg of body weight. And then, four weeks after administration of dose 11, dose 12 of the antibody is administered to the patient in an amount of 10 mg/kg of body .

Protocol (5) may comprise a total of 14 doses administered about 4 weeks apart over about 52 weeks, optionally continuing to dose about every 4 weeks thereafter, to thereby treat AD with reduced susceptibility of the patient to ARIA. In other words, four weeks after the administration of dose 12, doses 13-14 may be administered to the patient in an amount of 10 mg/kg body weight in four week intervals. In some embodiments, the antibody continues to be administered to the patient in an amount of 10 mg/kg of body weight every 4 weeks to at least week 76. In other words, in some embodiments, the method comprises administering doses 13-20to the patient in an amount of 6 mg/kg body weight in four week intervals following dose 12. In some embodiments, following dose 12, the dy is administered to the patient in an amount of 10 mg/kg of body weight every 4 weeks indefinitely. In some embodiments, after the last dose at 10 mg/kg body weight, the amount of antibody administered to the patient is reduced to 3 mg/kg body weight every 12 weeks. In some embodiments, this reduced dose is initially administered to the patient 12 weeks after week 52 (i.e., 12 weeks after dose 14); in other ments, this reduced dose is initially administered to the patient 12 weeks after week 76 (i.e., 12 weeks after dose 20). In some embodiments, after the last dose at 10 mg/kg body weight, the amount of antibody stered to the patient is reduced to 1mg/kg body weight every 4 weeks. In some embodiments, this reduced dose begins four weeks after week 52 (i.e., four weeks after dose 14); in other embodiments, this reduced dose begins four weeks after week 76 (i.e., four weeks after dose 20). In certain embodiments, the subject being administered under Protocol ( 5) is an ApoE4 r. Higher doses (such as 10 mg/kg ) of aducanumab can be administered in a titration regimen in ApoE4 carriers without incurring the same extent of ARIA observed with a fixed-dose regimen. In other embodiments, the subject being administered under Protocol (5) is an ApoE4 non-carrier.

In any of the alternative embodiments of Protocol (5), the anti-A� antibody may comprise a heavy chain variable region (VH) and a light chain variable region (VL), n the VH comprises a first mentarity determining region (VHCDRl ) with the amino acid sequence SEQ ID NO:3 or SEQ ID NO:9, a VHCDR2 with the amino acid sequence SEQ ID NO:4, and a VHCDR3 with the amino acid sequences SEQ ID NO:5, and wherein the VL comprises a VLCDRl with the amino acid sequence SEQ ID NO:6, a VLCDR2 with the amino acid sequence SEQ ID NO:7, and a VLCDR3 with the amino acid sequence SEQ ID NO:8. In some embodiments of Protocol (5), the anti-A� antibody comprises a VH and a VL, wherein the VH comprises VH CDRl, VH CDR2, and VH CDR3 of SEQ ID NO:1; and wherein the VL ses VL CDRl , VL CDR2, and VLCDR3 of SEQ ID NO:2, n the CDRs are defined based on Chothia, enhanced a, AbM, or the contact definition.

In some embodiments of ol (5), the anti-A� antibody comprises a VH and a VL, wherein the VH comprises or consists of SEQ ID NO: 1and the VL comprises or consists of SEQ ID NO:2. In certain embodiments of Protocol (5), the anti-A� antibody comprises a human IgG1 constant region. In a particular embodiment, the � antibody comprises a heavy chain comprising or consisting of SEQ ID NO:10 and a light chain comprising or consisting of SEQ ID NO:11.

Exemplary dosing schemes for ApoE4 carriers and ApoE4 non-carriers are described in Table 6 below: Table 6: Dosing Scheme for Anti-AP Antibody by n Dose (Month) 1 2 3 4 5 6 7 to Regimen Dose ( mg/kg) ApoE Low Dose 1 1 3 3 3 3 3 £4 (+) High Dose 1 1 1 3 3 3 3 6 High Dose 2 1 1 3 3 6 6 10 Placebo saline ApoE Low Dose 1 1 3 3 3 3 6 £4 (-) High Dose 1 1 3 3 6 6 10 Placebo saline The exemplary protocols discussed above optimize efficacy with safety requirements.

In certain embodiments of the invention, the patient's susceptibility to vasogenic edema (VE) is reduced, or the patient's susceptibility to cerebral microhemorrhages (mH) is reduced, or both VE and mH are reduced in the patient.

Variations of these preferred protocols are also possible. A dosing scheme of multiple doses of 1 mg/kg of the patient's body weight of the anti-A� antibody at periodic intervals n doses, followed by multiple doses of 3 mg/kg at periodic intervals between doses can be employed. For example, a dosing scheme comprises 2 doses of 1 mg/kg of the t's body weight at intervals of 4 weeks between doses, followed by 4 doses of 3 mg/kg at intervals of 4 weeks between doses. Another example of this dosing scheme comprises 2 doses of 1 mg/kg of the patient's body weight at als of 4 weeks n doses, ed by multiple doses of 3 mg/kg at intervals of 4 weeks n doses until treatment is terminated. Another example of this dosing scheme comprises 4 doses of 1 mg/kg of the patient's body weight at intervals of 4 weeks between doses, followed by multiple doses of 3 mg/kg at intervals of 4 weeks between doses until treatment is terminated. Given that ARIA lly occurs between doses 2 and 5, this abbreviated protocol can provide an additional margin of safety. Thus, it may not be ary for patients to continue to titrate to 6 mg/kg, but rather escalation of the dose can be stopped at about 3 mg/kg of the patient's body weight.

Another variation ofthese preferred protocols comprises a dosing scheme of multiple doses of 1 mg/kg of the patient's body weight of the anti-A� antibody at periodic intervals between doses, followed by multiple doses of 3 mg/kg at ic intervals n doses can be employed, and finally multiple doses of 6 mg/kg of the patient's body weight at periodic intervals between doses until treatment is terminated. An e of this dosing scheme comprises 2 doses of 1 mg/kg of the patient's body weight at intervals of4 weeks between doses, followed by 4 doses of 3 mg/kg at intervals of4 weeks between doses can be employed, and finally le doses of 6 mg/kg of the patient's body weight until the treatment is terminated.

In another embodiment, an exemplary dosing scheme begins with dosing at 3 mg/kg of the patient's body weight at intervals of4 weeks between doses (e.g., 2 doses, 4 doses, 5 doses), followed by multiple doses (e.g., 2 doses, 4 doses, 5 doses, 6 doses, 10 doses) at 6 mg/kg ofthe patient's body weight at intervals of4 weeks between doses, followed by multiple doses (e.g., 2 doses, 4 doses, 5 doses, 6 doses, 10 doses, 15 doses, 20 doses) at 10 mg/kg ofthe patient's body weight at als of4 weeks between doses until the treatment is terminated. An optional dose at 1 mg/kg ofthe patient's body weight at intervals of4 weeks between doses (e.g., 2 doses, 4 doses, 5 doses) may be administered prior to dosing at 3 mg/kg, if desired. The subject can be an ApoE4 carrier or an ApoE4 non-carrier.

In a further embodiment of the invention, titration of the monoclonal antibody to the patient can be dispensed with if the patient exhibits the appropriate responses without the titration steps. In this event, for example, an ApoE4 carrier can be administered a dose of the monoclonal antibody of 1 mg/kg, or 3 mg/kg, 6 mg/kg, or 10 mg/kg ofthe patient's body weight ofthe � antibody, and an ApoE4 rrier can be administered a dose of 3 mg/kg, or 6 mg/kg, or 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, or 30 mg/kg ofthe patient's body weight ofthe anti-A� antibody. A total of 14 doses can be stered about 4 weeks apart over about 52 weeks, optionally uing to dose about every 4 weeks thereafter, to thereby treat AD with d susceptibility of the patient to ARIA.

Managing ARIA During Treatment With An Anti-A/J Antibody Despite the methods described above to prevent or reduce the likelihood of occurrence ARIA, in some instances, a patient may develop ARIA (ARIA-E and/or ARIAH ). This disclosure also provides methods of modifying the treatment ofsuch patients. The methods can involve dose suspension, and/or dose modification, and/or termination of treatment with the anti-A� dy. (1) Disposition of ARIA-E Cases Table 7 below provides a disposition plan for ARIA-E cases that may arise during the treatment regimens described above.

Table 7: Disposition Plan for ARIA-E Cases Clinical ARIA-E Severity on MRI Symptom Severity Mild Moderate I Severe Suspend dosing.

Once ARIA-E resolves the subject may resume Continue dosing at dosing at the same dose. If the subject previously Asymptomatic current dose and had ARIA-E or ARIA-H that ed dose schedule suspension, the subject will resume at the next lower dose.

Moderate Suspend dosing. Once ARIA-E and clinical ms resolve, the subject Severe may resume dosing at the same dose. If the subject previously had ARIA-E Serious "other or ARIA-H that required dose suspension, the subject will resume at the medically next lower dose. important event" only1 Serious, except for "other medically Discontinue dosing event"2 1 "Other medically important events" requiring dose suspension include serious adverse events (SAEs) that are not hreatening (in the opinion ofthe Investigator), do not e inpatient hospitalization or gation of existing hospitalization, and do not result in significant/permanent disability or congenital anomalies/fetal defects, but may (in the opinion of the Investigator) jeopardize the subject or may require intervention to prevent one of the es listed above. 2 SAEs requiring permanent discontinuation of study treatment e those that are life­ threatening (in the opinion of the Investigator), require ent hospitalization or prolongation of existing hospitalization, and/or result in persistent or significant disability/incapacity or a congenital anomaly/birth defect.

The severity of clinical symptoms are d as follows: Mild: Symptom(s) barely noticeable to subject or does not make subject uncomfortable; does not influence performance or functioning; iption drug not ordinarily needed for relief of symptom(s) but may be given because of ality of subject.

Moderate: Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily activity is influenced; subject is able to continue in study; treatment for symptom(s) may be needed.

Severe: Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant impact on subject's daily life; severity may cause cessation of treatment with study treatment; ent for symptom(s) may be given and/or subject hospitalized.

The severity -E is defined as follows: Mild ARIA-E: mild Fluid-attenuated inversion recovery (FLAIR) hyper-intensity confined to sulcus and/or cortex or tical white matter (with or without gyral swelling and sulcal effacement) which affects an area of less than 5 cm in single greatest dimension.

Only a single region of involvement detected.

Moderate ARIA-E: moderate involvement area of FLAIR hyper-intensity ing -10 cm in single greatest dimension, or more than one site ofinvolvement, each measuring less than 10 cm in single greatest dimension.

Severe ARIA-E: severe involvement (area of FLAIR hyper-intensity measuring r than 10 cm in single greatest dimension), often with significant subcortical white matter and/or sulcal ement (with associated gyral swelling and sulcal effacement). One or more separate/independent sites of involvement may be ) According to Table 7, patients who develop mild , per MRI read, with no clinical symptoms at any time during treatment with the anti-A� antibody (e.g., BIIB037) can continue treatment with the anti-A� antibody at their current dose. Patients should have an MRI approximately every 4 weeks until the ARIA-E has resolved per the MRI read. Patients should also have an MMSE at every scheduled visit until the ARIA-E resolves. A health care tioner may require that the patients discontinue dosing, or continue dosing at a lower dose level, based on review of safety and MRI data.

Patients who p moderate or severe ARIA-E, per MRI read, with no clinical symptoms at any time during ent with the anti-A� antibody should temporarily suspend treatment, but should complete all scheduled clinic visits for assessments and, in addition, have an unscheduled visit for an MRI approximately every 4 weeks until the ARIA-E has resolved per MRI. These ts should also have an MMSE at every scheduled visit until the ARIA-E resolves. If the ARIA-E has resolved and the subject remains asymptomatic, the patient may resume treatment at the same dose of the anti-A� antibody. If the patient previously had ARIA-E or ARIA-H that required dose suspension, the patient should resume at the next lower dose of the anti-A� antibody.

Patients who develop mild, moderate, or severe ARIA-E, per MRI read, accompanied by mild, moderate, severe, or serious ("other medically important event" only) clinical symptoms at any time during treatment with the anti-A� antibody should temporarily suspend treatment, but should complete all schedule clinic visits for assessments and, in on, have an unscheduled visit for an MRI imately every 4 weeks until the ARIA-E has resolved per the MRI. Patients should also have an MMSE at every scheduled visit until the ARIA-E resolves. If the ARIA-E has resolved and the clinical symptoms have resolved, the patient may resume treatment at the same dose of the anti-A� antibody. If the patient previously had ARIA-E or ARIA-H that required dose suspension, the patient will resume at the next lower dose of the anti-A� antibody.

Patients who p mild, moderate, or severe ARIA-E, per MRI read, accompanied by s (except "other medically important event") clinical symptoms at any time during the treatment with the � antibody should discontinue treatment with the anti-A� antibody. Patients should complete all scheduled clinic visits for assessments and in addition, have an unscheduled visit for an MRI imately every 4 weeks until the ARIA-E has resolved per centrally read MRI. Patients will also have an MMSE at every scheduled visit until the ARIA-E resolves.

If a patient has a third e of ARIA that requires dose suspension, the patient discontinues ent with the anti-A� antibody. (2) ition of ARIA-H (Microhemorrhage) Cases Table 8 below provides a disposition plan for ARIA-H (microhemorrhage) cases that may arise during the treatment ns described above.

Table 8: Disposition Plan for ARIA-H (Microhemorrhage) Cases Clinical Cumulative Microhemorrhages1 Symptom Severity 1-4 5-9 2: 10 Suspend dosing. Once ARIA-His stable the subject may resume dosing ue dosing at at the same dose. If the Asymptomatic current dose and subject previously had schedule ARIA-E or ARIA-H that required dose suspension, the subject will resume at the next lower dose.

Moderate Suspend dosing. Once ARIA-His stable and Discontinue dosing Severe clinical symptoms resolve, the subject may resume dosing at same dose. If the subject previously had Serious "other ARIA-E or ARIA-Hthat required dose suspension, medically the t will resume at the next lower dose. important event" only2 Serious, except for "other Discontinue dosing medically important event"3 ative emorrhages = cumulative microhemorrhages on treatment; does not include microhemorrhages at baseline. 2 "Other medically important events" requiring dose suspension include SAEs that are not hreatening (in the opinion of the Investigator), do not require inpatient hospitalization or prolongation of existing hospitalization, and do not result in significant/permanent disability or congenital anomalies/fetal defects, but may (in the opinion of the Investigator) jeopardize the subject or may require intervention to prevent one of the outcomes listed above. 3 SAEs ing permanent discontinuation of study treatment include those that are life­ threatening (in the n of the Investigator), require inpatient hospitalization or prolongation ofexisting hospitalization, and/or result in persistent or significant disability/incapacity or a congenital anomaly/birth defect.

The ty of clinical symptoms are defined as follows: Mild: Symptom(s) barely able to subject or does not make subject uncomfortable; does not nce performance or functioning; prescription drug not ordinarily needed for relief of symptom( s) but may be given because of ality of subject.

Moderate: Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily activity is influenced; subject is able to continue in study; treatment for symptom(s) may be .

Severe: Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant impact on subject's daily life; severity may cause cessation of treatment with study treatment; treatment for symptom(s) may be given and/or subject hospitalized.

The severity ofARIA-H(microhemorrhage) is defined as follows: Mild: 1-4 microhemorrhages Moderate: 5-9 microhemorrhages Severe: 2:: 10 microhemorrhages Patients who develop 2:: 1 and :S 4 tive emorrhage(s) with no clinical symptoms during treatment with the anti-A� antibody may continue treatment at the current dose, but must have an unscheduled visit for an MRI approximately every 2 weeks until the microhemorrhage is confirmed stable per MRI. The microhemorrhage is considered stable if it is unchanged between 2 consecutive MRis including the initial detection MRI and the MRI performed 2 weeks later. Patients should also have an MMSE at every scheduled visit until the is stable.

Patients who develop 2:: 5 and :S 9 cumulative emorrhages with no clinical symptoms during treatment with the anti-A� antibody should temporarily suspend treatment, but should complete all scheduled clinic visits for assessments and, in addition, have an unscheduled visit for an MRI approximately every 2 weeks until the microhemorrhage is confirmed stable per the MRI. A microhemorrhage is considered stable if it is unchanged between 2 consecutive MRis including the initial ion MRI and the MRI med 2 weeks later. Patients will also have an MMSE at every scheduled visit until the ARIA-His stable. Once the microhemorrhage is deemed stable, patients may resume treatment at the same dose. If the subject previously had ARIA-E or ARIA-Hthat required dose suspension, the subject will resume at the next lower dose.

Patients who p :S 9 cumulative microhemorrhage(s) and mild, moderate, severe, or s r medically important event") al symptoms should temporarily suspend treatment with the anti-A� antibody, but should complete all scheduled clinic visits for assessments and, in addition, have an unscheduled visit for an MRI approximately every 2 weeks until the microhemorrhage(s) is med stable per MRI. A emorrhage is considered stable if it is unchanged between 2 utive MRis including the initial detection MRI and the MRI performed 2 weeks later. Patients should also have an MMSE at every scheduled visit until the ARIA-His stable. Once the microhemorrhage(s) is deemed stable and the al symptoms have ed, the patient may resume treatment at the same dose of the anti-A� antibody. If the subject previously had ARIA-E or ARIA-Hthat required dose suspension, the patient will resume at the next lower dose of the anti-A� antibody.

Patients who experience serious (except "other medically important event") clinical symptoms associated with microhemorrhage(s) should discontinue treatment, but should complete all scheduled clinic visits for assessments and in addition, have an unscheduled visit for an MRI approximately every 2 weeks until the microhemorrhage(s) is confirmed stable per MRI. Patients will also have an MMSE at every scheduled visit until the ARIA-His ts who p 2:: 10 cumulative microhemorrhages, regardless of symptom severity, during treatment with the anti-A� antibody should discontinue treatment. Patients should complete all scheduled clinic visits for assessments and in addition, have an unscheduled visit for an MRI imately every 2 weeks until the microhemorrhages are deemed stable per MRI. Patients will also have an MMSE at every scheduled visit until the ARIA-His stable.

If a t has a third episode ofARIA that requires dose suspension, the subject discontinues ent. (3) Disposition ofARIA-H(Superficial Siderosis) Cases Table 9 below provides a disposition plan for ARIA-H(superficial siderosis) cases that may arise during the treatment regimens described above.

The severity ofclinical symptoms are defined as follows: Mild: Symptom(s) barely noticeable to t or does not make subject uncomfortable; does not influence performance or functioning; prescription drug not rily needed for relief of symptom(s) but may be given because of personality of subject.

Moderate: Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily activity is influenced; subject is able to continue in study; treatment for symptom(s) may be needed.

Severe: Symptom(s) cause severe discomfort; symptoms cause citation or significant impact on subject's daily life; severity may cause ion of treatment with study treatment; treatment for symptom(s) may be given and/or subject hospitalized.

The severity ofARIA-H(superficial siderosis) is defined as follows: Mild Area ofsuperficial siderosis: 1 new focal region Moderate Area ofsuperficial siderosis: 2 new focal regions Severe Area ofsuperficial siderosis: >2 new focal regions.

Table 9: Disposition Plan for ARIA-H (Superficial Siderosis) Cases Clinical Cumulative Areas of Superficial Siderosis1 Symptom Severity 1 2 >2 Suspend dosing. Once ARIA-His stable the subject may resume dosing at the Continue dosing at same dose. Ifthe subject Asymptomatic current dose and previously had ARIA-E or schedule ARIA-Hthat required dose suspension, the subject will resume at the next lower dose.

Moderate Suspend dosing. Once ARIA-His stable and clinical Discontinue dosing Severe symptoms resolve, the t may resume dosing at the same dose. If the subject previously had ARIA-E Serious "other or ARIA-Hthat required dose suspension, the subject medically will resume at the next lower dose. event" only2 Serious, except for "other Discontinue dosing medically important 1 Cumulative superficial sis = cumulative superficial siderosis on treatment. 2"Other medically important events" requiring dose suspension e SAEs that are not life-threatening (in the opinion ofthe Investigator), do not require inpatient hospitalization or gation of existing hospitalization, and do not result in significant/permanent disability or congenital ies/fetal defects, but may (in the opinion of the Investigator) jeopardize the subject or may require intervention to prevent one of the outcomes listed above. 3 SAEs requiring permanent discontinuation of study ent include those that are life­ ening (in the opinion of the Investigator), require inpatient hospitalization or prolongation ofexisting hospitalization, and/or result in persistent or significant disability/incapacity or a congenital y/birth defect.

Patients who develop a single focal area ofsuperficial sis with no clinical symptoms may continue treatment with the anti-A� antibody at the current dose, but must have an duled visit for an MRI approximately every 2 weeks until the superficial siderosis is confirmed stable per the centrally read MRI. Superficial sis is considered stable if it is unchanged between 2 consecutive MRis including the initial detection MRI and the MRI performed 2 weeks later. Patients will also have an MMSE at every led visit until the ARIA-His stable.

Patients who develop 2 cumulative focal areas of icial siderosis occurring during treatment with the anti-A� antibody with no clinical symptoms should temporarily suspend ent but should complete all scheduled clinic visits for assessments and, in addition, have an duled visit for an MRI approximately every 2 weeks until the superficial siderosis is confirmed stable per MRI. Superficial siderosis is considered stable if it is unchanged between 2 consecutive MRis including the initial detection MRI and the MRI med 2 weeks later. Patients should also have an MMSE at every scheduled visit until the ARIA-His stable. Once the superficial siderosis is deemed stable, the t may resume treatment at the same dose. If the patient previously had ARIA-E or ARIA-Hthat required dose suspension, the t will resume at the next lower dose.

Patients who develop :S 2 cumulative focal areas of superficial siderosis and mild, moderate, severe, or serious ("other medically important event" only) al symptoms should temporarily d treatment with the anti-A� antibody, but should complete all scheduled clinic visits for assessments and, in addition, have an unscheduled visit for an MRI approximately every 2 weeks until the superficial siderosis is confirmed stable per the centrally read MRI. Superficial siderosis is considered stable if it is unchanged n 2 consecutive MRis including the initial detection MRI and the MRI performed 2 weeks later.

Patients will also have an MMSE at every scheduled visit until the ARIA-His stable. Once the superficial siderosis is deemed stable and the clinical symptoms have resolved, the patient may resume treatment at the same dose. If the patient previously had ARIA-E or ARIA-H that required dose suspension, the patient should resume at the next lower dose of the anti-A� antibody.

Patients who experience serious (except "other medically ant event") clinical symptoms associated with superficial siderosis will discontinue treatment with the anti-A� antibody, but should complete all scheduled clinic visits for assessments and in addition, have an unscheduled visit for an MRI imately every 2 weeks until the superficial siderosis is confirmed stable per MRI. Patients should also have an MMSEat every scheduled visit until the is stable.

Patients who develop > 2 cumulative focal areas ofsuperficial siderosis, less of clinical symptom severity, should discontinue treatment with the anti-A� antibody, but should complete all scheduled clinic visits for assessments and, in addition, have an unscheduled visit for an MRI approximately every 2 weeks until the superficial siderosis is confirmed stable per centrally read MRI. Patients should also have an MMSEat every scheduled visit until the ARIA-His stable.

If a patient has a third episode ofARIA that requires dose suspension, the patient discontinues treatment. (4) Disposition of Cases Where ARIA-His Coincident with ARIA-E Patients who p ARIA-Hcoincident with ARIA-Eat any time during treatment with the anti-A� antibody should follow the most restrictive guidelines of the guidelines discussed above. Prior to resuming treatment, where applicable, ARIA-Emust resolve, ARIA-Hmust be deemed , and the subject must be asymptomatic. (5) ition of ARIA-H(Macrohemorrhage) Cases ts who develop any incident macrohemorrhage, regardless of symptom severity during the study, must discontinue treatment with the anti-A� antibody, but should complete all scheduled clinic visits for assessments and, in addition, have an unscheduled visit for MRI approximately every 2 weeks until the macrohemorrhage is confirmed stable per MRI. ts should also have an MMSEat every scheduled visit until the macrohemorrhage is stable.

The ty ofARIA-H(Macrohemorrhage) is defined as follows: Mild: 1-2 cm in the st diameter Moderate: 2-4 cm in the greatest diameter Severe: >4 cm in the greatest diameter ( 6) ary Methods of Treating Patients Who Develop ARIA on Standard Dose Regimens In instances where a patient who is on a standard dose of the anti-A� antibody ps moderate or severe ARIA-Ewith no clinical symptoms a dose sion is required until the ARIA-Eresolves. Once the ARIA-Eis resolved, the patient can be administered the same dose that she/he was being administered immediately before development of the moderate or severe ARIA-E. If this t previously had ARIA-E or ARIA-Hthat required dose suspension, the patient should be administered a lower dose of the � antibody than that she/he was being administered immediately before development of the most recent moderate or severe ARIA-E. For e, if a patient on a standard dose of 6 mg/kg of the anti-A� dy develops te or severe ARIA-E with no al symptoms, treatment of the patient with the anti-A� antibody should be suspended until the ARIA-E resolves, after which the patient can continue treatment with 6 mg/kg of the anti-A� antibody. If, r, this patient had previously developed ARIA-E or ARIA-H that required dose sion, once the ARIA resolves, the patient should be stered a lower dose (e.g., 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg) of the anti-A� antibody.

In instances where a patient who is on a standard dose of the anti-A� antibody develops mild, moderate, or severe ARIA-E with mild, moderate, severe, or serious clinical symptoms a dose suspension is required until the ARIA-E resolves. Once the ARIA-E is resolved and clinical symptoms resolve, the patient can be administered the same dose that she/he was being administered immediately before development of the moderate or severe ARIA-E. If this patient previously had ARIA-E or ARIA-Hthat required dose suspension, the patient should be administered a lower dose of the anti-A� antibody than that she/he was being administered immediately before development of the most recent moderate or severe ARIA-E with mild, moderate, severe, or s clinical symptoms. For example, if a patient on a standard dose of 6 mg/kg of the anti-A� antibody develops mild, moderate, or severe ARIA-E with mild, moderate, severe, or serious clinical symptoms, ent of the patient with the anti-A� antibody should be suspended until the ARIA-E resolves and clinical symptoms resolve, after which the patient can continue treatment with 6 mg/kg of the anti-A� antibody. If, however, this patient had previously developed ARIA-E or ARIA-Hthat required dose suspension, once the ARIA resolves and clinical ms resolve, the patient should be administered a lower dose (e.g., 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg) of the anti-A� antibody.

In instances where a patient who is on a standard dose of the anti-A� antibody develops 5 to 9 cumulative microhemorrhages with no clinical symptoms a dose suspension is required until the ARIA-His stable. Once the ARIA-His , the patient can be stered the same dose that she/he was being administered immediately before development of 5 to 9 cumulative microhemorrhages. If this patient previously had ARIA-E or that required dose suspension, the patient should be administered a lower dose of the anti-A� antibody than that she/he was being administered immediately before development of the 5 to 9 tive microhemorrhages. For example, if a patient on a standard dose of 6 mg/kg of the anti-A� antibody develops 5 to 9 cumulative microhemorrhages with no clinical symptoms, treatment of the patient with the � antibody should be suspended until the ARIA-His stable, after which the patient can continue treatment with 6 mg/kg of the anti-A� antibody. If, however, this t had previously developed ARIA-E or ARIA-Hthat required dose suspension, once the ARIA-H stabilizes, the patient should be administered a lower dose (e.g., 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg) of the anti-A� antibody.

In instances where a patient who is on a standard dose of the anti-A� antibody develops 1 to 9 tive microhemorrhages with mild, moderate, severe, or serious clinical symptoms a dose suspension is required until the ARIA-His stable. Once the ARIA-His stable and clinical symptoms resolve, the patient can be administered the same dose that she/he was being administered immediately before development of 1 to 9 cumulative microhemorrhages. If this patient previously had ARIA-E or ARIA-Hthat required dose suspension, the patient should be administered a lower dose of the anti-A� antibody than that she/he was being administered immediately before development of the 1 to 9 cumulative microhemorrhages with mild, moderate, severe, or serious clinical symptoms. For example, if a patient on a standard dose of 6 mg/kg of the anti-A� antibody develops 1 to 9 cumulative microhemorrhages with mild, moderate, severe, or serious al symptoms, treatment of the patient with the anti-A� antibody should be suspended until the ARIA-His stable and clinical symptoms resolve, after which the t can continue treatment with 6 mg/kg of the anti-A� antibody. If, however, this t had previously developed ARIA-E or ARIA-H that required dose suspension, once the ARIA-Hstabilizes and clinical symptoms resolve, the patient should be stered a lower dose (e.g., 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg) of the anti-A� antibody.

In instances where a patient who is on a standard dose of the anti-A� antibody develops 2 tive areas of icial siderosis with no clinical symptoms a dose suspension is required until the ARIA-His stable. Once the is stable, the patient can be administered the same dose that she/he was being administered immediately before development of 2 cumulative areas of superficial siderosis. If this t previously had ARIA-E or ARIA-Hthat required dose suspension, the patient should be administered a lower dose of the anti-A� antibody than that she/he was being administered ately before development of the 2 tive areas of icial sis. For example, if a patient on a standard dose of 6 mg/kg of the anti-A� dy develops 2 cumulative areas of superficial siderosis with no clinical symptoms, treatment of the patient with the � antibody should be suspended until the ARIA-His stable, after which the patient can continue treatment with 6 mg/kg of the anti-A� antibody. If, however, this t had previously developed ARIA-E or ARIA-Hthat ed dose suspension, once the ARIA-H stabilizes, the patient should be administered a lower dose (e.g., 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg) of the anti-A� antibody.

Where a patient who is on a standard dose of the anti-A� dy develops 1 or 2 cumulative areas of superficial siderosis with mild, te, severe, or serious clinical symptoms a dose suspension is required until the ARIA-His stable and clinical symptoms resolve. Once the ARIA-His stable and clinical symptoms resolve, the patient can be administered the same dose that she/he was being administered immediately before pment of 2 cumulative areas of icial siderosis. If this t previously had ARIA-E or ARIA-Hthat required dose suspension, the patient should be administered a lower dose of the anti-A� antibody than that she/he was being administered immediately before development of the 1 or 2 cumulative areas of superficial siderosis. For example, if a t on a standard dose of 6 mg/kg of the anti-A� antibody develops 1 or 2 cumulative areas of superficial sis with mild, moderate, severe, or serious clinical symptoms, treatment of the patient with the anti-A� antibody should be suspended until the ARIA-His stable and clinical symptoms resolve, after which the patient can continue treatment with 6 mg/kg of the anti-A� antibody. If, however, this patient had previously developed ARIA-E or ARIA-Hthat required dose sion, once the ARIA-Hstabilizes and clinical symptoms resolve, the patient should be administered a lower dose (e.g., 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg) of the anti-A� antibody. (7) Exemplary Methods of Treating Patients Who Develop ARIA on Titration Regimens In instances where a patient who is on a titration regimen of the anti-A� antibody develops moderate or severe ARIA-E with no al symptoms a dose suspension is ed until the ARIA-E resolves. Once the ARIA-E is resolved, the patient can be administered the same dose that she/he was being administered immediately before development of the moderate or severe ARIA-E. If this patient usly had ARIA-E or ARIA-Hthat required dose sion, the patient should be administered a lower dose of the anti-A� antibody than that she/he was being administered immediately before development of the most recent ARIA requiring dose suspension. For example, if the patient is on the Protocol (5) regimen described above and develops moderate or severe ARIA-E with no clinical symptoms after step (C), treatment with the anti-A� antibody should be suspended until the ARIA-Eresolves. Once the ARIA-Eis resolved, the patient can be stered the same dose that she/he was being administered immediately before development of the moderate or severe ARIA-E(i.e., 3 mg/kg of body weight of the patient).

When treatment with the anti-A� antibody resumes after the dose suspension, patients must have a minimum of2 doses at the restarted dose (i.e., at least2 doses of 3 mg/kg). An MRI should be performed after the second administration of the restarted dose, and after the second administration of each increase in dose. After that, the patient can continue with the remaining steps of Protocol (5) (i.e., Steps (D) through (L)).

If, however, the patient being d according to the ol ( 5) regimen who ps moderate or severe with no clinical symptoms after step (C), previously had ARIA-Eor ARIA-H that required dose suspension, treatment with the anti-A� antibody should be suspended until the ARIA-Eresolves, and once the ARIA-Eresolves, this patient should be administered a lower dose of the � antibody than that she/he was being administered ately before development of the most recent moderate or severe ARIA requiring dose suspension (in this case 1 mg/kg of body weight of the patient). When treatment with the anti-A� antibody resumes after the dose suspension, patients must have a m of2 doses at the restarted dose (i.e., at least 2 doses of 1 mg/kg). An MRI should be med after the second administration of the ted dose, and after the second administration of each increase in dose. After that, the patient can continue with the remaining steps of Protocol (5) (i.e., Steps (D) through (L)).

In instances where a patient who is on a titration regimen of the anti-A� antibody develops mild, moderate, or severe ARIA-Ewith mild, moderate, or severe clinical symptoms, or clinical symptoms meeting the "other medically important" serious criteria a dose suspension is required until the ARIA-Eresolves. Once the ARIA-Eis resolved and clinical symptoms resolve, the patient can be administered the same dose that she/he was being stered immediately before development of the mild, moderate or severe ARIAE.

If this patient previously had ARIA-Eor ARIA-H that required dose suspension, the patient should be administered a lower dose of the anti-A� antibody than that she/he was being administered immediately before development of the most recent ARIA requiring dose suspension. For e, if the patient is on the Protocol (5) n bed above and ps mild, moderate or severe ARIA-Ewith mild, moderate, or severe clinical symptoms, or clinical symptoms meeting the "other medically important" serious criteria after step (E), treatment with the anti-A� antibody should be suspended until the ARIA-E resolves and the clinical symptoms resolve. Once the ARIA-E and the clinical symptoms resolve, the t can be administered the same dose that she/he was being administered immediately before development of the moderate or severe ARIA-E (i.e., 3 mg/kg of body weight of the t). When treatment with the � antibody s after the dose suspension, patients must have a minimum of2 doses at the restarted dose (i.e., at least 2 doses of 3 mg/kg). An MRI should be performed after the second administration of the restarted dose, and after the second administration of each increase in dose. After that, the patient can continue with the remaining steps of Protocol ( 5) (i.e., Steps (F) through (L) ).

If, r, the patient being treated according to the Protocol ( 5) regimen who develops mild, moderate, or severe ARIA-E with mild, moderate, or severe clinical symptoms, or clinical symptoms meeting the "other medically important" serious criteria after step (E), previously had ARIA-E or ARIA-H that required dose suspension, treatment with the anti-A� antibody should be suspended until the ARIA-E resolves and/or ARIA-H is stable and the clinical symptoms resolve, and once they resolve, this t should be administered a lower dose of the anti-A� antibody than that she/he was being administered immediately before development of the most ARIA (in this case 1 mg/kg of body weight of the patient). When ent with the anti-A� antibody resumes after the dose suspension, patients must have a minimum of2 doses at the restarted dose (i.e., at least 2 doses of 1 mg/kg). An MRI should be performed after the second stration of the restarted dose, and after the second administration of each increase in dose. Afterthat, the patient can continue with the remaining steps of Protocol (5) (i.e., Steps (F) through (L)).

If, for example, the patient is on the Protocol ( 5) regimen bed above and develops mild, moderate or severe ARIA-E with mild, moderate, , or clinical symptoms meeting the "other medically important" serious criteria after step (G), treatment with the anti-A� antibody should be suspended until the ARIA-E es and the clinical symptoms resolve. Once the ARIA-E and the clinical symptoms resolve, the patient can be administered the same dose that she/he was being administered immediately before pment of the moderate or severe ARIA-E (i.e., 6 mg/kg of body weight of the patient).

When treatment with the anti-A� antibody resumes after the dose suspension, patients must have a minimum of2 doses at the restarted dose (i.e., at least 2 doses of 6 mg/kg). An MRI should be performed after the second administration of the restarted dose, and after the second administration of each increase in dose. After that, the patient can continue with the ing steps of Protocol (5) (i.e., Steps (H) h (L)). If, however, the patient being treated ing to the Protocol (5) regimen who develops mild, moderate, or severe ARIAE with mild, moderate, severe, or serious clinical symptoms afterstep (G), previously had ARIA-E or ARIA-Hthat required dose suspension, treatment with the anti-A� antibody should be suspended until the ARIA-E resolves and the clinical symptoms e, and once they resolve, this patient should be administered a lower dose of the anti-A� antibody than that she/he was being administered immediately before development of the most recent moderate or severe ARIA-E (in this case 3 mg/kg of body weight of the patient). When treatment with the anti-A� antibody s after the dose suspension, patients must have a minimum of 2 doses at the restarted dose (i.e., at least 2 doses of 3 . An MRI should be performed after the second administration of the restarted dose, and after the second administration of each increase in dose. After that, the patient can continue with the remaining steps of Protocol (5) (i.e., Steps (F) h (L)).

In instances where a patient who is on a titration regimen of the anti-A� dy develops 5 to 9 cumulative microhemorrhages with no clinical symptoms a dose suspension is required until the ARIA-His stable. Once the ARIA-His stable, the patient can be administered the same dose that she/he was being administered immediately before development of 5 to 9 tive microhemorrhages. If this patient previously had ARIA-E or ARIA-Hthat required dose suspension, the t should be administered a lower dose of the anti-A� antibody than that she/he was being stered immediately before pment of the 5 to 9 cumulative microhemorrhages. For example, if a patient on the Protocol (5) treatment n of the anti-A� antibody develops 5 to 9 cumulative microhemorrhages with no clinical symptoms after step (D), treatment of the patient with the anti-A� antibody should be suspended until the ARIA-His stable, after which the patient can continue treatment with the same amount of the anti-A� antibody of step (D) (i.e., 3 mg/kg of body weight of the patient). When treatment with the anti-A� dy resumes after the dose suspension, patients must have a minimum of 2 doses at the restarted dose (i.e., at least 2 doses of 3 mg/kg). After that, the patient can continue with the remaining steps of Protocol (5) (i.e., Steps (E) through (L)).

If, however, this patient had previously developed ARIA-E or ARIA-Hthat required dose suspension, once the ARIA-Hstabilizes, the patient should be administered a lower dose of ol (5) (i.e., 1 mg/kg of the body weight of the patient) of the anti-A� antibody. The patient is administered a minimum of 2 doses of 1 mg/kg of the body weight of the patient of the � antibody. After that, the patient may continue with the remaining steps of Protocol (5) (i.e., Steps (E) through (L)).

In instances where a patient who is on a titration regimen of the anti-A� antibody develops 1 to 9 tive microhemorrhages with mild, te, severe, or serious clinical symptoms a dose suspension is required until the ARIA-His stable and the clinical symptoms resolve. Once the ARIA-His stable and the al symptoms resolve, the patient can be administered the same dose that she/he was being administered immediately before development of 1 to 9 cumulative microhemorrhages. If this patient previously had ARIA-E or ARIA-Hthat required dose suspension, the patient should be administered a lower dose of the anti-A� antibody than that she/he was being administered immediately before development of the 1 to 9 cumulative microhemorrhages with mild, moderate, or severe clinical symptoms, or clinical symptoms meeting the "other medically important" serious criteria. For example, if a patient on Protocol ( 5) ps 1 to 9 cumulative microhemorrhages with mild, te, severe, or serious clinical symptoms, after step (E), treatment of the patient with the anti-A� antibody should be suspended until the ARIA-His stable and clinical symptoms resolve, after which the t can continue ent with the same amount of the anti-A� antibody as used in step (E) (i.e., 3 mg/kg of body weight of the patient). When treatment with the anti-A� antibody resumes after the dose suspension, patients must have a minimum of 2 doses at the restarted dose (i.e., at least 2 doses of 3 mg/kg). After that, the patient can continue with the remaining steps of ol (5) (i.e., Steps (F) through (L)).

If, however, this patient had previously developed ARIA-E or ARIA-Hthat required dose suspension, once the ARIA-Hstabilizes and clinical symptoms resolve, the patient should be administered a lower dose (i.e., 1 mg/kg of body weight of the patient) of the anti­ A� antibody. The patient is stered a minimum of 2 doses of 1 mg/kg of the body weight of the patient of the anti-A� antibody. After that, the patient may continue with the remaining steps of Protocol (5) (i.e., Steps (F) through (L)).

In instances where a patient who is on a titration regimen of the anti-A� antibody develops 2 cumulative areas of superficial siderosis with no clinical symptoms a dose suspension is ed until the is stable. Once the ARIA-His stable, the patient can be administered the same dose that she/he was being administered immediately before development of 2 tive areas of superficial siderosis. If this t previously had ARIA-E or ARIA-Hthat required dose suspension, the patient should be administered a lower dose of the � antibody than that she/he was being administered immediately before pment of the 2 cumulative areas of icial siderosis. For example, if a patient on Protocol ( 5) develops 2 tive areas of superficial siderosis with no clinical symptoms after step (E), treatment of the patient with the anti-A� antibody should be suspended until the ARIA-His stable, after which the t can continue treatment with the same amount of the antibody as in step (E) (i.e., 3 mg/kg of body weight of the patient). The patient is administered a minimum of 2 doses of 3 mg/kg of the body weight of the t of the anti-A� antibody. After that, the patient can continue with the remaining steps of Protocol (5) (i.e., Steps (F) through (L)).

If, however, this patient had previously developed ARIA-E or ARIA-Hthat ed dose suspension, once the ARIA-Hstabilizes, the patient should be administered a minimum of 2 doses of the next lower dose of the ol (i.e., 1 mg/kg of body weight of the patient) of the anti-A� antibody. After that, the patient may continue with the remaining steps of ol (5) (i.e., Steps (F) through (L)).

Where a t who is on a titration regimen of the anti-A� dy develops 1 or 2 cumulative areas of icial siderosis with mild, moderate, or severe clinical symptoms, or clinical symptoms meeting the "other medically important" serious criteria a dose suspension is ed until the ARIA-His stable and clinical symptoms resolve. Once the ARIA-His stable and the clinical symptoms resolve, the patient can be administered the same dose that she/he was being administered ately before development of 2 cumulative areas of superficial siderosis. If this t previously had ARIA-E or ARIA-H thatrequired dose suspension, the patient should be administered a lower dose of the anti-A� antibody than that she/he was being administered immediately before development of the 1 or 2 cumulative areas of superficial siderosis. For example, if a patient on Protocol (5) develops 1 or 2 cumulative areas of superficial siderosis with mild, te, severe, or serious clinical symptoms after Step (C), ent of the patient with the anti-A� antibody should be suspended until the ARIA-His stable and clinical symptoms resolve, after which the patient can continue ent with a minimum of two doses of the same amount of the anti-A� antibody as Step (C) of Protocol (5) (i.e., 3 mg/kg of the body weight of the patient). After that, the patient can continue with the remaining steps of Protocol (5) (i.e., Steps (D) through (L)).

If, however, this patient had previously developed ARIA-E or ARIA-Hthat required dose suspension, once the ARIA-Hstabilizes and clinical symptoms resolve, the patient should be administered a minimum of two doses of the next lower amount of the anti-A� antibody of Protocol (5) (i.e., 1 mg/kg of the body weight of the patient). After that, the patient may continue with the remaining steps of ol (5) (i.e., Steps (D) through (L)). (8) Restarting Treatment after Dose Suspension Due to ARIA In all of the above cases, when treatment with an anti-A� antibody (e.g., BIIB037) resumes after a dose suspension, patients must have a minimum of 2 doses at the restarted dose. An MRI should be performed after the second administration of the restarted dose, and after the second administration of each increase in dose.

Measurement and Reduction in the Symptoms ofAD Measurement of the risk, existence, severity, and progression of AD can be determined by al sis over time; assessment of the global functional level of the patient; evaluation of the daily living capacities or behavioral deficits; volumetric analysis of brain structures; in vivo measurement of pathological deposits of abnormal proteins in brain (e.g. PET beta-amyloid imaging), or biochemical variables in body fluids (e.g. tau proteins or A� peptides); and by comparison to the natural course/history of the disease.

The ing clinical assessments can be employed in determining the stage of AD in the patient: CDR, FCSRT, Neuropsychiatric Inventory-Questionnaire ), and a neuropsychological test y comprising Rey Auditory Verbal Leaming Test (RA VLT) Immediate and Delayed Recall, er Memory Scale (WMS) Verbal Pair Associate Leaming Test Immediate and Delayed Recall, Delis-Kaplan Executive Function System Verbal Fluency Conditions 1 and 2, and the Wechsler Adult Intelligence Scale Fourth Edition Symbol Search and Coding Subsets; and the Cognitive Drug Research computerized test In one ment, a diagnostic regime comprises determining the change from ne on the Clinical Dementia Rating (CDR) Scale, a neuropsychological test battery, Cognitive Drug Research computerized test battery, the Free and Cued Selective ing Test (FCSRT), Mini Mental State ation (MMSE), Columbia Suicide Severity Rating Scale (C-SSRS), and Neuropsychiatric Inventory-Questionnaire (NPI-Q).

Biomarkers have emerged as essential for defining AD and for g of the disease along its spectrum. ker phenotypes can bridge the gap between clinical phenotypes and neuropathology phenotypes, such as amyloid plaques, neurofibrillary tangles, inflammation, and neurodegeneration. Biomarkers of AD include ApoE isotype, CSF A�42, d PET, CSF Tau, and hippocampal volumetric (HCV) MRI.

Amyloid plaque burden in certain areas of the brain can be measured by 18F-AV-45 PET. 18F-AV-45 is an amyloid ligand developed by Avid Radiopharmaceuticals (Philadelphia, lvania). It binds to fibrillar A� with a high affinity (Kd = 3.1 nM).

Results with 18F-AV-45 PET imaging have shown that patients with AD have selective retention of tracer in cortical areas expected to be high in amyloid deposition, whereas healthy controls have shown rapid washout from these areas, with only minimal cortical tracer retention. A icant difference in mean uptake of 18F-AV-45 has been observed between AD and age-matched control subjects. etest variance of18F-AV-45 PET imaging is low (less than 5%) in both AD patients and cognitively healthy controls. Visual interpretation of the 18F-AV-45 PET images and mean quantitative estimates of cortical uptake correlate with presence and quantity of d pathology at autopsy as measured by immunohistochemistry and silver stain neuritic plaque score (Clark CM, et al. Use of florbetapir-PET for g �-amyloid pathology. JAMA, 2011 Jan; 305(3):275-283).

Radiation dosimetry of18F-AV-45 is in the range of typical PET ligands. The average human whole body effective dose is estimated to be 0.019 mSv/MBq. A dose of370 MBq per injection has also been shown to yield good imaging results.

Patients with AD have characteristic reductions in FDG PET measurements of regional glucose metabolism, which are related to progressive impairment of cognitive function u SM, et al. Associations n cognitive, functional, and FDG-PET es of decline in AD and MCI. Neurobiol Aging, 2011 Jul;32(7):1207-18; Mielke R, et al. HMPAO SPET and FDG PET in Alzheimer's disease and vascular dementia: comparison of perfusionand metabolic pattern. Eur J Nucl Med.,1994 Oct;21(10):1052-60). The effect of anti-A� antibody in halting the progression of e lic deficit can be periodically assessed using FDG PET measurements. Radiation try of FDG is in the range of typical PET ligands. The average human whole body effective dose is estimated to be 0.019 mSv/MBq. The standard FDG imaging protocol uses a dose of 185 MBq per injection.

Patients can typically receive up to 185 MBq with each scan.

Measurement 42 and T-Tau or P-Tau levels in CSF are gaining ance as predictive biomarkers ofAD. Evidence suggests that Tau aggregation pathology is a very early event in pathogenesis. (Duyckaerts (2011) Lancet Neural. IO, 774-775, and Braak et al., (2013), Acta Neuropath., 126:631-41).

AD-related biomarkers can also be employed. These include, but are not limited, to pyroglutamate-A�, A�40, and A�42 in blood, and total Tau, phospho-Tau, pyroglutamate-A� A�40, and A�42 in CSF. metric MRI measures can also aid in the ment ofAD. These include whole brain volume, hippocampal volume, ventricle volume, and cortical gray matter volume. Cerebral blood flow as measured by ASL-MRI and functional connectivity as measured by tf-fMRI can be included in the assessment ols.

Use of an anti-A� antibody (e.g., BIIB037) for the treatment of AD patients according to the disclosure results in an improvement in one or more of these parameters over baseline measurements or at least prevents or slows the progression of AD from one stage to the next stage. ement of ARIA AD patients generally respond to anti-A� antibody (e.g., BIIB037) in a dose dependent manner. Therefore, it is advantageous to use high doses for maximum effectiveness. But the incidence or rate of ARIA can se in n patient populations when doses of the anti-A� antibody are increased. This disclosure makes it possible to reduce the incidence of ARIA in susceptible patients undergoing ent for mer's disease, especially those patients receiving high doses of the anti-A� antibody, as well as ApoE4 carriers. In ular, this disclosure makes it possible to reduce the incidence of amyloid related imaging abnormalities-edema (ARIA-E), or reduce the incidence of amyloid d imaging abnormalities-hemorrhage or hemosiderosis (ARIA-H), or reduce both ARIA-E and ARIA-H.

ARIA, including edema (ARIA-E) and microhemorrhage or hemosiderosis (ARIAH ), are readily detectable by MRI (i.e., fluid attenuated inversion recovery (FLAIR/T2 for ARIA-E and T2*/gradient echo for ). (Sperling R, et al. Amyloid-related imaging abnormalities in patients with mer's disease treated with bapineuzumab: a retrospective analysis. Lancet Neural., 2012;11(3):241-9). Susceptibility weighted imaging (SWI), an MRI que ially more sensitive than T2*/gradient echo in detecting ARIA-H (Sperling RA, et al. Amyloid-related imaging alities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimer's and Dementia, 2011;7(4):367-85), can also be employed.

Signs of vasogenic edema include hyperintense signal on T2-weighted and FLAIR sequences generally confined to the white matter and often associated with gyral swelling.

Symptoms of vasogenic edema when present include headache, worsening cognitive function, alteration of consciousness, seizures, unsteadiness, and vomiting.

ARIA-H is rable by MRI and believed to be an imaging finding without clinical correlate (i.e., patients are asymptomatic) ing RA, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimer's and Dementia, 2011;7(4):367-85). ically, hemorrhage is detectable using MRI sequences ofgradient echo, Tl-weighted, T2-weighted, and FLAIR. Microhemorrhage is usually asymptomatic, whereas macrohemorrhage typically has focal signs and symptoms reflecting the area of the affected brain as well as non-specific symptoms that include those for vasogenic edema. The frequency ofMRI acquisition is driven by safety monitoring needs.

The following are examples ofthe practice ofthe ion. They are not to be ued as limiting the scope of the invention in any way.

Examples Example 1: Toxicology study of BIIB037 in vivo The Tg2576 mouse and cynomolgus monkey were used for BIIB037 toxicology evaluation. Of the 2 species, the Tg2576 mouse is considered the primary pharmacologically nt species given that these mice accumulate amyloid plaques in the cerebral parenchyma and vasculature.

In on to the standard athologic evaluation in mice, Perls staining of hemosiderin (a breakdown product of hemoglobin) was performed to quantify microhemorrhage. emorrhage has been observed both as a background finding in transgenic mouse models of AD (Winkler DT, et al. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J. Neurosci., 2001 Mar 1;21(5):1619-27), including Tg2576 mice (Kumar-Singh S, et al. Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls. American Journal of ogy, 2005 Aug;167(2):527-43), and as a drug-related finding in transgenic mice treated with some anti-A� antibodies [Pfeifer M, et al. Cerebral hemorrhage after passive anti-A� immunotherapy. Science 2002 Nov 15;298(5597):1379; Racke MM, et al. Exacerbation of cerebral amyloid angiopathy- associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is ent on antibody recognition of deposited forms of amyloid beta. J Neurosci., 2005 Jan 3):629-36.; Wilcock OM, Colton CA.

Immunotherapy, vascular pathology, and microhemorrhages in transgenic mice. CNS & Neurological Disorders Drug Targets, 2009 Mar;8(1):50-64).

Example 2: Short term study of BIIB037 in vivo In a 13-week study, Tg2576 mice were administered weekly IV doses of 10 or 70 mg/kg of ch12F6A, or 500 mg/kg of either ch12F6A or BIIB037. l to mild acute hemorrhage was observed in 2 mice dosed at >70 week as assessed by the standard histopathologic ng. Additional findings ed a slight increase in the incidence and/or severity of meningeal vascular inflammation in mice d at >70 mg/kg/week compared with control animals, and the occurrence of thrombosis in 2 animals dosed at 500 mg/kg/week. At the end of a 6-week drug-free recovery period, the incidence and severity of findings observed in ch12F6A and BIIB037-treated mice were within the range observed in the control group throughout the study.

In addition to standard histopathology of the brain, presence of microhemorrhage was evaluated by Perls staining; no significant differences in microhemorrhage were observed n ch12F6A/BIIB037 and control treated groups after 13 weeks of .

The increased incidence and/or severity of eal ar inflammation and acute hemorrhage observed at or greater than 70 mg/kg/week contributed towards the no observed adverse effect level (NOAEL) determination of 10 mg/kg/week.

Example 3: Longer term study of BIIB037 in vivo In a 6-month study, Tg2576 mice were administered weekly N doses of 10 or 40 mg/kg of ch12F6A, or 250 mg/kg of either ch12F6A or BIIB037. There were no treatmentrelated s in any of the parameters evaluated during the main and recovery periods, with the exception of a slight increase in the combined nce and/or severity of meningeal/cerebral vascular mation and vascular thickening in the brains of main and early death animals treated with chimeric 12F6A (ch12F6A) comprising murine nt domains at doses >40 mg/kg, and an increase in area of micro hemorrhage in a subset of the 250 mg/kg ch12F6A treated animals.

There were no treatment-related findings, nor increase in the incidence and/or severity of eal/cerebral vascular inflammation and/or vascular thickening in Tg2576 mice that received weekly intravenous injection stration of 250 mg/kg 7 and no statistically significant difference in the number of foci and/or percent area of microhemorrhage in the brain of animals receiving ch12F6A or BIIB037.

After a 6-week recovery period, the incidence and/or severity of the vascular inflammation or thickening was similar across d and control groups. Although a potential treatment-related exacerbation of these changes cannot be totally excluded, the vascular inflammation, ning, and possible exacerbated microhemorrhage in the brain were considered of equivocal relationship to treatment and potentially due to the age-related degenerative changes inherent to the disease model alone. Consequently, the NOAEL is 250 mg/kg/week for this study.

No treatment-related findings were observed in a 4-week monkey study, the NOAEL was 300 mg/kg/week.

In y, the toxicology evaluation for BIIB037 identified a toxicity profile consistent with binding of the antibody to deposited A�.

Example 4: Reduction of amyloid beta in vivo In Tg2576 mice, a dose-dependent reduction in cerebral d was observed after chronic dosing with ch12F6A (0.3 mg/kg to 30 mg/kg). A significant amyloid reduction was observed at 3 mg/kg, deemed the minimal effective dose, and efficacy appeared to reach a plateau between 10 mg/kg and 30 mg/kg. The no observed adverse effect level (NOAEL) ed from a 13-week Tg2576 mouse toxicology study (10 mg/kg/week) was used for the purpose of safety margin determination.

BIIB037 mean steady state exposure in humans (calculated as AUCo-4wk) at 1 and 3 mg/kg is projected to be approximately one-twelfth and one-fourth the nonclinical NOAEL dose re (calculated as AUCo-4wk) observed in the 13-week mouse toxicology study. 7 mean steady state exposure following a 10 mg/kg dose is projected to be similar to NOAEL dose res. The highest dose, 30 mg/kg, is projected to achieve mean steady state exposures 2- to s the NOAEL exposure and one-third the exposure at the 70 mg/kg dose where slight increases in the severity of meningeal vascular inflammation and incidences of cerebral hage were observed.

Example 5: Clinical Experience with BIIB037 The first clinical study is a Phase 1, randomized, blinded, o-controlled single ascending dose (SAD) study of the , tolerability, and pharmacokinetics (PK) of BIIB037 in subjects with mild to moderate AD. Fifty-three subjects were enrolled in the SAD study.

The starting dose of BIIB037 was 0.3 mg/kg, sing to 60 mg/kg, a dose predicted to provide a mean exposure (AUCinf) that does not exceed the mean exposure in Tg2576 mice given 500 mg/kg (AUCTAU = 402000 µg*hr/mL). Doses up to 30 mg/kg (0.3, 1, 3, 10, , and 30 mg/kg) were generally well tolerated.

Two serious adverse events (SAEs) of matic amyloid related imaging abnormalities-edema (ARIA-E), and one adverse event (AE) of asymptomatic ARIA-E were reported in the 60 mg/kg cohort. Further enrollment into the 60 mg/kg cohort was terminated per study protocol. No deaths or withdrawals due to AEs were reported in the SAD study.

Serum exposures of BIIB037 have demonstrated linearity with doses up through 30 mg/kg. e 6: Clinical Study ofBIIB037 A. Phase I b Clinical Study ofBIIB037 in Human AD Subjects A Phase 1 b clinical trial was conducted. The trial was a randomized, blinded, placebocontrolled , ascending dose study ofBIIB037 in prodromal to mild AD subjects and positive amyloid scans. The primary endpoint of the trial was safety. Secondary endpoints included assessment ofthe effect on al amyloid plaque content as measured by 18F-AV-45 PET imaging. Change from baseline in 18F-AV-45 PET signal was assessed in certain brain areas. Exploratory endpoints assessed cognition in the subjects. Subjects received 1, 3, 6, or mg/kg ofBIB037 based on the t's body weight, or placebo.

B. Pre-Specified m Analysis #1 Pre-specified Interim Analysis # 1 provided 26 week data for the 1, 3, and 10 mg/kg groups and the placebo group.

The AD subjects were randomized into 4 groups, placebo, those receiving BIIB037 at 1 mg/kg of the patient's body weight, those receiving BIIB037 at 3 mg/kg ofbody weight, and those receiving BIIB037 at 10 mg/kg of body weight. There were approximately 31 subjects in each group. The average age of the ts was about 72 years (mean). Apo E4 carriers comprised to 63%, 61%, 66%, and 63%, ofthe groups, respectively.

The clinical stage ofAD in the subjects was ed. Subjects with prodromal AD comprised to 47%, 32%, 44%, and 41 % of the groups, respectively. ts with mild AD comprised to 53%, 68%, 56%, and 59% of the groups, respectively.

A static PET acquisition protocol was employed. Tracer was injected into each subject and a single scan was conducted. The tracer was AV45, a PET ligand targeting lar A� plaques.

The results ofthe amyloid PET imaging protocol were expressed as a standard update value ratio, which is a measure of the uptake ofthe oid ligand used for PET imaging and corresponds to the amount of�-amyloid present. The rdized uptake value ratio normalizes the PET signal by taking a ratio of a target region over a reference region. In the target region, specific binding and change in binding signal reflect treatment-induced modulation of pharmacology. In the reference region, nonspecific binding indicates no effect ofthe ent.

A dose-dependent reduction of amyloid was ed. There was a statistically significant reduction observed at 3 mg/kg and at 10 mg/kg at week 26. The effect appeared to continue to week 54 based on a small subset of subjects. There was no obvious ApoE modification of the observed effects. Greater effects were observed in subjects with higher baseline standard update value .

Safety and tolerability of the treatment were assessed. e events were generally mild or moderate. Headache was the most common adverse event and ed to be dosedependent.

There were no significant changes in try, hematology, urinalysis, ECGs, or vital signs. Twenty seven subjects exhibited ARIA-E or ARIA-E/H.

Higher incidence of ARIA was observed with higher BIIB037 doses and with Apo E4 carriage. Homozygous and heterozygous E4-carriers appeared to be at a similar risk for ARIA.

The onset of ARIA-E usually occurred early in the course of treatment. ARIA-E occurred at doses of 1 and 3 mg/kg after 3-5 doses (week 18 or week 10). No case was detected after the fifth dose. ARIA-E occurred at doses of 6 and 10 mg/kg after 2 doses (week 6) and at week 30. Imaging gs generally resolved in 4-12 weeks, indicating that ARIA-E was reversible.

All subjects with ARIA-H events also had ARIA-E events. The incidence of ARIA-E was greater than the incidence of ARIA-H in each of the 3 mg/kg and 10 mg/kg ent groups. The incidence of each event in the group receiving the 1 mg/kg doses was the same.

C. Pre-Specified m Analysis #2 Pre-specified Interim Analysis #2 provided 54 week data for the 1, 3, and 10 mg/kg groups and the placebo group, as well as 26 week data for the 6 mg/kg group. shows the mean PET ite standardized uptake ratio values (SUVR) by time point based on observed data for each of the treatment groups. shows that there was a reduction in amyloid burden in each of the treatment groups receiving antibody BIIB037 from baseline to week 26. There was a further reduction in amyloid burden in each of the treatment groups receiving BIIB037 between week 26 and week 54. The placebo group did not exhibit a corresponding reduction in amyloid burden. also shows that the reduction of amyloid burden by administration of BIIB037 was dose-dependent. Higher doses of BIIB037 were anied by a greater amyloid reduction in the brain using the amyloid scan. A similar effect was not observed in the placebo group. shows the adjusted mean change from baseline PET composite SUVR at week 26 by baseline al stage, namely, prodromal or mild AD. is based on observed data. shows that amyloid reduction was ependent in the amyloid scans. shows the reduction in amyloid burden by ApoE4 status of the subjects. Both the carrier group and the non-carrier group showed a reduction in amyloid burden compared to the placebo. The reduction was dose-dependent in each case.

The incidence -E and/or ARIA-Hin the study was estimated. The results are shown in The incidence ofARIA in ApoE4 rs and ApoE4 non-carriers are also reported in The incidence was dose-dependent and the ApoE4 carriage dependent at 6 and 10 mg/kg. The onset ofARIA-E was usually early in the course of treatment. ARIA-E was, in l, reversible. ARIA-Hwas stable. Imaging findings generally resolved in 4-12 weeks.

D. Clinical Assessment ofPatient Cognition Clinical assessments were employed as indicators of changes in the symptoms of Alzheimer's disease in the patients treated. Specifically, s from baseline were determined on the Clinical Dementia Rating (CDR) Scale and the Mini Mental State Examination (MMSE). The results of these ments based on observed data are summarized in FIGs. 5 and 6. shows the adjusted mean change from baseline CDR-SB for patients receiving a placebo compared with patient populations receiving 1 mg/kg, 3 mg/kg, or 10 mg/kg of antibody BIIB037. Measurements were made at week 54 of treatment with the specified doses. shows the adjusted mean change from baseline MMSE for patients receiving a o compared with patient populations receiving 1 mg/kg, 3 mg/kg, or 10 mg/kg of antibody BIIB037. Measurements were made at week 54 of treatment with the specified doses.

Example 7: Randomized, Double-blind, Placebo-controlled, Phase lbStudy ofAducanumab (BIIB037), an B Monoclonal Antibody, in Patients with mal or Mild Alzheimer's Disease: Interim Results by Disease Stage and ApoE £4 Status Aducanumab 37) is a human monoclonal antibody selective for aggregated forms of beta-amyloid (A�) peptide, including e oligomers and insoluble fibrils. A single ascending dose study ofaducanumab demonstrated acceptable safety and in patients with o-moderate AD at does up to 30 mg/kg. This Phase lb study evaluated the , tolerability, pharmacokinetics (PK), and pharmacodynamics ofaducanumab in patients with prodromal or mild AD.

The ive was to present interim safety and A� removal (change in florbetapir [18-AV-45] positron emission tomography [PET] s) with aducanumab by disease stage and ApoE £4 status.

Study Design PRIME is a multicenter, randomized, double-blind, placebo-controlled, multiple-dose study [NCT01677572].

Patients were aged 50-90 years, had stable concomitant medications, had a Mini­ Mental State Examination (MMSE) score �20 and met clinical and radiologic criteria as follows: • Prodromal AD: MMSE 24-30 spontaneous memory complaint; total free recall score :::_27 of the Free and Cued Selective ing Test; a global Clinical Dementia Rating (CDR) score of 0.5; e of significant levels of impairment in other cognitive domains; essentially preserved activities of daily living and absence of dementia; had a positive florbetapir PET scan by visual ment.

• Mild AD: MMSE 20-26; global CDR 0.5 or 1.0; meeting National Institute on Aging and Alzheimer's Association core clinical criteria for probable AD; had a positive florbetapir PET scan by visual ment.

The PRIME study design is shown in . Patients (planned N 188) were randomized to 1 of 9 treatment arms (target enrollment: n 30 per active treatment arm) in a staggered, ascending dose design at a ratio of 3: 1 active vs. placebo. Primary and secondary endpoints are presented in . The PRIME ment timeline is shown in .

PRIME is ongoing. For interim analysis, data were analyzed to Week 54 for the 1, 3, and 10 mg/kg arms and to Week 30 for the 6 mg/kg arm.

Patients Ofthe 166 patients randomized, 165 were dosed; 107 (65%) were ApoE £4 carriers, and 68 (41%) had prodromal AD. Patient disposition is shown in . Baseline demographic and disease characteristics were generally well balanced across treatment groups as shown in FIG 18.

Safety Adverse events (AE) were reported in 84%-98% of patients across treatment .

The most common AE and serious AE (SAE) were amyloid-related g abnormalities (ARIA; based on MRI) (Table 9); other AEs /SAEs were consistent with the patient population. provides a summary of ARIA findings and patient disposition following ARIA-E.

Three deaths were reported (2 with placebo, 1 with aducanumab 10 mg/kg); none were ered treatment related (2 occurred after study discontinuation). nce of isolated ARIA-edema (ARIA-E) was dose- and ApoE £4-statusdependent (): • l nce of ARIA-E among ApoE £4 carriers was 5%, 5%, 43%, and 55% for 1, 3, 6, and 10 mg/kg aducanumab, respectively, versus 0% for placebo.

• Corresponding incidence among ApoE £4 non-carriers was 0%, 9%, 11%, and 17% versus 0%.

• Incidence of isolated ARIA-microhemorrhage/hemosiderosis (ARIA-H) was similar across doses and ApoE £4 status (data not shown).

Based on small sample sizes, there was no apparent difference in incidence of ARIAE between subjects with prodromal or mild AD when accounting for ApoE £4 status (FIG.

Most (92%) ARIA-E events were observed within the first 5 doses; 65% of ARIA-E events were asymptomatic.

• When present, symptoms typically resolved within 4 weeks.

• MRI findings typically solved within 4-12 weeks.

The majority of patients (54%) who developed ARIA-E continued treatment (93% of those who continued did so at a reduced dose); no patients developed recurrent ARIA-E.

Treatment discontinuations in ts with ARIA-E were consistent across mild and prodromal subgroups (data not .

There were no significant changes in chemistry, hematology, urinalysis, electrocardiogram , or vital signs.

Brain A/J Plaque Reduction Brain A� plaque reduction was evaluated by composite SUVR from a volume of 6 regions; frontal, parietal, lateral temporal, imotor, anterior cingulate, and posterior cingulate.

Dose- and time-dependent ions in brain A� plaque nced by SUVR reduction) at weeks 26 and 54 were generally consistent across mild and prodromal AD subgroups and across ApoE £4 carriers and non-carriers within the doses tested as shown in Clinical Endpoints There was statistically significant dose-dependent slowing of decline on the exploratory endpoints, MMSE ( and CDR-sb ( at 1 year.

Conclusions There was a significant dose-and time-dependent reduciton of brain A� plaques as measured by PET Imaging versus placebo. This effect was evident at 6 months and 1 year of The pattern ofthe aducanumab effect versus placebo on A� plaque reduction was generally consistent across disease stage and ApoE £4 status.

A statistically significant dose-dependent slowing of decline on MMSE and CDR-sb was ed at 1 year. umab demonstrated an able safety profile over 54 weeks. ARIA was the main safety and tolerability finding and was able to be monitored and managed. The incidence ofARIA was dose- and ApoE-£4-status-dependent. ARIA was y observed early in the course of treatment and was asymptomatic or with mild, ent symptoms.

Interim Analysis #3 Interim Analysis #3 includes data to 54 weeks for the 6mg/kg arm and the corresponding placebo arm (which is incorporated into the pooled placebo tion for the analysis).

Brain A/J Plaque Reduction Brain A� plaque reduction was evaluated by composite SUVR from a volume of 6 regions; frontal, parietal, lateral temporal, sensorimotor, anterior cingulate, and posterior cingulate. As shown in , there was a dose-dependent reduction in brain A� plaque (evidenced by SUVR reduction) at week 54.

Clinical nts There was statistically significant dose-dependent slowing of decline on the exploratory endpoints, MMSE () and CDR-sb () at 1 year.

Other Embodiments While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope ofthe invention, which is defined by the scope of the appended claims. Other s, advantages, and modifications are within the scope of the following claims.

Various specific ments of the invention are as follows: 1. A method for treating Alzheimer’s disease (AD) in a human subject in need f, the method comprising: administering to the human subject multiple doses of an anti-beta-amyloid antibody, wherein the subject develops an Amyloid Related Imaging Abnormality (ARIA) during treatment with the anti-beta-amyloid antibody, wherein the ARIA is (i) ARIA-E that is moderate or severe and is accompanied by no clinical symptoms, (ii) ARIA-E that is mild, moderate, or severe and is accompanied by mild, moderate, severe, or serious clinical ms, (iii) ARIA-H with 5 to 9 cumulative microhemorrhages and accompanied by no clinical symptoms, (iv) ARIA-H with 1 to 9 cumulative emorrhages and accompanied by mild, moderate, severe, or serious clinical symptoms, (v) ARIA-H with 2 cumulative areas of superficial siderosis and anied by no al symptoms, or (vi) ARIA-H with 1 or 2 cumulative areas of superficial siderosis and accompanied by mild, te, severe, or serious clinical symptoms; suspending administration to the subject of the eta-amyloid antibody, after onset of the ARIA, until the ARIA resolves; and resuming administration to the subject of the same dose of the anti-beta-amyloid antibody that was administered immediately prior to the subject developing the ARIA, wherein the anti-beta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDR1) with the amino acid sequence of SEQ ID NO:3, a VHCDR2 with the amino acid sequence of SEQ ID NO:4, and a VHCDR3 with the amino acid ce of SEQ ID NO:5, and wherein the VL comprises a VLCDR1 with the amino acid sequence of SEQ ID NO:6, a VLCDR2 with the amino acid sequence of SEQ ID NO:7, and a VLCDR3 with the amino acid sequence of SEQ ID NO:8. 2. The method of embodiment 1, wherein the multiple doses of the anti-beta-amyloid antibody are doses of the same amount. 3. The method of ment 1, wherein the multiple doses of the anti-beta-amyloid antibody se doses of different amounts. 4. The method of embodiment 2, wherein the multiple doses are 1 mg/kg of body weight of the subject.

. The method of embodiment 2, wherein the multiple doses are 3 mg/kg of body weight of the subject. 6. The method of embodiment 2, wherein the le doses are 6 mg/kg of body weight of the subject. 7. The method of embodiment 2, wherein the multiple doses are 10 mg/kg of body weight of the subject. 8. The method of embodiment 2, wherein the multiple doses are 15 mg/kg of body weight of the subject. 9. The method of embodiment 2, wherein the multiple doses are 30 mg/kg of body weight of the subject.

. The method of embodiment 3, wherein the multiple doses comprise 1 mg/kg and 3 mg/kg of body weight of the subject. 11. The method of embodiment 3, wherein the multiple doses se 1 mg/kg, 3 mg/kg, and 6 mg/kg of body weight of the subject. 12. The method of embodiment 3, wherein the multiple doses comprise 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg of body weight of the subject. 13. The method of embodiment 3, wherein the subject is an ApoE4 carrier and the multiple doses comprise two or more of the doses 1 mg/kg, 3 mg/kg, or 6 mg/kg of body weight of the subject. 14. The method of ment 3, wherein the subject is an ApoE4 non-carrier and the le doses comprise two or more of the doses 1 mg/kg, 3 mg/kg, 6 mg/kg, 10 mg/kg, mg/kg, or 30 mg/kg of body weight of the subject.

. The method of any one of embodiments 1, 3, or 10 to 14, r comprising subsequently administering the eta-amyloid antibody at a dose that is higher than the dose that is administered upon resumption of administration after resolution of the ARIA. 16. The method of any one of embodiments 1 to 15, wherein the multiple doses are administered at intervals of 4 weeks. 17. The method of any one of embodiments 1 to 16, wherein the number of multiple doses administered to the subject prior to the onset of the ARIA is 2 to 14. 18. The method of any one of embodiments 1 to 14, wherein the number of multiple doses stered to the subject prior to the onset of the ARIA is 2 to 5. 19. The method of embodiment 1, wherein administering to the human subject multiple doses of the anti-beta-amyloid antibody comprises, in order, ing with step (a) performing two or more of the following administering steps prior to the onset of the ARIA: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the dy to the subject in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the t; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the t in an amount of 3 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (h) in consecutive intervals of 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject.

. The method of embodiment 19, wherein the method comprises, after tion of the ARIA, performing from the following administering steps, in order, those steps that were not performed prior to the onset of the ARIA: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the dy to the subject in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the t in an amount of 6 mg/kg of body weight of the subject; and (h) in consecutive intervals of 4 weeks after step (g), administering the antibody to the t in an amount of 6 mg/kg of body weight of the subject. 21. The method of embodiment 1, wherein stering to the human subject multiple doses of the anti-beta-amyloid antibody comprises, in order, beginning with step (a) performing two or more of the following administering steps prior to the onset of the ARIA: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the t; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the t; and (g) in consecutive intervals of 4 weeks after step (f), administering the dy to the t in an amount of 10 mg/kg of body weight of the subject, wherein the subject is an ApoE4 rrier. 22. The method of ment 21, wherein the method comprises, after resolution of the ARIA, performing from the following administering steps, in order, those steps that were not performed prior to the onset of the ARIA: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the dy to the subject in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (g) in consecutive intervals of 4 weeks after step (f), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject. 23. The method of embodiment 1, wherein administering to the human subject multiple doses of the anti-beta-amyloid antibody comprises: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; and (c) in consecutive intervals of 4 weeks after step (b), administering the dy to the subject in an amount of 3 mg/kg of body weight of the subject, wherein the subject is an ApoE4 carrier. 24. The method of any one of embodiments 1 to 23, wherein, after resuming administration of the anti-beta-amyloid antibody, the human subject develops a second ARIA that is (i) ARIA-E that is moderate or severe and is accompanied by no clinical ms, (ii) ARIA-E that is mild, moderate, or severe and is accompanied by mild, moderate, severe, or s clinical ms, (iii) ARIA-H with 5 to 9 cumulative microhemorrhages and accompanied by no al symptoms, (iv) ARIA-H with 1 to 9 cumulative microhemorrhages and accompanied by mild, moderate, severe, or serious clinical ms, (v) ARIA-H with 2 cumulative areas of superficial siderosis and accompanied by no clinical symptoms, or (vi) ARIA-H with 1 or 2 cumulative areas of superficial siderosis and accompanied by mild, moderate, severe, or serious al symptoms, and the method further comprises: suspending administration of the anti-beta-amyloid antibody to the subject until the second ARIA resolves; and resuming administration of the anti-beta-amyloid antibody to the subject at a dose that is lower than the dose that was administered to the subject immediately prior to the subject developing the second ARIA.

. The method of any one of embodiments 1 to 24, wherein the ARIA is accompanied by no clinical symptoms. 26. The method of any one of embodiments 1 to 24, n the ARIA is accompanied by mild clinical symptoms. 27. The method of any one of embodiments 1 to 24, wherein the ARIA is accompanied by moderate clinical symptoms. 28. The method of any one of embodiments 1 to 24, wherein the ARIA is accompanied by severe clinical symptoms. 29. The method of any one of embodiments 1 to 28, n administration is performed intravenously.

. The method of any one of embodiments 1 to 29, wherein: the VH consists of SEQ ID NO:1; and the VL consists of SEQ ID NO:2. 31. The method of any one of embodiments 1 to 30, wherein the antibody comprises a human IgG1 constant region. 32. The method of any one of embodiments 1 to 29, n the antibody comprises a heavy chain and a light chain, wherein: the heavy chain consists of SEQ ID NO:10; and the light chain consists of SEQ ID NO:11. 33. A method for treating Alzheimer’s disease in a human subject in need thereof, the method comprising stering to the human subject multiple doses of an anti-betaamyloid antibody, wherein the multiple doses are administered as follows: (a) administering the anti-beta-amyloid antibody to the t in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the t; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the t in an amount of 6 mg/kg of body weight of the subject; (h) 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (i) 4 weeks after step (h), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the t; (j) 4 weeks after step (i), stering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (k) 4 weeks after step (j), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (l) in consecutive intervals of 4 weeks after step (k), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject. 34. A method for treating Alzheimer’s disease in a human t in need f, the method comprising stering to the human subject multiple doses of an anti-betaamyloid antibody, wherein the multiple doses are administered as follows: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (b) 4 weeks after step (a), stering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), stering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (h) 4 weeks after step (g), stering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (i) 4 weeks after step (h), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (j) in consecutive intervals of 4 weeks after step (i), stering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject.

. A method for treating mer’s disease in a human subject in need thereof, the method comprising administering to the human subject multiple doses of an anti-betaamyloid antibody, wherein the multiple doses are administered as follows: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the dy to the t in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (g) in consecutive intervals of 4 weeks after step (f), administering the antibody to the t in an amount of 10 mg/kg of body weight of the subject. 36. A method for treating Alzheimer’s disease in a human subject in need thereof, the method comprising administering to the human subject multiple doses of an anti-betaamyloid dy, wherein the multiple doses are administered as follows: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the t in an amount of 6 mg/kg of body weight of the subject; and (e) in consecutive intervals of 4 weeks after step (d), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the t. 37. The method of any one of embodiments 33 to 36, n the human subject is an ApoE4 carrier. 38. The method of any one of embodiments 1 to 37, wherein administration is performed intravenously. 39. The method of any one of embodiments 1 to 38, n the anti-beta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH consists of SEQ ID NO:1; and the VL consists of SEQ ID NO:2. 40. The method of any one of embodiments 1 to 39, wherein the antibody comprises a human IgG1 constant region. 41. The method of any one of embodiments 1 to 38, n the anti-beta-amyloid antibody comprises a heavy chain and a light chain, wherein: the heavy chain consists of SEQ ID NO:10; and the light chain consists of SEQ ID NO:11.

WE

Claims (27)

CLAIM :

1. A method for ng Alzheimer’s disease (AD) in a human t in need thereof, the method comprising: administering to the human subject multiple doses of an anti-beta-amyloid antibody, wherein the subject develops an Amyloid Related Imaging Abnormality (ARIA) during treatment with the anti-beta-amyloid antibody, wherein the ARIA is (i) ARIA-E that is moderate or severe and is accompanied by no clinical symptoms, (ii) ARIA-E that is mild, moderate, or severe and is accompanied by mild, moderate, severe, or s clinical symptoms, (iii) ARIA-H with 5 to 9 cumulative microhemorrhages and anied by no clinical symptoms, (iv) ARIA-H with 1 to 9 cumulative microhemorrhages and accompanied by mild, moderate, severe, or serious clinical symptoms, (v) ARIA-H with 2 cumulative areas of superficial siderosis and accompanied by no clinical symptoms, or (vi) ARIA-H with 1 or 2 cumulative areas of superficial siderosis and anied by mild, moderate, severe, or serious clinical symptoms; suspending administration to the subject of the anti-beta-amyloid antibody, after onset of the ARIA, until the ARIA resolves; and resuming administration to the subject of the same dose of the anti-beta-amyloid antibody that was administered immediately prior to the subject ping the ARIA, wherein the eta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a first complementarity determining region (VHCDR1) with the amino acid sequence of SEQ ID NO:3, a VHCDR2 with the amino acid ce of SEQ ID NO:4, and a VHCDR3 with the amino acid sequence of SEQ ID NO:5, and wherein the VL comprises a VLCDR1 with the amino acid ce of SEQ ID NO:6, a VLCDR2 with the amino acid sequence of SEQ ID NO:7, and a VLCDR3 with the amino acid sequence of SEQ ID NO:8.

2. The method of claim 1, wherein the le doses of the anti-beta-amyloid antibody are doses of the same amount.

3. The method of claim 1, wherein the multiple doses of the anti-beta-amyloid antibody comprise doses of different amounts.

4. The method of claim 3, wherein the multiple doses comprise 1 mg/kg and 3 mg/kg of body weight of the subject.

5. The method of claim 3, wherein the multiple doses comprise 1 mg/kg, 3 mg/kg, and 6 mg/kg of body weight of the subject.

6. The method of claim 3, wherein the multiple doses comprise 1 mg/kg , 3 mg/kg, 6 mg/kg, and 10 mg/kg of body weight of the t.

7. The method of claim 3, n the subject is an ApoE4 carrier and the multiple doses comprise two or more of the doses 1 mg/kg, 3 mg/kg, or 6 mg/kg of body weight of the subject.

8. Th e method of claim 3, wherein the subject is an ApoE4 non-carrier and the le doses comprise two or more of the doses 1 mg/kg, 3 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg, or 30 mg/kg of body weight of the subject.

9. The method of any one of claims 1 or 3 to 8, further comprising subsequently administering the anti-beta-amyloid antibody at a dose that is higher than the dose that is administered upon resumption of administration after resolution of the ARIA.

10. The method of any one of claims 1 to 9, wherein the multiple doses are administered at intervals of 4 weeks.

11. The method of any one of claims 1 to 10, n the number of multiple doses administered to the subject prior to the onset of the ARIA is 2 to 14.

12. The method of any one of claims 1 to 11, wherein the number of multiple doses administered to the subject prior to the onset of the ARIA is 2 to 5.

13. The method of claim 1, wherein administering to the human t multiple doses of the anti-beta-amyloid antibody comprises, in order, beginning with step (a) performing two or more of the following administering steps prior to the onset of the ARIA: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the t in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the t; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the t in an amount of 6 mg/kg of body weight of the t; and (h) in consecutive intervals of 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject.

14. The method of claim 1 3, wherein the method comprises, after resolution of the ARIA, performing from the following administering steps, in order, those steps that were not performed prior to the onset of the ARIA: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the t in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the t in an amount of 6 mg/kg of body weight of the subject; and (h) in consecutive intervals of 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject.

15. The method of claim 1, wherein administering to the human subject multiple doses of the anti-beta-amyloid antibody comprises, in order, ing with step (a) performing two or more of the following stering steps prior to the onset of the ARIA: (a) administering the anti-beta-amyloid dy to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the t; and (g) in consecutive intervals of 4 weeks after step (f), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject, wherein the subject is an ApoE4 non-carrier.

16. The method of claim 15, wherein the method comprises, after tion of the ARIA, performing from the following administering steps, in order, those steps that were not performed prior to the onset of the ARIA: (a) administering the anti-beta-amyloid dy to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the t in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the dy to the subject in an amount of 6 mg/kg of body weight of the subject; and (g) in consecutive intervals of 4 weeks after step (f), administering the antibody to the t in an amount of 10 mg/kg of body weight of the subject.

17. The method of claim 1, wherein administering to the human subject multiple doses of the anti-beta-amyloid antibody comprises: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the t; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; and (c) in consecutive intervals of 4 weeks after step (b), administering the dy to the subject in an amount of 3 mg/kg of body weight of the subject, wherein the subject is an ApoE4 carrier.

18. The method of any one of claims 1 to 17, wherein, after resuming administration of the anti-beta-amyloid antibody, the human subject develops a second ARIA that is (i) ARIA-E that is te or severe and is accompanied by no clinical symptoms, (ii) ARIA-E that is mild, moderate, or severe and is accompanied by mild, moderate, severe, or serious clinical symptoms, (iii) ARIA-H with 5 to 9 cumulative emorrhages and accompanied by no clinical symptoms, (iv) ARIA-H with 1 to 9 cumulative microhemorrhages and accompanied by mild, moderate, severe, or serious clinical symptoms, (v) ARIA-H with 2 cumulative areas of superficial siderosis and accompanied by no clinical ms, or (vi) ARIA-H with 1 or 2 cumulative areas of superficial siderosis and accompanied by mild, moderate, severe, or s clinical symptoms, and the method further comprises: suspending administration of the eta-amyloid antibody to the subject until the second ARIA resolves; and resuming administration of the anti-beta-amyloid antibody to the subject at a dose that is lower than the dose that was administered to the subject immediately prior to the subject developing the second ARIA.

19. The method of any one of claims 1 to 18, wherein the ARIA is accompanied by no clinical symptoms, mild clinical symptoms, moderate clinical symptoms, or severe al symptoms.

20. The method of any one of claims 1 to 19, n administration is med intravenously.

21. The method of any one of claims 1 to 20, wherein: the VH consists of SEQ ID NO:1; and the VL consists of SEQ ID NO:2.

22. The method of any one of claims 1 to 21, wherein the antibody comprises a human IgG1 constant region.

23. The method of any one of claims 1 to 21, wherein the antibody comprises a heavy chain and a light chain, wherein: the heavy chain consists of SEQ ID NO:10; and the light chain consists of SEQ ID NO:11.

24. A method for treating Alzheimer’s disease in a human subject in need thereof, the method comprising administering to the human subject multiple doses of an anti-betaamyloid antibody, n the multiple doses are administered as follows: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the dy to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), stering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (h) 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (i) 4 weeks after step (h), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (j) 4 weeks after step (i), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (k) 4 weeks after step (j), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (l) in consecutive intervals of 4 weeks after step (k), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject.

25. A method for treating Alzheimer’s disease in a human subject in need thereof, the method sing administering to the human t multiple doses of an anti-betaamyloid antibody, wherein the multiple doses are administered as follows: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (b) 4 weeks after step (a), administering the dy to the subject in an amount of 3 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), stering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the dy to the subject in an amount of 6 mg/kg of body weight of the subject; (g) 4 weeks after step (f), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; (h) 4 weeks after step (g), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the t; (i) 4 weeks after step (h), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (j) in utive intervals of 4 weeks after step (i), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject.

26. A method for treating Alzheimer’s disease in a human subject in need thereof, the method comprising stering to the human subject multiple doses of an anti-betaamyloid antibody, wherein the multiple doses are administered as follows: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (b) 4 weeks after step (a), stering the antibody to the subject in an amount of 1 mg/kg of body weight of the subject; (c) 4 weeks after step (b), stering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (e) 4 weeks after step (d), administering the antibody to the t in an amount of 6 mg/kg of body weight of the subject; (f) 4 weeks after step (e), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the subject; and (g) in consecutive intervals of 4 weeks after step (f), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject.

27. A method for treating Alzheimer’s disease in a human subject in need thereof, the method sing administering to the human subject multiple doses of an anti-betaamyloid antibody, wherein the multiple doses are administered as follows: (a) administering the anti-beta-amyloid antibody to the subject in an amount of 3 mg/kg of body weight of the t; (b) 4 weeks after step (a), administering the antibody to the subject in an amount of 3 mg/kg of body weight of the subject; (c) 4 weeks after step (b), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the t; (d) 4 weeks after step (c), administering the antibody to the subject in an amount of 6 mg/kg of body weight of the t; and (e) in consecutive intervals of 4 weeks after step (d), administering the antibody to the subject in an amount of 10 mg/kg of body weight of the subject. � WEEK54 OBSERVED DATA 26, 21) , 23) mg/kg (n=26, = 23 mg/kg (n WEEK26 1 BIIB0371 BIIB0376 BY TIMEPOINT - COMPOSITE SUVR MEAN PET ::i:: = 1.13 27, 21) 27, 26) = 29, 34, 21) = 28, BASELINE = 34, O (n mg/kg (n BIIB0373 mg/kg (n B11B03710 NORMAL VALUE 1.50 1.40 1.20 1.10 -+- -a- -o- ) 10 mg/kg -0.206 = 12 ) , (n ) 6 mg/kg = 10 (n ) STAGE - CHANGE 3 mg/kg MILD ANCOVA FOR AND NON-CARRIER = 11 (n = 10 ) ABASEDON STATUS ( CARRIER 1 mg/kg (n 17) BASELINE PET ITE SUVR ARE 2 BASELINE CLINICAL PLACEBO (n = - BY 95% Cls CHG FROM -0.207 1G. ) J_ LABORATORY APoE OBSERVED DATA 10 mg/kg = 12 (n ) ADJUSTED MEAN J_ ERRORS AND 6 mg/kg = 10 (n WEEK 26 ANALYSIS TIMEPOINT -0.13 OF TREATMENT, ) J_ PRODROMAL 3 mg/kg = 11 ( n ) -0.026 .l CHANGES, STANDARD WTH FACTORS COMPOSITE SUVR. = 1 0 PLACEBO 1 mg/kg (n = 1 7) (n 0.051 0.025 O : , 0.1 5 -0.25 -0.3 ADJUSTED MEAN FROM BASELINE AND BASELINE w -- N � 10mg/kg = 1 2 (n ) ) -0.219 4 6 mg/kg = 10 (n � I I - 0 �14 ER SUVR mg/kg = 11 ) (n PET COMPOS TE 3 -0.081 NON-CARR FOR CHANGE APoE STATUS mg/kg ) 1 = 10 (n AN COVA SUVR. 1 7 ) BASELINE = (n 0 BY BASEL NE PLACEBO ARE BASED ON NE COMPOS TE 3 FROM - T MEPO NT ED DATA Cls OB SERV = 12 ) /. . w -0.916 ORS AND 9 AND BASEL 10mg/kg (n I = 10 ) 1 , I CARR ER STANDARD ERR MEAN CHG ANALYS S 6 mg/kg (n l � - • 0141 TREATMENT I OF UJ CHANGES, ED WEEK 26 mg/kg 3 = 11 ) (n Lr l -0.087 FACTORS 1 mg/kg = 10 ) (n TH I -0.T16 W j PLACEBO NE = 1 7) -, 1 . 006 (n - 0 i � 0.1 0.05 0 -0.05 01 . . -0.1 5 -0.2 5 - 0 2 · -0.3 - 0.35 -0.4 ADJUSTED MEAN FROM BASEL � � (.9� :z� ;§-±!- �� <C_J ww ::E Cl) 0� w � c3 <C 1