Anti-amyloid beta antibodies and uses thereof

Abstract

The present invention is directed to the treatment or prevention of diseases characterized by Aβ deposition in the brain using anti-Aβ antibodies. Diseases that can be treated or prevented include, for example, Alzheimer's disease, Down's syndrome, and cerebral amyloid angiopathy. The present invention also relates to selecting human subjects based on the tau load in the brain of the human subject that responds to the treatment or prevention of diseases characterized by Aβ deposition in the brain, comprising administering anti-Aβ antibodies, in some embodiments. The present invention also relates to human subjects that have one or two alleles of APOE e4.

Description

[Technical Field]

[0001] In some embodiments, the present invention relates to a method for preventing or treating a disease with an anti-Aβ antibody, wherein the disease is characterized by amyloid beta (Aβ) deposits in a human subject. Diseases that can be treated or prevented using the antibodies, dosing regimens, or methods disclosed herein include, for example, Alzheimer's disease (AD), Down's syndrome, and cerebral amyloid angiopathy (CAA). One aspect of the present invention relates to treating or preventing a disease characterized by Aβ deposits in a human subject, wherein the human subject is selected for treatment or prevention based on tau levels / burden in the whole brain (e.g., global tau), in a portion of the brain (e.g., within different lobes of the brain), and / or the presence of one or two alleles of APOE e4 in the patient's genome. [Background technology]

[0002] Treatment of AD is one of society's most important unmet needs. Accumulation of amyloid-β (Aβ) peptides in the form of cerebral amyloid deposits is an early and essential event in Alzheimer's disease (AD), which leads to neurodegeneration and consequent clinical manifestations: cognitive impairment (Selkoe, "The Origins of Alzheimer's Disease: A is for Amyloid," JAMA, Vol. 283: 1615-7 (2000); Hardy et al., "The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics," Science, Vol. 297: 353-6 (2002); Masters et al., "Alzheimer's Disease," Nat. Rev. Dis. Primers, Vol. 1: 15056 (2015); and Selkoe et al., "The Amyloid Hypothesis of Alzheimer's Disease at 25 years," EMBO Mol. Med., Vol. 8: pp. 595-608 (2016)).

[0003] Amyloid beta (Aβ) is formed by proteolytic cleavage of a larger glycoprotein called amyloid precursor protein (APP). APP is an integral membrane protein expressed in many tissues, but particularly in neuronal synapses. APP is cleaved by γ-secretase to release Aβ peptides, which comprise a group of peptides ranging in size from 37 to 49 amino acid residues. Aβ monomers aggregate into various higher-order structures, including oligomers, protofibrils, and amyloid fibrils. Amyloid oligomers are soluble and can spread throughout the brain, while amyloid fibrils are larger and insoluble and can further aggregate to form amyloid deposits or plaques. Amyloid deposits found in human patients contain a heterogeneous mixture of Aβ peptides, some of which contain N-terminal truncations and may also contain N-terminal modifications, such as N-terminal pyroglutamic acid residues (pGlu).

[0004] The role of amyloid deposits in driving disease progression is supported by studies of rare genetic variants that either increase or decrease Aβ deposition (Fleisher et al., "Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred: A Cross-sectional Study," JAMA Neurol, 72:316-24 (2015); Jonsson et al., "A Mutation in APP Protects Against Alzheimer's Disease and Age-related Cognitive Decline," Nature, 488:96-9 (2012)). Additionally, the presence of amyloid deposits early in the disease increases the likelihood of progression from mild cognitive impairment (MCI) to AD dementia (Doraiswamy et al., "Amyloid-β Assessed by Florbetapir F18 PET and 18-month Cognitive Decline: A Multicenter Study," Neurology, 79:1636-44 (2012)). Interventions aimed at removing Aβ deposits (including amyloid plaques) are hypothesized to slow the clinical progression of AD.

[0005] A second neuropathological hallmark of AD is the presence of intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. Current disease models suggest that Aβ drives tau pathology, and that more complex and synergistic interactions between Aβ and tau emerge at later stages, driving disease progression (Busche et al., "Synergy Between Amyloid-β and Tau in Alzheimer's Disease," Nature Neuroscience, 23:1183-93 (2020)).

[0006] Antibodies to Aβ and their use in methods of treating diseases such as Alzheimer's disease are known in the art. (See, e.g., U.S. Patent Nos. 10,851,156; 10,738,109; 10,662,239; 10,654,917; 10,647,759; 10,603,367; 10,519,223; 10,494,425; 10,464,976; 10,112,991; 10,112,987; 10,035,847; 9,944,696; 9,939,452; 9,895,429; 9,834,598; 9,738 , No. 9,585,956; No. 9,573,994; No. 9,382,312; No. 9,329,189; No. 9,382,312; No. 9,329,189; No. 9,309,309; No. 9,309,307; No. 9,272,031; No. 9,181,332; No. 9,176, No. 150; No. 9,175,094; No. 9,146,244; No. 9,133,267; No. 9,125,846; No. 9,125,846; No. 9,062,102; No. 9,051,364; No. 9,051,363; No. 9,034,334; No. 8,999,9 No. 36; No. 8,916,165; No. 8,906,370; No. 8,906,367; No. 8,889,138; No. 8 , 796,439; 8,795,664; 8,710,193; 8,636,981; 8,614,29 No. 9; No. 8,591,894; No. 8,507,206; No. 8,491,903; No. 8,470,321; No. 8, No. 425,905; No. 8,420,093; No. 8,414,893; No. 8,409,575; No. 8,404,459 No. 8,398,978; No. 8,383,113; No. 8,337,848; No. 8,333,967; No. 8,3 No. 23,654; No. 8,303,954; No. 8,268,973; No. 8,268,593; No. 8,246,954 ; Same No. 8,227,576; Same No. 8,222,002; Same No. 8,221,750; Same No. 8,173,127; Same No. 8,12 No. 8,930; No. 8,128,928; No. 8,124,353; No. 8,124,076; No. 8,106,164;Same No. 8,105,594; Same No. 8,105,593; Same No. 8,025,878; Same No. 7,955,812; Same No. 7,939,075; Same No. No. 7,932,048; No. 7,927,594; No. 7,906,625; No. 7,902,328; No. 7,893,214; No. 7,8 No. 92,545; No. 7,892,544; No. 7,871,615; No. 7,811,563; No. 7,807,165; No. 7,807 , No. 7,790,856; No. 7,780,963; No. 7,772,375; No. 7,763,250; No. 7,763,24 No. 9; No. 7,741,448; No. 7,731,962; No. 7,700,751; No. 7,625,560; No. 7,582,733 ; Same No. 7,575,880; Same No. 7,339,035; Same No. 7,320,790; Same No. 7,318,923; Same No. 7,256,273; Same No. See, e.g., 7,195,761; 7,189,819; 7,179,892; 7,122,374; 7,060,270; 6,815,175; 6,787,637; and 6,750,324, which are incorporated by reference in their entireties.

[0007] In one example, U.S. Patent No. 8,679,498 (incorporated herein by reference in its entirety, including the anti-N3pGlu Aβ antibodies disclosed therein) discloses anti-N3pGlu Aβ antibodies and methods for treating diseases such as Alzheimer's disease with the antibodies. Passive immunization through long-term chronic administration of antibodies against Aβ, including N3pGlu Aβ, found in deposits, has been shown to disrupt Aβ aggregates in the brain in various animal models and promote plaque clearance. Donanemab (disclosed in U.S. Patent No. 8,679,498 and designated antibody B12L) is an antibody directed against a pyroglutamic acid modification of the third amino acid in the amyloid beta (N3pGlu Aβ) epitope, which is present only in cerebral amyloid plaques. Donanemab's mechanism of action is to target and remove existing amyloid plaques, a key pathological feature of AD.

[0008] Therapeutic and preventive strategies using anti-Aβ antibodies involve targeting Aβ populations in early-symptomatic AD patients with pre-existing cerebral amyloid burden. The rationale for this is based on the amyloid hypothesis of AD, which states that Aβ generation and deposition are early and necessary events in the pathogenesis of AD. See, e.g., Selkoe, "The Origins of Alzheimer's Disease: A is for Amyloid," JAMA, Vol. 283:1615-1617 (2000). Clinical support for this hypothesis comes from the demonstration that parenchymal Aβ levels are elevated before AD symptoms appear and are supported by genetic variants of AD that overproduce brain Aβ and genetic variants that prevent Aβ production. See, for example, Jonsson et al., "A Mutation in APP Protects Against Alzheimer's Disease and Age-related Cognitive Decline," Nature, Vol. 488(No. 7409): pp. 96-99 (2012), and Fleisher et al., "Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred: A Cross-sectional Study," JAMA Neurol, Vol. 72: pp. 316-24 (2015).

[0009] Antibodies targeting amyloid plaques, such as those targeting Aβ, have shown promise as treatments for Alzheimer's disease in both preclinical and clinical studies. Despite this promise, amyloid-targeting antibodies have failed to meet therapeutic endpoints in multiple clinical trials. The history of anti-amyloid clinical trials spans nearly 20 years, most of which have questioned the potential of such therapies to effectively treat AD (Aisen et al., "The Future of Anti-amyloid Trials," The Journal of Prevention of Alzheimer's Disease, Vol. 7, pp. 146-151 (2020)). To date, only a few AD treatments have been approved.

[0010] One of the challenges in treating Alzheimer's disease is that it is still primarily diagnosed and treated based on symptoms, like psychiatric disorders, rather than on brain pathology. Another challenge is the replication crisis faced during clinical trials, where replicable results are often difficult to obtain even when clinical trials are nearly identically designed. This is caused by two main factors. First, most trials set enrollment criteria based on symptoms rather than pathology. Thus, they ultimately enroll heterogeneous populations with widely varying levels of underlying pathology, or worse, patients with different underlying conditions. Therefore, these patients progress at very different rates, and within-group variability, measured, for example, by the standard deviation of the mean, is very large in AD trials. Second, the issue of population heterogeneity is complicated by within-subject noise in outcome measurements.

[0011] Determining whether a subject with Aβ deposits will respond to anti-Aβ antibody therapy is uniquely difficult. This is due, in part, to the physiological and clinical heterogeneity among subjects with Aβ deposits. For example, it remains a challenge for clinicians to determine whether a patient with subtle cognitive symptoms, such as memory decline, has prodromal or preclinical Alzheimer's disease (AD) and may progress to AD dementia in the near future.

[0012] AD clinical trial placebo populations vary widely in trajectories of cognitive and functional decline (Veitch et al., "Understanding Disease Progression and Improving Alzheimer's Disease Clinical Trials: Recent Highlights from the Alzheimer's Disease Neuroimaging Initiative," Alzheimer's & Dementia, Vol. 15.1:106-152 (2019)), likely due to heterogeneity in the trial population (Devi et al., "Heterogeneity of Alzheimer's Disease: Consequence for Drug Trials?" Alzheimer's Research & Therapy, Vol. 10.1:1-3 (2018)). Identifying and treating subjects who may benefit from specific treatments continues to pose substantial challenges. The task of properly identifying whether a patient will respond to anti-Aβ antibody treatment is paramount for, for example, timely memory clinic referral, accurate and early AD diagnosis, initiation of symptomatic treatment, future planning, and initiation of disease-modifying treatment.

[0013] Historically, study cohorts have been selected based on clinical characteristics such as cognitive test score range and self-reported memory problems. After years of failure, experts in the field have advocated testing anti-amyloid disease-modifying therapies (DMTs) early in the disease course (Aisen, PS et al., "The future of anti-amyloid trials," The Journal of Prevention of Alzheimer's Disease, Vol. 7.3 (2020): pp. 146-151). However, several clinical studies of anti-amyloid DMTs have failed to meet their endpoints despite targeting patients in the early stages of Alzheimer's disease. An example is the Phase III clinical trial (Cread) of crenezumab recruiting patients with prodromal-to-mild AD. The results of this study were exclusively negative. For both endpoints (primary and secondary), no differences were found between treatment versus placebo groups or within prodromal versus mild AD subgroups (NCT03114657 at clinicaltrials.gov; Therapeutics:Crenezumab.Alzforum.AC Immune SA, Genentech, Hoffmann-La Roche; 2019 [cited September 7, 2020], available at alzforum.org / therapeutics / crenezumab). Similarly, a Phase II / III clinical trial evaluating the efficacy and safety of gantenerumab in patients with prodromal AD (SCarlet RoAD trial) was terminated due to low efficacy rates for the primary and secondary endpoints in the trial (Ostrowitzki et al., "A Phase III Randomized Trial of Gantenerumab in Prodromal Alzheimer's Disease," Alzheimer's Research & Therapy, Vol. 9.1:1-15 (2017)).

[0014] Therefore, there is a need for improved methods to appropriately identify whether a subject is likely to respond to an amyloid-targeting therapeutic agent. Summary of the Invention

[0015] One aspect of the present invention is based on the discovery that even if Alzheimer's patients with low or moderate tau levels are responsive to treatment with anti-Aβ antibodies and are clinically classified as having preclinical or early-stage AD, patients with high tau levels may not be effectively treated with anti-Aβ antibodies. Identifying subjects who are most responsive to treatment with anti-Aβ antibodies solves the over 20-year-old problem of finding clinically effective anti-amyloid therapies and thus represents a significant advance in the art. Some aspects of the present invention are directed to diagnosing and treating patients based on their brain pathology. Selecting patients based on their brain pathology not only provides a more homogenous population for clinical trials, reducing noise and ensuring highly replicable results, but also allows for appropriate identification of AD stages and their progression. Appropriate identification of AD stages also enables accurate and early AD diagnosis, initiation of symptomatic treatment, future planning, and initiation of disease-modifying treatment, for example, for timely referral to a memory clinic.

[0016] Some aspects of the present invention relate to identifying the stage / progression of AD in a patient based on (i) the global or overall tau burden in the brain of a human subject, (ii) the spread of tau in the subject's brain or a portion thereof, and / or (iii) the presence of one or two alleles of apolipoprotein E epsilon-4 (referred to herein as APOE e4 or APOE4) in the subject's genome.

[0017] In some embodiments, patients can be stratified / identified / selected / treated based on the amount of tau present in the subject's brain (e.g., the whole brain or a portion of the brain) and / or the presence of one or two alleles of APOE e4 in the subject's genome.

[0018] In other embodiments, patients are stratified / identified / selected / treated based on the stage of AD progression (e.g., based on the spread of tau in the brain) and / or based on the presence of one or two alleles of APOE e4 in the subject's genome. For example, in some stages, the tau burden in AD patients is isolated to regions of the frontal lobe or temporal lobe that do not include the posterior lateral temporal region (PLT). In another stage of AD, the tau burden in AD patients is limited to the posterior lateral temporal region (PLT) or occipital region. In yet another stage of AD, the tau burden in AD patients is present in the parietal or precuneus or frontal region, with tau burden in the PLT or occipital region. In some embodiments, AD patients have one or two alleles of APOE e4 in the subject's genome and have tau burden isolated to regions of the frontal lobe or temporal lobe that do not include the posterior lateral temporal region (PLT). Another stage of AD is when an AD patient has one or two alleles of APOE e4 and tau burden is limited to the posterolateral temporal region (PLT) or occipital region. Yet another stage of AD is when an AD patient has one or two alleles of APOE e4 and tau burden is present in the parietal, precuneus, or frontal regions, with tau burden in the PLT or occipital regions.

[0019] Patient stratification based on the amount of tau in the brain or the progression of AD in a portion of the brain can be used to determine, for example, whether a patient will respond to anti-Aβ antibody treatment. Stratification / selection of patient populations based on the amount of tau in the brain or the progression of AD in a portion of the brain can also help solve the problems of patient heterogeneity and replicability encountered during the design and implementation of clinical trials. Identification of patients based on the amount of tau or AD progression can also be useful for, for example, timely referral to memory clinics, accurate and early AD diagnosis, initiation of symptomatic treatment, future planning, and initiation of disease-modifying treatment.

[0020] Additionally, Doody et al., "Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease," NEJM, Vol. 370; No. 4, pp. 311-321 (2014), state that "no clear differential treatment effects on efficacy measures were observed between APOE ε4 carriers and non-carriers." It has now been discovered that administering an anti-N3pGlu Aβ antibody to human subjects with one or two alleles of APOE e4 (e.g., APOE e4 carriers) provides unexpected and surprising efficacy when compared with non-carriers of one or more of these alleles. Accordingly, some embodiments include administering a dose of an anti-N3pGlu Aβ antibody to a patient with the allele as a method of slowing cognitive decline in the patient. Specifically, it was found that administering an anti-N3pGlu Aβ antibody to patients with APOE e4 carriers had a greater effect than non-carriers. This means that patients with APOE e4 experience less cognitive decline than non-carriers, as measured at various endpoints using various clinical measures. Thus, patients can be stratified / identified / selected / treated based on their tau levels, based on their stage of AD progression (e.g., based on the spread of tau in the brain), and / or based on the presence of one or two alleles of APOE e4 in their genome.

[0021] One aspect of the invention provides human subjects that respond to treatment or prevention of a disease characterized by amyloid beta (Aβ) deposits in the brain of the human subject. In some embodiments of this aspect of the invention, the responsive human subjects include human subjects with low to moderate tau burden, very low to moderate tau burden, or very low to moderate tau burden. In some embodiments of this aspect of the invention, the responsive human subjects include human subjects with low to moderate tau burden or very low to moderate tau burden, and / or one or two alleles of APOE e4. In some embodiments of this aspect of the invention, the responsive human subjects exclude human subjects with high tau burden and a change of about -20 or more on the integrated Alzheimer's Disease Rating Scale (iADRS) in the past about 18 months. In some embodiments, an anti-Aβ antibody of the invention is administered to a responsive human subject for treatment or prevention of a disease characterized by amyloid beta (Aβ) deposits in the brain of the human subject. [Brief explanation of the drawings]

[0022] (Not stated in the original text) DETAILED DESCRIPTION OF THE INVENTION

[0023] One aspect of the present invention relates to a method for treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject determined to have very low to moderate tau burden or low to moderate tau burden, the method comprising administering one or more doses of an anti-Aβ antibody to the subject. In some embodiments, the method comprises: (i) administering one or more doses of an anti-Aβ antibody to the human subject (e.g., one or more first doses of an anti-Aβ antibody between about 100 mg and about 700 mg), wherein each first dose is administered approximately every four weeks; and (ii) approximately four weeks after the one or more first doses, administering one or more second doses of the anti-Aβ antibody to the human subject (e.g., one or more second doses of an anti-Aβ antibody between greater than 700 mg and about 1400 mg), wherein each second dose is administered approximately every four weeks. In some embodiments, the Alzheimer's patient has one or two alleles of APOE e4.

[0024] Another aspect of the present invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising: determining whether the human subject has a very low to moderate tau load or a low to moderate tau load; and, if the human subject has a very low to moderate tau load or a low to moderate tau load, then administering one or more doses of an anti-Aβ antibody to the human subject. In some embodiments, the method comprises: (i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, wherein each first dose is administered once about every four weeks; and (ii) about four weeks after the one or more first doses, administering to the human subject one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody, wherein each second dose is administered once about every four weeks.

[0025] Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising determining whether the human subject has one or two alleles of APOE e4, a very low to moderate tau load, and / or a low to moderate tau load, and if the human subject has one or two alleles of APOE e4, a very low to moderate tau load, and / or a low to moderate tau load, then administering one or more doses of an anti-Aβ antibody to the human subject. In some embodiments, the method includes: (i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, wherein each first dose is administered about once every four weeks; and (ii) about four weeks after the one or more first doses, administering to the human subject one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody, wherein each second dose is administered about once every four weeks.

[0026] Another aspect of the present invention relates to methods for treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject determined to not have a high tau burden, the method comprising administering an anti-Aβ antibody to the human subject. In some embodiments, the method comprises: (i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, wherein each first dose is administered approximately once every four weeks; and (ii) about four weeks after the one or more first doses, administering to the human subject one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody, wherein each second dose is administered approximately once every four weeks. In some embodiments, the human subject has been determined to not have a high tau burden and has one or two alleles of APOE e4.

[0027] Another aspect of the present invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising: determining whether the human subject has a high tau burden; and, if the human subject does not have a high tau burden, administering one or more doses of an anti-Aβ antibody to the human subject. In some embodiments, the method comprises: (i) administering to the human subject one or more first doses of an anti-Aβ antibody between about 100 mg and about 700 mg, wherein each first dose is administered once about every four weeks; and (ii) about four weeks after the one or more first doses, administering to the human subject one or more second doses of an anti-Aβ antibody between about 700 mg and about 1400 mg, wherein each second dose is administered once about every four weeks.

[0028] Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising determining whether the human subject has a high tau burden and one or two alleles of APOE e4, and if the human subject does not have a high tau burden and has one or two alleles of APOE e4, then administering one or more doses of an anti-Aβ antibody to the human subject. In some embodiments, the method includes: (i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, wherein each first dose is administered about once every four weeks; and (ii) about four weeks after the one or more first doses, administering to the human subject one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody, wherein each second dose is administered about once every four weeks.

[0029] Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, wherein the human subject has been determined to have very low to moderate tau load, or low to moderate tau load, comprising administering to the human subject an effective amount of an anti-Aβ antibody.

[0030] Another aspect of the invention relates to a method for treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, wherein the human subject has been determined to have one or two alleles of APOE e4 and very low to moderate tau burden, or low to moderate tau burden, comprising administering to the human subject an effective amount of an anti-Aβ antibody.

[0031] Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising determining whether the human subject has a low to moderate tau load or a very low to moderate tau load, and if the human subject has a low to moderate tau load or a very low to moderate tau load, then administering an effective amount of an anti-Aβ antibody to the human subject.

[0032] Another aspect of the invention relates to a method for treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising determining whether the human subject has one or two alleles of APOE e4 and a low to moderate tau load or a very low to moderate tau load, and if the human subject has one or two alleles of APOE e4 and a low to moderate tau load or a very low to moderate tau load, then administering an effective amount of an anti-Aβ antibody to the human subject.

[0033] Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-Aβ antibody, wherein the human subject has been determined to not have a high tau burden, and the human subject has not demonstrated a decrease in the integrated Alzheimer's Disease Rating Scale (iADRS) of greater than about -20 over the past about 18 months. In some embodiments, the human subject has one or two alleles of APOE e4.

[0034] Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising determining whether the human subject has a high tau burden, and if the human subject does not have a high tau burden, then administering an effective amount of an anti-Aβ antibody to the human subject.

[0035] Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising determining whether the human subject has a high tau burden and one or two alleles of APOE e4, and if the human subject has one or two alleles of APOE e4 and does not have a high tau burden, then administering an effective amount of an anti-Aβ antibody to the human subject.

[0036] In some aspects of the disclosed methods, an anti-Aβ antibody may be used to reduce, prevent further increase, or slow the rate of tau burden / accumulation in different parts of the human brain, e.g., different lobes of the human brain of a human subject. In some embodiments, an anti-Aβ antibody is used to reduce, prevent further increase, or slow the rate of tau burden / accumulation in the frontal lobe of a human brain. In some embodiments, an anti-Aβ antibody is used to reduce, prevent further increase, or slow the rate of tau burden / accumulation in the parietal lobe of a human brain. In some embodiments, an anti-Aβ antibody is used to reduce, prevent further increase, or slow the rate of tau burden / accumulation in the occipital lobe of a human brain. In some embodiments, an anti-Aβ antibody is used to reduce, prevent further increase, or slow the rate of tau burden / accumulation in the temporal lobe of a human brain. In some embodiments, an anti-Aβ antibody is used to reduce, prevent further increase, or slow the rate of tau burden / accumulation in the posterior lateral temporal lobe. In some embodiments, a human subject is administered (i) one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, where each first dose is administered once about every four weeks, and (ii) about four weeks after the one or more first doses, one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody are administered to the human subject, where each second dose is administered once about every four weeks.

[0037] Aspects of the present invention relate to methods of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject determined to have tau burden in the temporal lobe of the brain, wherein the method comprises administering an anti-Aβ antibody to the human subject. Another aspect of the present invention relates to methods of treating or preventing a disease characterized by amyloid beta deposits in the brain of a human subject, comprising determining whether the human subject has tau burden in the temporal lobe of the brain and administering an anti-Aβ antibody to the human subject. In some embodiments, the human subject has tau burden in the posterior lateral temporal lobe. In some embodiments, a human subject is administered (i) one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, where each first dose is administered about once every four weeks, and (ii) about four weeks after the one or more first doses, one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody are administered to the human subject, where each second dose is administered about once every four weeks. In some embodiments, the human subject has been determined to have one or two alleles of APOE e4.

[0038] Another aspect of the present invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject determined to have tau burden in the occipital lobe of the brain, wherein the method comprises administering an anti-Aβ antibody to the human subject. Another aspect of the present invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, comprising determining whether the human subject has tau burden in the occipital lobe of the brain and administering an anti-Aβ antibody to the human subject. In some embodiments, a human subject is administered (i) one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, where each first dose is administered about once every four weeks, and (ii) about four weeks after the one or more first doses, one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody are administered to the human subject, where each second dose is administered about once every four weeks. In some embodiments, the human subject has been determined to have one or two alleles of APOE e4.

[0039] Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject determined to have tau burden in the parietal lobe of the brain, wherein the method comprises administering an anti-Aβ antibody to the human subject. Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, comprising determining whether the human subject has tau burden in the parietal lobe of the brain and administering an anti-Aβ antibody to the human subject. In some embodiments, a human subject is administered (i) one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, where each first dose is administered about once every four weeks, and (ii) about four weeks after the one or more first doses, one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody are administered to the human subject, where each second dose is administered about once every four weeks. In some embodiments, the human subject has been determined to have one or two alleles of APOE e4.

[0040] Another aspect of the present invention relates to a method for treating or preventing a disease characterized by amyloid beta deposits in the brain of a human subject determined to have tau burden in the frontal lobe of the brain, wherein the method comprises administering an anti-Aβ antibody to the human subject. Another aspect of the present invention relates to a method for treating or preventing a disease characterized by amyloid beta deposits in the brain of a human subject, comprising determining whether the human subject has tau burden in the frontal lobe of the brain and administering an anti-Aβ antibody to the human subject. In some embodiments, the human subject (i) is administered one or more first doses of an anti-Aβ antibody of about 100 mg to about 700 mg, wherein each first dose is administered once about every four weeks, and (ii) about four weeks after the one or more first doses, the human subject is administered one or more second doses of an anti-Aβ antibody of greater than about 700 mg to about 1400 mg, wherein each second dose is administered once about every four weeks. In some embodiments, the human subject has been determined to have one or two alleles of APOE e4.

[0041] Another aspect of the present invention relates to a method for treating or preventing a disease characterized by amyloid beta deposits in the brain of a human subject determined to have tau burden in the posterolateral temporal (PLT) and / or occipital lobes of the brain, wherein the method comprises administering an anti-Aβ antibody to the human subject. Another aspect of the present invention relates to a method for treating or preventing a disease characterized by amyloid beta deposits in the brain of a human subject, comprising determining whether the human subject has tau burden in the posterolateral temporal (PLT) and / or occipital lobes of the brain, and administering an anti-Aβ antibody to the human subject. In some embodiments, a human subject is administered (i) one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, where each first dose is administered about once every four weeks, and (ii) about four weeks after the one or more first doses, one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody are administered to the human subject, where each second dose is administered about once every four weeks. In some embodiments, the human subject has been determined to have one or two alleles of APOE e4.

[0042] Another aspect of the present invention relates to a method of treating or preventing a disease characterized by amyloid beta deposits in the brain of a human subject determined to have (i) a tau load in the parietal or precuneus region, or (ii) a tau load in the frontal region, along with a tau load in the PLT or occipital region of the brain, wherein the method comprises administering an anti-Aβ antibody to the human subject. Another aspect of the present invention relates to a method of treating or preventing a disease characterized by amyloid beta deposits, wherein the method comprises determining whether the human subject has (i) a tau load in the parietal or precuneus region, or (ii) a tau load in the frontal region, along with a tau load in the PLT or occipital region of the brain, and administering an anti-Aβ antibody to the human subject. In some embodiments, a human subject is administered (i) one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, where each first dose is administered about once every four weeks, and (ii) about four weeks after the one or more first doses, one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody are administered to the human subject, where each second dose is administered about once every four weeks. In some embodiments, the human subject has been determined to have one or two alleles of APOE e4.

[0043] Another aspect of the present invention relates to a method for treating or preventing a disease characterized by amyloid beta deposits in the brain of a human subject determined to have (i) a tau burden isolated to the frontal lobe or (ii) a tau burden in a region of the temporal lobe that is not included in the posterolateral temporal region (PLT) of the brain, wherein the method comprises administering an anti-Aβ antibody to the human subject. Another aspect of the present invention relates to a method for treating or preventing a disease characterized by amyloid beta deposits, comprising determining whether the human subject has (i) a tau burden isolated to the frontal lobe or (ii) a tau burden in a region of the temporal lobe that is not included in the posterolateral temporal region (PLT) of the brain, and administering an anti-Aβ antibody to the human subject. In some embodiments, a human subject is administered (i) one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, where each first dose is administered about once every four weeks, and (ii) about four weeks after the one or more first doses, one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody are administered to the human subject, where each second dose is administered about once every four weeks. In some embodiments, the human subject has been determined to have one or two alleles of APOE e4.

[0044] In some aspects, the present invention relates to methods for selecting a human subject for treatment or prevention of a disease characterized by amyloid beta deposits in the human subject's brain. In some embodiments, the human subject is selected based on the global (overall) amount of tau in the human subject's brain. For example, the human subject is selected for treatment or prevention of a disease characterized by amyloid beta deposits in the brain because the patient has very low to moderate levels of tau in the brain. In another embodiment, the human subject is selected for treatment or prevention of a disease characterized by amyloid beta deposits in the brain because the patient has low to moderate levels of tau (or intermediate tau) in the brain. In another embodiment, the human subject is excluded from treatment or prevention of a disease characterized by amyloid beta deposits in the brain because the patient has high tau in the brain. In some embodiments, the human subject is selected based on the progression of AD in the human subject's brain. For example, the human subject is selected for treatment or prevention of a disease characterized by amyloid beta deposits in the brain because the patient has a tau burden present in the frontal lobe of the brain. In another embodiment, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta deposits in the brain because the patient has a tau load present in the parietal lobe of the brain. In another embodiment, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta deposits in the brain because the patient has a tau load present in the occipital lobe of the brain. In another embodiment, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta deposits in the brain because the patient has a tau load present in the temporal lobe of the brain. In some embodiments, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta deposits in the brain because the patient has a tau load present in the posterolateral temporal (PLT) and / or occipital lobe of the brain. In some embodiments, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta deposits in the brain because the patient has a tau load present in (i) the parietal or precuneus region or (ii) the frontal region of the brain together with a tau load in the PLT or occipital region of the brain.In some embodiments, a human subject is selected for treatment or prevention of a disease characterized by amyloid beta deposits in the brain because the patient has (i) tau burden isolated to the frontal lobe, or (ii) tau burden in a region of the temporal lobe that does not include the posterior lateral temporal region (PLT) of the brain. In some embodiments, the human subject is (i) administered one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, where each first dose is administered approximately once every four weeks, and (ii) approximately four weeks after the administration of the one or more first doses, the human subject is administered one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody, where each second dose is administered approximately once every four weeks. In some embodiments, the human subject has been determined to have one or two alleles of APOE e4.

[0045] In some embodiments, the subject described in various aspects of the invention is determined to have a posterior lateral temporal lobe tau load. In some embodiments, the subject described in various aspects of the invention is determined to have a posterior lateral temporal lobe tau load and an occipital lobe tau load. In some embodiments, the subject described in various aspects of the invention is determined to have a posterior lateral temporal lobe tau load, an occipital lobe tau load, and / or a parietal lobe tau load. In some embodiments, the subject described in various aspects of the invention is determined to have a posterior lateral temporal lobe tau load, an occipital lobe tau load, a parietal lobe tau load, and / or a frontal lobe tau load. In some embodiments, the subject described in various aspects of the invention is determined to have a posterior lateral temporal lobe tau load, an occipital lobe tau load, a parietal lobe tau load, and / or a frontal lobe tau load. In some embodiments, the subject described in various aspects of the invention is determined to have a posterolateral temporal lobe tau load, an occipital lobe tau load, a parietal lobe tau load, and / or a frontal lobe tau load corresponding to a tau load of greater than 1.46 SUVr based on PET imaging. In some embodiments, the human subject is determined to have one or two alleles of APOE e4.

[0046] In some embodiments, tau burden in a portion of a human brain (e.g., in a lobe of the brain) can be used to determine whether administration of an anti-Aβ antibody should be discontinued. For example, a reduction in, prevention of further increase in, or slowing of the rate of tau burden / accumulation in a portion of the brain can be used as a metric for determining the duration of administration of an anti-Aβ antibody. In some embodiments, an anti-Aβ antibody is administered to a subject until a reduction in, prevention of further increase in, or slowing of the rate of tau burden / accumulation in the temporal, occipital, parietal, or frontal lobe occurs.

[0047] In some embodiments, the amount of tau burden present in a portion of a human subject's brain (e.g., in a defined lobe of the human subject's brain) can be used to select an optimal treatment regimen or administer a treatment modality in combination with an anti-Aβ antibody. For example, the presence of tau burden in the frontal lobe of an amyloid-positive human subject's brain can be used as a metric to determine whether the human subject will benefit from administration of an anti-Aβ antibody alone or in combination with an anti-tau antibody. In some embodiments, an anti-Aβ antibody in combination with an anti-tau antibody can be administered to a subject to reduce, prevent further increase, or slow the rate of tau burden / accumulation in different portions of the human brain, e.g., different lobes of the human subject's human brain. In some embodiments, tau burden in different portions of the human brain, e.g., different lobes of the human subject's human brain, can be used (i) to track a patient's response to treatment or (ii) to determine when treatment may need to be resumed.

[0048] In some embodiments, the antibodies, methods, or dosing regimens described in various aspects of the invention cause (i) a reduction in Aβ deposits in the brain of a human subject, and / or (ii) a slowing of cognitive or functional decline in a human subject. In some embodiments, for the antibodies, methods, or dosing regimens described herein, the method results in a reduction of amyloid plaques.

[0049] In some embodiments, the anti-Aβ antibodies described in various aspects of the invention (i) comprise, (ii) may replace, or (iii) may be used together with an anti-N3pGlu Aβ antibody, such as, for example: an anti-N3pGlu Aβ antibody comprising a light chain complementarity determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 5, a light chain complementarity determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO: 6, a light chain complementarity determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence having at least 95% homology to light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 5, an amino acid sequence having at least 95% homology to light chain complementarity determining region 2 (LCDR2) of SEQ ID NO: 6, and an amino acid sequence having at least 95% homology to light chain complementarity determining region 3 (LCDR3) of SEQ ID NO: 7; an anti-N3pGlu Aβ antibody comprising a heavy chain complementarity determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 8, a heavy chain complementarity determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO: 9, a heavy chain complementarity determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having at least 95% homology to heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 8, an amino acid sequence having at least 95% homology to heavy chain complementarity determining region 2 (HCDR2) of SEQ ID NO: 9, and an amino acid sequence having at least 95% homology to heavy chain complementarity determining region 3 (HCDR3) of SEQ ID NO: 10; a light chain complementarity determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO: 5, a light chain complementarity determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO: 6, a light chain complementarity determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO: 7, a heavy chain complementarity determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO: 8, a heavy chain complementarity determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO: 9, a heavy chain complementarity determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having at least 95% homology to the light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 5, and the sequence an anti-N3pGlu Aβ antibody, comprising an amino acid sequence having at least 95% homology to light chain complementarity determining region 2 (LCDR2) of SEQ ID NO: 6, an amino acid sequence having at least 95% homology to light chain complementarity determining region 3 (LCDR3) of SEQ ID NO: 7, an amino acid sequence having at least 95% homology to heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 8, an amino acid sequence having at least 95% homology to heavy chain complementarity determining region 2 (HCDR2) of SEQ ID NO: 9, and an amino acid sequence having at least 95% homology to heavy chain complementarity determining region 3 (HCDR3) of SEQ ID NO: 10; an anti-N3pGlu Aβ antibody comprising an LCVR and an HCVR, wherein the LCVR comprises LCDR1, LCDR2, and LCDR3, and the HCVR comprises HCDR1, HCDR2, and HCDR3, wherein LCDR1 is SEQ ID NO: 5, LCDR2 is SEQ ID NO: 6, LCDR3 is SEQ ID NO: 7, HCDR1 is SEQ ID NO: 8, HCDR2 is SEQ ID NO: 9, and HCDR3 is SEQ ID NO: 10, or an anti-N3pGlu Aβ antibody comprising an LCVR and an HCVR, wherein the LCVR comprises LCDR1, LCDR2, and LCDR3, and the HCVR comprises HCDR1, HCDR2, and HCDR3, wherein LCDR1 is SEQ ID NO: 5, LCDR2 is SEQ ID NO: 6, LCDR3 is SEQ ID NO: 7, HCDR1 is SEQ ID NO: 8, HCDR2 is SEQ ID NO: 9, and HCDR3 is SEQ ID NO: 10; an anti-N3pGlu Aβ antibody comprising CDR1, HCDR2, and HCDR3 selected from the group consisting of: LCDR1 having at least 95% homology to SEQ ID NO:5; LCDR2 having at least 95% homology to SEQ ID NO:6; LCDR3 having at least 95% homology to SEQ ID NO:7; HCDR1 having at least 95% homology to SEQ ID NO:8; HCDR2 having at least 95% homology to SEQ ID NO:9; and HCDR3 having at least 95% homology to SEQ ID NO:10. an N3pGlu Aβ antibody comprising a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 95% homology to SEQ ID NO: 3; an N3pGlu Aβ antibody comprising a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 95% homology to SEQ ID NO: 4; an anti-N3pGlu Aβ antibody comprising an LC and an HC, wherein the LC comprises the amino acid sequence of SEQ ID NO: 3 and the HC comprises the amino acid sequence of SEQ ID NO: 4, or wherein the LC comprises an amino acid sequence having at least 95% homology to SEQ ID NO: 3 and the HC comprises an amino acid sequence having at least 95% homology to SEQ ID NO: 4; an anti-N3pGlu Aβ antibody comprising two light chains and two heavy chains, wherein LC comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence with at least 95% homology to SEQ ID NO: 3, and HC comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence with at least 95% homology to SEQ ID NO: 4. an N3pGlu Aβ antibody containing an LCVR comprising the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 95% homology to SEQ ID NO: 1; an HCVR-containing N3pGlu Aβ antibody comprising the amino acid sequence of SEQ ID NO:2 or an amino acid sequence having at least 95% homology to SEQ ID NO:2; an anti-N3pGlu Aβ antibody comprising an LCVR and an HCVR, wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 95% homology to SEQ ID NO: 1, and the HCVR comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 95% homology to SEQ ID NO: 2.

[0050] The anti-Aβ antibodies described in various aspects of the present invention (i) include, (ii) may replace, or (iii) be used in conjunction with anti-Aβ antibodies disclosed in the art, such as donanemab, aducanumab, bapineuzumab, GSK933776, solanezumab, crenezumab, ponezumab, lecanemab (BAN2401), and gantenerumab. In some embodiments, the anti-Aβ antibodies of the present invention comprise a kappa LC and an IgG HC. In certain embodiments, the anti-Aβ antibodies of the present invention are of the human IgG4 or IgG1 isotype.

[0051] In some embodiments of the disclosed methods, a human subject is administered one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody described herein. In some embodiments, the one or more first doses are administered to the human subject such that each first dose is administered once every four weeks. In several embodiments, the first dose is administered once to the subject. In some embodiments, the first dose is administered twice to the subject, wherein each first dose is administered once every four weeks. In some embodiments, the first dose is administered three times to the subject, wherein each first dose is administered once every four weeks.

[0052] In some embodiments, a subject is administered a first dose, two first doses, or three first doses of about 100 mg to about 700 mg, where each first dose is administered once about every four weeks. In certain embodiments, a human subject is administered three first doses of about 700 mg, where each first dose is administered once about every four weeks. In some embodiments, a human subject is administered one, two, or three first doses before administering the second dose.

[0053] In some embodiments, three first doses of about 700 mg are administered to a subject once every four weeks for a period of 12 weeks, followed by a second dose of about 1400 mg. In some embodiments, one or more first doses of about 700 mg are administered to a subject once every four weeks for a period of about three months, followed by a second dose of about 1400 mg.

[0054] In some embodiments, the first dose is about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or about 700 mg. In some embodiments, the first dose is from about 1 mg / kg to about 10 mg / kg of the anti-Aβ antibody. In certain embodiments, the subject is administered up to three first doses of about 1 mg / kg to about 10 mg / kg. In some embodiments, the subject is administered a first, second, or third dose of about 1 mg / kg to about 10 mg / kg. In one specific embodiment, the subject is administered three first doses of about 10 mg / kg, once every four weeks. In some embodiments, the first dose is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg.

[0055] In certain embodiments, the first dose is administered once every four weeks or once every month. In one embodiment, the subject receives three first doses of about 10 mg / kg once every four weeks. In some embodiments, the first dose of anti-Aβ antibody is administered to the subject for about one month, about two months, or about three months.

[0056] In some embodiments, the subject is administered one or more second doses of greater than 700 mg to about 1400 mg of anti-Aβ antibody. In some embodiments, the subject is administered one or more second doses of greater than 700 mg to about 1400 mg of anti-Aβ antibody, wherein each second dose is administered once about every four weeks. In some embodiments, the second dose is administered four weeks after the one or more first doses.

[0057] In several embodiments, the subject is administered one or more second doses of greater than 700 mg. In some embodiments, the subject is administered one or more second doses of about 1400 mg. In some embodiments, the second dose is greater than 700 mg, greater than about 800 mg, greater than about 900 mg, greater than about 1000 mg, greater than about 1100 mg, greater than about 1200 mg, greater than about 1300 mg, or greater than about 1400 mg. In certain embodiments, the second dose is administered once every four weeks. In one embodiment, the subject is administered one or more second doses of greater than 700 mg once every four weeks. In one embodiment, the subject is administered one or more second doses of greater than about 1400 mg once every four weeks.

[0058] An MRI scan may be administered to the human subject to check / assess any adverse event(s) caused by administration of the anti-Aβ antibody. In some embodiments, the human subject is administered an MRI scan between doses of the anti-Aβ antibody. In some embodiments, the human subject is administered an MRI scan before increasing the dose of the anti-Aβ antibody, for example, from 700 mg to 1400 mg. In some embodiments, the human subject is administered an MRI scan before administering the 1400 mg dose. In some embodiments, the human subject is administered an MRI scan before administering the 20 mg / kg dose. In some embodiments, the human subject is administered an MRI scan after administering the final 700 mg dose. In some embodiments, the human subject is administered an MRI scan after administering the final 10 mg / kg dose.

[0059] In some embodiments, the subject is administered one or more second doses of greater than 10 mg / kg to about 20 mg / kg of anti-Aβ antibody. In some embodiments, the second dose is greater than about 10 mg / kg, greater than about 11 mg / kg, greater than about 12 mg / kg, greater than about 13 mg / kg, greater than about 14 mg / kg, greater than about 15 mg / kg, greater than about 16 mg / kg, greater than about 17 mg / kg, greater than about 18 mg / kg, greater than about 19 mg / kg, or greater than about 20 mg / kg. In one embodiment, the subject is administered one or more second doses of greater than 10 mg / kg. In one embodiment, the subject is administered one or more second doses of about 20 mg / kg. In one embodiment, the first dose is administered monthly. In one embodiment, the subject is administered one or more second doses of greater than 10 mg / kg, where each second dose is administered about once every four weeks or once monthly. In one embodiment, the subject is administered one or more second doses of about 20 mg / kg, wherein each second dose is administered about once every four weeks or once monthly.

[0060] In some embodiments, a first dose of anti-Aβ antibody is administered to a subject once, followed by one or more second doses, where the second dose is administered four weeks after the one or more first doses and once every four weeks thereafter. In some embodiments, a first dose of anti-Aβ antibody is administered to a subject twice (once every four weeks), followed by one or more second doses administered four weeks after the first dose and once every four weeks thereafter. In some embodiments, a first dose of anti-Aβ antibody is administered to a subject three times (once every four weeks), followed by one or more second doses administered four weeks after the first dose and once every four weeks thereafter.

[0061] In some embodiments, a subject is treated with one or more first doses, one or more second doses of about 1400 mg, followed by one or more second doses of greater than 700 mg to about 1300 mg. In one embodiment, a subject is treated with one or more first doses of about 700 mg, one or more second doses of about 1400 mg, followed by one or more doses of about 700 mg.

[0062] In some embodiments, the dosing regimen of the present invention includes one or more first doses of about 100 mg to about 700 mg, and one or more second doses of greater than 700 mg to about 1400 mg, followed by one or more additional doses (also referred to herein as third doses). In some embodiments, the third dose is administered to a subject to reduce Aβ deposition in the subject's brain, prevent further Aβ deposition in the subject's brain, prevent further cognitive decline, prevent memory loss, or prevent functional decline. The third dose can be about 100 mg to about 1400 mg. In some embodiments, different antibodies or the same antibody are used for the first, second, and third doses. In some embodiments, a different Aβ-targeting antibody is administered in the third dose. For example, some embodiments of the present invention include (i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-Aβ antibody, wherein each first dose is administered approximately every four weeks; (ii) about four weeks after the one or more first doses, administering to the human subject one or more second doses of greater than about 700 mg to about 1400 mg of an anti-Aβ antibody, wherein each second dose is administered approximately every four weeks; and (iii) subsequently administering to the human subject one or more third doses of about 100 mg to about 1400 mg of an anti-Aβ antibody. In some embodiments, the one or more third doses of an anti-Aβ antibody of the present invention may be administered to the subject every two or four weeks, monthly, annually, every two years, every three years, every four years, every five years, or every ten years. In some embodiments, the third dose is given every two weeks. In some embodiments, the third dose is given every four weeks. In some embodiments, the third dose is given every year. In one embodiment, the third dose is given every two years. In another embodiment, the third dose is given every three years. In another embodiment, the third dose of antibody is given every five years. In another embodiment, the third dose of antibody is given every ten years. In another embodiment, the third dose of antibody is given every two to five years. In another embodiment, the third dose of antibody is given every five to ten years.

[0063] In some embodiments, the anti-Aβ antibody is administered to the subject for a period sufficient to treat or prevent the disease. In some embodiments, the anti-Aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject, optionally once every four weeks or once monthly, for a period of up to about 72 weeks. In some embodiments, the anti-Aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject, optionally once every four weeks or once monthly, for a period of up to about 98 weeks. In some embodiments, the anti-Aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject, optionally once every four weeks or once monthly, for a period of up to about 124 weeks. In some embodiments, the anti-Aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the human subject until a normal level of amyloid is achieved in the subject. In some embodiments, the anti-Aβ antibody (comprising a first dose of the antibody and a second dose of the antibody) is administered to a human subject until the subject becomes amyloid-negative (a subject is considered amyloid-negative if the subject's brain amyloid plaque level is less than 24.1 CL). In some embodiments, the anti-Aβ antibody (comprising a first dose of the antibody and a second dose of the antibody) is administered to a human subject until the subject's brain amyloid plaque level is in the normal range or is eliminated. The normal range of amyloid plaques is defined as demonstrating an amyloid plaque level of 25 centiloids or less for two consecutive PET scans at least six months apart, or a single PET scan demonstrating a plaque level of less than 11 centiloids. In the present disclosure, the term "normal range" of amyloid plaques in the brain is used interchangeably with "cleared" brain amyloid plaques.

[0064] In some embodiments, the anti-Aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject, optionally once every four weeks or once monthly, for a period of up to about 18 months. In some embodiments, the anti-Aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject, optionally once every four weeks or once monthly, for a period of up to about 24 months. In some embodiments, the anti-Aβ antibody (including the first dose of antibody and the second dose of antibody) is administered to the subject, optionally once every four weeks or once monthly, for a period of up to about 30 months.

[0065] In one embodiment, a subject receives three first doses of 700 mg once every four weeks, followed by a second dose of 1400 mg once every four weeks for up to 72 weeks. In some embodiments, the anti-Aβ antibody (e.g., comprising a first dose of antibody and a second dose of antibody) is administered to the subject for a period of about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or about 76 weeks. In some embodiments, the anti-Aβ antibody (e.g., comprising a first dose of antibody and a second dose of antibody) is administered to the subject for a period of about 76 weeks, about 80 weeks, about 84 weeks, about 88 weeks, about 92 weeks, about 96 weeks, about 100 weeks, about 104 weeks, about 108 weeks, about 112 weeks, about 116 weeks, or about 120 weeks.

[0066] In certain embodiments, the anti-Aβ antibody is administered to the subject for a period of about 24 weeks. In certain embodiments, the antibody is administered to the subject for a period of about 28 weeks. In certain embodiments, the antibody is administered to the subject for a period of about 52 weeks. In certain embodiments, the antibody is administered to the subject for a period of about 72 weeks.

[0067] In some embodiments, the anti-Aβ antibody (e.g., comprising a first dose of antibody and a second dose of antibody) is administered to the subject over a period of about 1 month to about 18 months. In some embodiments, the anti-Aβ antibody is administered to the subject over a period of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, or about 18 months. In some embodiments, the anti-Aβ antibody is administered to the subject over a period of about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months, about 25 months, about 26 months, about 27 months, about 28 months, about 29 months, or about 30 months.

[0068] In some embodiments, the antibody is administered to the subject until cerebral amyloid plaques reach normal range or are cleared.

[0069] In certain embodiments, the antibody is administered to the subject for a period of about 3 months. In certain embodiments, the antibody is administered to the subject for a period of about 6 months. In certain embodiments, the antibody is administered to the subject for a period of about 12 months. In certain embodiments, the antibody is administered to the subject for a period of about 18 months.

[0070] In some embodiments, a human subject is administered an anti-Aβ antibody for a period sufficient to treat or prevent a disease characterized by amyloid beta (Aβ) deposits in the brain of the human subject. In some embodiments, the human subject is administered an anti-Aβ antibody (e.g., including a first dose and / or a second dose) for a period sufficient to bring amyloid plaques in the subject's brain into the normal range. The normal range of amyloid plaques is defined as demonstrating an amyloid plaque level of 25 centiloids or less for two consecutive PET scans at least six months apart, or a single PET scan demonstrating a plaque level of less than 11 centiloids.

[0071] In some embodiments, an antibody of the invention is administered to a subject until the amyloid plaque level in the subject is about 25 centiloids or less. In some embodiments, the amyloid plaque is measured by PET imaging. In other embodiments, an antibody of the invention is administered to a subject until the amyloid plaque level in the subject is about 25 centiloids or less for two consecutive PET imaging scans. In some embodiments, the two consecutive PET imaging scans are at least six months apart. In some embodiments, an antibody of the invention is administered to a subject until the amyloid plaque level in the subject is about 11 centiloids or less, as measured by a single PET imaging scan.

[0072] In a specific embodiment, a subject is administered three first doses of 700 mg of an antibody of the invention, where each first dose is administered once every four weeks, followed by one or more second doses of 1400 mg of the antibody, where each second dose is administered once every four weeks until amyloid plaque levels in the patient are about 25 centiloids or less.

[0073] In other embodiments, a subject is administered three first doses of 700 mg of an antibody of the invention, where each first dose is administered once every four weeks, followed by a second dose of 1400 mg of the antibody, where each second dose is administered once every four weeks until amyloid plaque levels in the patient are about 25 centiloids or less for two consecutive PET imaging scans, or about 11 centiloids or less for one PET imaging scan. In some embodiments, the two consecutive PET imaging scans are separated by at least six months.

[0074] In some embodiments, the subject is not given an anti-Aβ antibody dose after the amyloid plaque level in the patient is about 25 centiloids or less for two consecutive PET imaging scans, or about 11 centiloids or less for one PET imaging scan, in some embodiments, the two consecutive PET imaging scans are separated by at least six months.

[0075] In some embodiments, after the amyloid plaque level in the patient is about 25 centiloids or less for two consecutive PET imaging scans, or about 11 centiloids or less for one PET imaging scan, the subject may be given one or more 700 mg doses of an anti-Aβ antibody.

[0076] In some embodiments, an antibody of the invention is administered to a subject until amyloid plaques in the subject's brain are reduced by about 25 to about 150 centiloids. See, e.g., Klunk et al., "The Centiloid Project: Standardizing Quantitative Amyloid Plaque Estimation by PET," Alzheimer's & Dementia, Vol. 11.1:1-15 (2015), and Navitsky et al., "Standardization of Amyloid Quantitation with Florbetapir Standardized Uptake Value Ratios to the Centiloid Scale," Alzheimer's & Dementia, Vol. 14.12:1565-1571 (2018), which are incorporated by reference in their entireties.

[0077] In some embodiments, an antibody of the invention is administered to a subject until there is about a 50 to about 150 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 25, about a 30, about a 40, about a 50, about a 60, about a 70, about a 80, about a 90, about a 100, about a 110, about a 120, about a 130, about a 140, or about a 150 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 50 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 60 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 70 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about an 80 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about an 84 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 90 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 100 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 110 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 120 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 130 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 140 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 150 centiloid reduction in Aβ deposits in the subject's brain.

[0078] In some embodiments, an antibody of the invention is administered to a subject until there is an average reduction in Aβ deposits in the subject's brain of about 25 to about 100 centiloids. In some embodiments, an antibody of the invention is administered to a subject until there is an average reduction in Aβ deposits in the subject's brain of about 50 to about 100 centiloids. In some embodiments, an antibody of the invention is administered to a subject until there is an average reduction in Aβ deposits in the subject's brain of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, or about 100 centiloids. In some embodiments, an antibody of the invention is administered to a subject until there is an average reduction in Aβ deposits in the subject's brain of about 50 centiloids. In some embodiments, an antibody of the invention is administered to a subject until there is an average reduction in Aβ deposits in the subject's brain of about 60 centiloids. In some embodiments, an antibody of the invention is administered to a subject until there is an average reduction of about 70 centiloids in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is an average reduction of about 80 centiloids in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is an average reduction of about 84 centiloids in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is an average reduction of about 90 centiloids in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is an average reduction of about 100 centiloids in Aβ deposits in the subject's brain.

[0079] In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 25 to about 150 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 50 to about 150 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 25, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, about 100, about 110, about 120, about 130, about 140, or about 150 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 50 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 60 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 70 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about an 80 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about an 84 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 90 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 100 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 110 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 120 centiloid reduction in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 130 centiloid reduction in Aβ deposits in the subject's brain.In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 140 centiloid reduction in Aβ deposits in the subject's brain, hi some embodiments, a second dose of an antibody of the invention is administered to a subject until there is about a 150 centiloid reduction in Aβ deposits in the subject's brain.

[0080] In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is an average reduction of about 25 to about 100 centiloids in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is an average reduction of about 50 to about 100 centiloids in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is an average reduction of about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, or about 100 centiloids in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is an average reduction of about 50 centiloids in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is an average reduction of about 60 centiloids in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is an average reduction of about 70 centiloids in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is an average reduction of about 80 centiloids in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is an average reduction of about 84 centiloids in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is an average reduction of about 90 centiloids in Aβ deposits in the subject's brain. In some embodiments, a second dose of an antibody of the invention is administered to a subject until there is an average reduction of about 100 centiloids in Aβ deposits in the subject's brain.

[0081] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the invention result in a reduction of Aβ deposits in the brain of a human subject. In certain embodiments, Aβ deposits are removed or reduced by about 20-100% following treatment. In some embodiments, an antibody of the invention is administered to a subject until there is about a 20-100% reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 20%, about a 25%, about a 30%, about a 35%, about a 40%, about a 45%, about a 50%, about a 75%, or about a 100% reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 20% reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 25% reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 30% reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 35% reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 40% reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 50% reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 75% reduction in Aβ deposits in the subject's brain. In some embodiments, an antibody of the invention is administered to a subject until there is about a 100% reduction in Aβ deposits in the subject's brain.

[0082] In some embodiments, the first and / or second dose of an antibody of the invention is administered to a subject until there is about a 20-100% reduction in Aβ deposits in the subject's brain. In multiple embodiments, the second dose of an antibody of the invention is administered to a subject until there is about a 20-100% reduction in Aβ deposits in the subject's brain. In some embodiments, the second dose of an antibody of the invention is administered to a subject until there is about a 20%, 25%, 30%, 35%, 40%, 45%, 50%, 75%, or 100% reduction in Aβ deposits in the subject's brain. In some embodiments, the second dose is administered to a subject until there is about a 20% reduction in Aβ deposits in the subject's brain. In some embodiments, the second dose is administered to a subject until there is about a 25% reduction in Aβ deposits in the subject's brain. In some embodiments, the second dose is administered to the subject until there is about a 30% reduction in Aβ deposits in the subject's brain. In some embodiments, the second dose is administered to the subject until there is about a 35% reduction in Aβ deposits in the subject's brain. In some embodiments, the second dose is administered to the subject until there is about a 40% reduction in Aβ deposits in the subject's brain. In some embodiments, the second dose is administered to the subject until there is about a 50% reduction in Aβ deposits in the subject's brain. In some embodiments, the second dose is administered to the subject until there is about a 75% reduction in Aβ deposits in the subject's brain. In some embodiments, the second dose is administered to the subject until there is about a 100% reduction in Aβ deposits in the subject's brain.

[0083] In some embodiments, the percent reduction in Aβ deposits in the subject's brain is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

[0084] In some embodiments, the centiloid reduction in Aβ deposits in the subject's brain is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

[0085] In some embodiments, the mean centiloid reduction in Aβ deposits in the subject's brain is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

[0086] In some embodiments, the present invention slows the decline from baseline in a composite cognitive endpoint by about 15 to about 45 percent over about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or about 76 weeks.

[0087] In some embodiments, the present invention slows the decline from baseline in a cognitive composite endpoint by about 15 to about 45 percent over a 76-week period. In some embodiments, the slowing of decline from baseline in a cognitive composite endpoint is provided by the MMRM model or the Bayesian Disease Progression Model (DPM). In some embodiments, an antibody of the present invention is administered to a subject until a slowing of decline from baseline in a cognitive composite endpoint of about 15 to about 45 percent is achieved. In some embodiments, a first dose or a second dose of the present invention is administered to a subject until a slowing of decline from baseline in a cognitive composite endpoint of about 15 to about 45 percent is achieved.

[0088] In some embodiments, the present invention slows the decline from baseline in the Integrated Alzheimer's Disease Rating Scale (iADRS) by about 15 to about 45 percent. In some embodiments, the present invention slows the decline from baseline in the Integrated Alzheimer's Disease Rating Scale by about 15 to about 45 percent over about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, or 76 weeks.

[0089] In some embodiments, the present invention results in a slowing of the decline from baseline on the Integrated Alzheimer's Disease Rating Scale by about 20 percent, about 25 percent, about 30 percent, about 32 percent, about 35 percent, about 40 percent, or about 45 percent.

[0090] In some embodiments, the present invention slows the decline from baseline on the Integrated Alzheimer's Disease Rating Scale by about 15 to about 45 percent over a 76-week period. In a particular embodiment, the present invention slows the decline from baseline on the Integrated Alzheimer's Disease Rating Scale by about 32 percent over a 76-week period. In some embodiments, an antibody of the present invention is administered to a subject until a slowing of the decline from baseline on the Integrated Alzheimer's Disease Rating Scale of about 15 to about 45 percent is reached. In some embodiments, a first dose or a second dose of the present invention is administered to a subject until a slowing of the decline from baseline on the Integrated Alzheimer's Disease Rating Scale of about 15 to about 45 percent is reached.

[0091] In some embodiments, a subject's composite cognitive endpoint comprising iADRS is measured at about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, or about 72 weeks.

[0092] In some embodiments, the antibodies of the present invention can be administered simultaneously, separately, or sequentially in combination with an effective amount of a symptomatic treatment agent to treat Alzheimer's disease. The symptomatic treatment agent can be selected from a cholinesterase inhibitor (ChEI) and / or a partial N-methyl-D-aspartate (NMDA) antagonist. In a preferred embodiment, the agent is a ChEI. In another preferred embodiment, the agent is an NMDA antagonist or a combination drug comprising a ChEI and an NMDA antagonist.

[0093] In some embodiments, the subject's disease characterized by Aβ deposits in the brain is selected from preclinical Alzheimer's disease, clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy. In some embodiments, the subject is an early symptomatic AD patient. In some embodiments, the subject has prodromal AD and mild dementia due to AD. In some embodiments, the subject has mild cognitive impairment or mild dementia due to AD.

[0094] The present invention includes the use of biomarkers for diseases characterized by Aβ deposits in the brain of human subjects, including Alzheimer's disease. Such biomarkers include, for example, amyloid deposits, amyloid plaques, Aβ in CSF, Aβ in plasma, brain tau deposits, tau in plasma, or tau in cerebrospinal fluid, and their use in screening, diagnosis, treatment, or prevention. Non-limiting potential uses of such biomarkers include: (1) identifying subjects expected to be affected or in the "preclinical" stage of disease; (2) reducing disease heterogeneity in clinical trials or epidemiological studies; (3) reflecting the natural history of disease, including stages of induction, latency, and detection; and (4) targeting subjects for clinical trials or disease treatment / prevention.

[0095] In some embodiments, biomarkers can be used to assess whether a subject can be treated with an antibody, dosing regimen, or method described herein. In some embodiments, biomarkers can be used to assess whether a disease (as described herein) can be prevented in a subject using an antibody, dosing regimen, or method described herein. In some embodiments, biomarkers can be used to assess whether a subject will be responsive to treatment or prevention of a disease (as described herein) using an antibody, dosing regimen, or method described herein. In some embodiments, biomarkers can be used to stratify or classify subjects into groups and to identify which groups of subjects will be responsive to treatment / prevention of a disease (as described herein) using an antibody, dosing regimen, or method described herein. In some embodiments, biomarkers can be used to assess a subject's disease status and / or the duration for administering an antibody or dose thereof, as described herein, to a subject.

[0096] In some embodiments, the subject has a genetic mutation that causes autosomal dominant Alzheimer's disease or is at higher risk of developing AD by carrying one or two APOE e4 alleles. In several embodiments, the subject carries one or two APOE e4 alleles, i.e., the patient is heterozygous or homozygous.

[0097] In some embodiments, the subject has a low to moderate tau burden or has been determined to have a low to moderate tau burden. 18A subject may be characterized as having low to moderate tau burden if their tau burden, as measured by F (using flortaucipir), is ≦1.10 standardized uptake value ratio (SUVr) to ≦1.46 SUVr. In some embodiments, the subject has, or has been determined to have, low to moderate tau burden and carries one or two APOE e4 alleles.

[0098] In some embodiments, the subject has or has been determined to have an extremely low tau burden. 18 A subject may be characterized as having an extremely low tau burden if their tau burden, as measured by F (using flortaucipir), is less than 1.10 SUVr. In some embodiments, the subject has, or has been determined to have, an extremely low tau burden and carries one or two APOE e4 alleles.

[0099] In some embodiments, the subject has been determined to have very low to moderate tau burden, or very low to moderate tau burden. 18 A subject may be characterized as having very low to moderate tau burden if their tau burden, as measured by F (using flortaucipir), is ≦1.46 SUVr. In some embodiments, the subject has or has been determined to have very low to moderate tau burden and carries one or two APOE e4 alleles.

[0100] In some embodiments, the subject does not have high tau burden or has been determined not to have high tau burden. In some embodiments, the subject is assessed by PET brain imaging (e.g., 18A human subject may be characterized as having a high tau burden if their tau burden, as measured by Fflourtaucipir (using Fflourtaucipir), exceeds 1.46 SUVr. In some embodiments, a subject with high tau is not administered an antibody of the invention. In some embodiments, the subject does not have, or has been determined to not have, a high tau burden and carries one or two APOE e4 alleles.

[0101] In some embodiments of the disclosed methods, the subject has a high tau burden. In some embodiments, PET brain imaging (e.g., 18 A human subject may be characterized as having a high tau burden if their tau burden, as measured by F (using flortaucipir), exceeds 1.46 SUVr. In some embodiments, the subject has, or has been determined to have, a high tau burden and carries one or two APOE e4 alleles.

[0102] Subjects with high tau burden may exhibit slow decline. Subjects exhibiting slow decline may be characterized as those who have not exhibited a decline in the integrated Alzheimer's Disease Rating Scale (iADRS) score of greater than about -20 over the past approximately 18 months. The iADRS is known in the art as a composite tool that combines scores from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL). The iADRS may demonstrate acceptable psychometric properties, and the iADRS may be effective in capturing both disease progression and separating placebo and active drug effects. In some embodiments, subjects with high tau and slow decline are administered an antibody of the invention. In other embodiments, subjects with high tau and rapid decline are not administered an antibody of the invention. A subject exhibiting rapid decline may be characterized as one who has exhibited a decrease in the integrated Alzheimer's Disease Rating Scale (iADRS) of greater than about -20 over the past about 18 months.

[0103] According to embodiments of the invention provided herein, a human subject has been determined to be slowly declining by one or more of ADAS-Cog, iADL, CDR-SB, MMSE, APOE-4 genotyping, and / or iADRS. In some embodiments, the human subject has been determined to be slowly declining by iADRS. In some embodiments, the iADRS has decreased by less than 20. In some embodiments, the iADRS has decreased by less than 20 over 6 months. In some embodiments, the iADRS has decreased by less than 20 over 12 months. In some embodiments, the iADRS has decreased by less than 20 over 18 months. In some embodiments, the iADRS has decreased by less than 20 over 24 months. In some embodiments, the human subject has been determined to be slowly declining by APOE-4 genotyping. In some embodiments, the human subject has been determined to be APOE-4 heterozygote. In some embodiments, the human subject has been determined to be APOE-4 homozygote negative. In some embodiments, the human subject has been determined to be slowly declining by MMSE. In some embodiments, the human subject is determined to have an MMSE of greater than 27. In some embodiments, the MMSE has decreased by less than 3. In some embodiments, the MMSE has decreased by less than 3 over a 6-month period. In some embodiments, the MMSE has decreased by less than 3 over a 12-month period. In some embodiments, the MMSE has decreased by less than 3 over a 18-month period. In some embodiments, the MMSE has decreased by less than 3 over a 24-month period.

[0104] In some embodiments of the disclosed methods of treatment and prevention, the human subject has a PET brain imaging (e.g., 18 In some embodiments of the disclosed methods of treatment and prevention, the human subject has a tau burden as measured by PET brain imaging (e.g., using Fflourtaucipir) that is less than about 1.46 SUVr, and the subject may be administered an antibody of the invention. 18In other embodiments of the disclosed methods of treatment and prevention, a human subject has a tau load as measured by PET brain imaging (e.g., using Fflourtaucipitin) and has one or two alleles of APOE e4, and the subject may be administered an antibody of the invention. 18 In some embodiments of the disclosed methods of treatment and prevention, the human subject has a tau burden as measured by PET brain imaging (e.g., using Fflourtaucipir) that is less than about 1.27 SUVr, and the subject may be administered an antibody of the invention. 18 A subject has a tau load as measured by Fflourtaucipir (using Fflourtaucipir) and has one or two alleles of APOE e4, and may be administered an antibody of the invention.

[0105] In some embodiments, the anti-Aβ antibodies, dosing regimens, or methods described herein are effective in human subjects with very low to moderate levels of tau. In some embodiments, the anti-Aβ antibodies, dosing regimens, or methods described herein are effective in human subjects with low to moderate levels of tau. In some embodiments, the antibodies of the invention are most effective in human subjects with tau levels of (i) about 1.14 SUVr or less, or (ii) about 1.14 SUVr to about 1.27 SUVr.

[0106] In some embodiments, the anti-Aβ antibodies, dosing regimens, or methods described herein are effective in human subjects with very low to moderate tau and one or two APOE e4 alleles. In some embodiments, the anti-Aβ antibodies, dosing regimens, or methods described herein are effective in human subjects with low to moderate tau and one or two APOE e4 alleles. In some embodiments, the antibodies of the invention are most effective in human subjects with one or two APOE e4 alleles and having tau levels of (i) about 1.14 SUVr or less, or (ii) about 1.14 SUVr to about 1.27 SUVr.

[0107] Tau levels in a human subject can be determined by techniques and methods well known to diagnosticians or those skilled in the art. In some embodiments, a human subject suffering from a disease characterized by amyloid beta (Aβ) deposits is determined to have very low to moderate tau, low to moderate tau, or no high tau using techniques and methods well known to diagnosticians or those skilled in the art. In some embodiments, such methods can also be used to pre-screen, screen, diagnose, evaluate increases or decreases in brain tau burden, and / or evaluate progress achieved in treating or preventing a disease described herein. In some embodiments, the methods can also be used to stratify subjects into groups and / or identify which groups of subjects will be responsive to treatment / prevention of a disease (as described herein) using the antibodies, dosing regimens, or methods described herein. In some embodiments, the methods or techniques used to determine / detect tau levels in a human subject can be used to pre-screen or screen subjects and determine which subjects will respond to treatment / prevention of a disease (as described herein) using the antibodies, dosing regimens, or methods described herein.

[0108] For purposes of the present invention, tau levels in a human subject can be determined, for example, using techniques or methods that detect or quantify (i) brain tau deposits, (ii) plasma tau, or (iii) cerebrospinal fluid tau. In some embodiments, brain tau load, plasma tau, or cerebrospinal fluid tau can be used to stratify subjects into groups and to identify which groups of subjects will be responsive to treatment / prevention of a disease (described herein) using the antibodies, dosing regimens, or methods described herein.

[0109] Tau levels in the brains of human subjects can be measured using tau imaging with radiolabeled PET compounds (Leuzy et al., "Diagnostic Performance of RO948 F18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease from Other Neurodegenerative Disorders," JAMA Neurology, Vol. 77.8: 955-965 (2020); Ossenkoppele et al., "Discriminative Accuracy of 18 F]-flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders,” JAMA, 320:1151-1162, doi:10.1001 / jama.2018.12917 (2018), which are incorporated herein by reference in their entireties.

[0110] In some embodiments, the biomarker is a PET ligand [ 18[F]-flortaucipir may be used for purposes of the present invention. PET tau imaging can be performed using published methods (e.g., Pontecorvo et al., "A Multicentre Longitudinal Study of Flortaucipir (18F) in Normal Aging, Mild Cognitive Impairment and Alzheimer's Disease Dementia," Brain, Vol. 142: 1723-35 (2019); Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," Journal of Nuclear Medicine, Vol. 59: 937-43 (2018); Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signals," Journal of Nuclear Medicine, Vol. 142: 937-43 (2018)). Intensity,” J. Nucl. Med., 59:944-51 (2018), which are incorporated herein by reference in their entireties), and / or can be quantitatively assessed to visually assess the patient, for example, to determine whether the patient has an AD pattern (Fleisher et al., “Positron Emission Tomography Imaging With 18[F]-flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes," JAMA Neurology, 77:829-39 (2020), which is incorporated herein by reference in its entirety. Lower SUVr values ​​indicate lower tau burden, while higher SUVr values ​​indicate higher tau burden. In one embodiment, quantitative assessment of flortaucipir scans is achieved by the automated image processing pipeline described in Southekal et al., "F-flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med., 59:944-951 (2018), which is incorporated herein by reference in its entirety. In some embodiments, counts within specific target regions of interest in the brain (e.g., multiblock centroid discriminant analysis or MUBADA; see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med., 59:937-943 (2018), which is incorporated herein by reference in its entirety) are compared to a reference region, e.g., whole cerebellum (wholeCere), cerebellar GM (cereCrus), atlas-based white matter (atlasWM), subject-specific WM (ssWM), e.g., using parametric estimation of reference signal intensity (PERSI), see Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity (PERSI)," J. Nucl. Med., 59:937-943 (2018), which is incorporated herein by reference in its entirety). See, "Intensity," J. Nucl. Med., 59:944-951 (2018), which is incorporated herein by reference in its entirety.

[0111] The preferred method for determining tau burden is quantitative analysis reported as the standardized uptake value ratio (SUVr), which represents counts within a specific target region of interest in the brain (e.g., MUBADA) when compared to a reference region (e.g., using PERSI).

[0112] In some embodiments, phosphorylated tau (P-tau; either phosphorylated at threonine 181 or 217) can be used to measure tau load / burden for purposes of the present invention (Barthelemy et al., "Cerebrospinal Fluid Phospho-tau T217 Outperforms T181 as a Biomarker for the Differential Diagnosis of Alzheimer's Disease and PET Amyloid-Positive Patient Identification," Alzheimer's Res. Ther., Vol. 12, No. 26, doi:10.1186 / s13195-020-00596-4 (2020); Mattsson et al., "Aβ Deposition is Associated with Increases in Soluble and Phosphorylated Tau that Precede a Positive Tau PET in Alzheimer's Disease," Science Advances, Vol. 6, eaaz2387 (2020), which are incorporated herein by reference in their entireties. In certain embodiments, antibodies against human tau phosphorylated at threonine residue 217 can be used to measure tau load / burden in a subject for purposes of the present invention (see International Patent Application Publication No. WO2020 / 242963, which is incorporated by reference in its entirety). The present invention, in some embodiments, comprises measuring tau load / burden in a subject using the anti-tau antibodies disclosed in International Publication No. WO2020 / 242963. The anti-tau antibodies disclosed in International Publication No. WO2020 / 242963 are directed against an isoform of human tau expressed in the CNS (e.g., recognize an isoform expressed in the CNS and not an isoform of human tau that is exclusively expressed outside the CNS).Such antibodies against isoforms of human tau expressed in the CNS can be used in methods to identify / select patients as one or more of: (i) having a disease disclosed herein; (ii) at risk of having a disease disclosed herein; (iii) in need of treatment for a disease disclosed herein; or (iv) in need of neurological imaging.

[0113] A subject is positive for amyloid deposits if amyloid is detected in the brain by methods such as amyloid imaging with radiolabeled PET compounds, or by using diagnostic methods that detect Aβ or a biomarker of Aβ. Exemplary methods that can be used in the present invention to measure brain amyloid load / burden include, for example, florbetapir (Carpenter et al., "The Use of the Exploratory IND in the Evaluation and Development of 18 F-PET Radiopharmaceuticals for Amyloid Imaging in the Brain: A Review of One Company's Experience," The Quarterly Journal of Nuclear Medicine and Molecular Imaging, Vol. 53.4:387 (2009), which is incorporated herein by reference in its entirety); florbetaben (Syed et al., "[ 18 [F]Florbetaben: A Review in β-Amyloid PET Imaging in Cognitive Impairment,” CNS Drugs, Vol. 29, pp. 605-613 (2015), which is incorporated herein by reference in its entirety); and flutemetamol (Heurling et al., “Imaging β-amyloid Using [ 18[F]Flutemetamol Positron Emission Tomography: From Dosimetry to Clinical Diagnosis,” European Journal of Nuclear Medicine and Molecular Imaging, Vol. 43.2: pp. 362-373 (2016), which is incorporated herein by reference in its entirety.

[0114] [ 18 [F]-florbetapir can provide qualitative and quantitative measurements of brain plaque load in patients, including those with prodromal AD or mild AD dementia. For example, significant [F]-florbetapir can be measured by visual reading. 18 The absence of [F]-florbetapir signal indicates that patients who clinically present with cognitive impairment have few or no amyloid plaques. 18 [F]-Florbetapir also provides confirmation of amyloid pathology. 18 [F]-florbetapir PET also provides a quantitative assessment of fibrillar amyloid plaques in the brain and, in some embodiments, can be used to assess amyloid plaque reduction from the brain by antibodies of the invention.

[0115] Amyloid imaging with radiolabeled PET compounds can also be used to determine whether Aβ deposits are decreasing or increasing in the brain of a human patient (e.g., to calculate the percentage reduction in Aβ deposits after treatment or to assess the progression of AD). One skilled in the art can correlate the standardized uptake value ratio (SUVr) values ​​obtained from amyloid imaging (with radiolabeled PET compounds) to calculate the percentage reduction in Aβ deposits in the patient's brain before and after treatment. SUVr values ​​can be converted to standardized centiloid units, where 100 is the mean for AD and 0 is the mean for young controls, allowing for comparability between amyloid PET tracers and calculation of centiloid unit decline (Klunk et al., "The Centiloid Project: Standardizing Quantitative Amyloid Plaque Estimation by PET," Alzheimer's & Dementia, Vol. 11.1:1-15 (2015), and Navitsky et al., "Standardization of Amyloid Quantitation with Florbetapir Standardized Uptake Value Ratios to the Centiloid Scale," Alzheimer's & Dementia, Vol. 14.12:1565-1571 (2018), which are incorporated by reference in their entireties). In some embodiments, change in cerebral amyloid plaque deposition from baseline is measured as [ 18 F]-florbetapir PET scan.

[0116] Cerebrospinal fluid or plasma-based analysis of β-amyloid can also be used to measure amyloid load / burden for purposes of the present invention. For example, Aβ42 can be used to measure brain amyloid (Palmqvist, S. et al., "Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid Beta-amyloid 42: a Cross-validation Study Against Amyloid Positron Emission Tomography." JAMA Neurol, 71, 1282-1289 (2014), which is incorporated herein by reference in its entirety). In some embodiments, the ratio of Aβ42 / Aβ40 or Aβ42 / Aβ38 can be used as a biomarker for amyloid beta (Janelidze et al., "CSF Abeta42 / Abeta40 and Abeta42 / Abeta38 Ratios: Better Diagnostic Markers of Alzheimer Disease," Ann Clin Transl Neurol, vol. 3, pp. 154-165 (2016), which is incorporated herein by reference in its entirety).

[0117] In some embodiments, deposited cerebral amyloid plaques or Aβ in the CSF or plasma can be used to stratify subjects into groups and to identify which groups of subjects will be responsive to treatment / prevention of a disease (as described herein) using the antibodies, dosing regimens, or methods described herein.

[0118] As used herein, "anti-Aβ antibody" refers to an antibody that binds to an epitope present on Aβ. In some embodiments, the anti-Aβ antibody binds to a soluble form of Aβ. In other embodiments, the anti-Aβ antibody binds to an insoluble form of Aβ, such as Aβ plaques. In some embodiments, the anti-Aβ antibody binds to an epitope present on Aβ1-40 or Aβ1-42. In other embodiments, the anti-Aβ antibody binds to an epitope present on a truncated form of Aβ1-40 or Aβ1-42, e.g., a truncated form lacking 1-20 N-terminal amino acids and / or a truncated form lacking 1-20 C-terminal amino acids and optionally including an N-terminal pyroglutamic acid residue (e.g., N3pGlu Aβ). In other embodiments, the anti-Aβ antibody binds to an epitope present in a fragment of Aβ1-40 or Aβ1-42, having a length of about 5-20 amino acids and optionally including an N-terminal pyroglutamic acid. Anti-Aβ antibodies have been disclosed in the art (e.g., U.S. Patent Nos. 10,851,156; 10,738,109; 10,662,239; 10,654,917; 10,647,759; 10,603,367; 10,519,223; 10,494,425; 10,464,976; 10,112,9 No. 91; No. 10,112,987; No. 10,035,847; No. 9,944,696; No. 9,939,452; No. 9,895,429; No. 9,834,598; No. 9,738,712; No. 9,585,956; No. 9,573,994; No. 9,382,312; No. 9,329,1 No. 89; No. 9,309,309; No. 9,309,307; No. 9,272,031; No. 9,181,332; No. 9,176,150; No. 9 , 175,094; 9,146,244; 9,133,267; 9,125,846; 9,062,102; 9,051,364 No. 9,051,363; No. 8,916,165; No. 8,906,370; No. 8,906,367; No. 8,889,138; No. 8,7 No. 96,439; No. 8,795,664; No. 8,710,193; No. 8,636,981; No. 8,614,299; No. 8,591,894;8,507,206; 8,491,903; 8,470,321; 8,425,905; 8,420,093; 8,414,893; 8,398,978; 8,383,113; 8,337,848; 8,333,967; 8,323,654; 8,303,954; 8,268,973; 8,268,593; 8,246,954; 8,227,576; 8, 222,002; 8,221,750; 8,173,127; 8,128,930; 8,128,928; 8,124,353; 8,124,076; 8,106,164; 8,10 No. 5,594; No. 8,105,593; No. 8,025,878; No. 7,955,812; No. 7,939,075; No. 7,932,048; No. 7,927,594; No. 7,906,625; No. 7,902,3 No. 28; No. 7,893,214; No. 7,892,545; No. 7,892,544; No. 7,871,615; No. 7,811,563; No. 7,807,165; No. 7,807,157; ​​No. 7,790,856 No. 7,780,963; No. 7,772,375; No. 7,763,250; No. 7,763,249; No. 7,741,448; No. 7,731,962; No. 7,700,751; No. 7,625,560; See Nos. 7,582,733; 7,575,880; 7,339,035; 7,320,790; 7,318,923; 7,256,273; 7,195,761; 7,189,819; 7,179,892; 7,122,374; 7,060,270; 6,815,175; 6,787,637; and 6,750,324, which are incorporated by reference in their entireties. Anti-Aβ antibodies can also include donanemab, aducanumab, bapineuzumab, GSK933776, solanezumab, lecanemab, crenezumab, ponezumab, and gantenerumab;

[0119] In some embodiments, the disclosed antibodies target N3pGlu Aβ (i.e., anti-N3pGlu Aβ antibodies). The disclosed antibodies may selectively bind to N3pGlu Aβ peptides relative to other Aβ peptides, such as peptides lacking N-terminal pyroglutamic acid or the Aβ(1-40) or Aβ(1-42) peptides. Those skilled in the art will understand and appreciate that "anti-N3pGlu Aβ antibodies," as well as several specific antibodies, including "hE8L," "B12L," and "R17L," are identified and disclosed (along with methods of making and using) in U.S. Patent No. 8,679,498 B2, which is incorporated herein by reference in its entirety. See, e.g., Table 1 of U.S. Patent No. 8,679,498 B2. Each of the antibodies disclosed in U.S. Patent No. 8,679,498 B2, including the "hE8L," "B12L," and "R17L" antibodies, may be used as the anti-N3pGlu Aβ antibody of the present invention or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present invention. Other representative species of anti-N3pGlu Aβ antibodies include, but are not limited to, the antibodies disclosed in U.S. Patent Nos. 8,961,972; 10,647,759; 9,944,696; WO 2010 / 009987 A2; WO 2011 / 151076 A2; WO 2012 / 136552 A1; and equivalents thereof, e.g., under 35 U.S.C. 112(f).

[0120] Those skilled in the art will understand and appreciate that "anti-N3pGlu Aβ antibodies" and several specific antibodies are identified and disclosed (together with methods of making and using) in U.S. Patent Nos. 8,961,972 (incorporated herein by reference in its entirety); 10,647,759 (incorporated herein by reference in its entirety); and 9,944,696 (incorporated herein by reference in its entirety). Any of the anti-N3pGlu Aβ antibodies disclosed in U.S. Patent Nos. 8,961,972; 9,944,696; and 10,647,759 can be used as the anti-N3pGlu Aβ antibody of the present invention or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present invention.

[0121] Those skilled in the art will understand and appreciate that several specific antibodies, including "anti-N3pGlu Aβ antibodies," as well as "Antibody VI," "Antibody VII," "Antibody VIII," and "Antibody IX," are identified and disclosed (along with methods of making and using such antibodies) in WO 2010 / 009987 A2, which is incorporated herein by reference in its entirety. Each of these four antibodies (e.g., "Antibody VI," "Antibody VII," "Antibody VIII," and "Antibody IX") can be used as the anti-N3pGlu Aβ antibody of the present invention or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present invention.

[0122] Those skilled in the art will understand and appreciate that several specific antibodies, including "anti-N3pGlu Aβ antibodies," and "Antibody X" and "Antibody XI," are identified and disclosed (along with methods of making and using such antibodies) in WO2011 / 151076A2, which is incorporated herein by reference in its entirety. Each of these two antibodies (e.g., "Antibody X" and "Antibody XI") can be used as the anti-N3pGlu Aβ antibody of the present invention or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present invention.

[0123] Those skilled in the art will understand and appreciate that several specific antibodies, including "anti-N3pGlu Aβ antibodies," as well as "Antibody XII" and "Antibody XIII," are identified and disclosed (along with methods for making and using such antibodies) in WO2012 / 136552A1, which is incorporated herein by reference in its entirety. Each of these two antibodies (e.g., "Antibody XII" and "Antibody XIII") can be used as the anti-N3pGlu Aβ antibody of the present invention or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present invention.

[0124] As used herein, an "antibody" is an immunoglobulin molecule comprising two HCs and two LCs interconnected by disulfide bonds. The amino-terminal portions of each LC and HC comprise variable regions involved in antigen recognition via the complementarity-determining regions (CDRs) contained therein. The CDRs are interspersed with more conserved regions called framework regions. The assignment of amino acids to the CDR domains within the LCVR and HCVR regions of the antibodies of the present invention is based on the Kabat numbering convention (Kabat et al., Ann. NY Acad. Sci., Vol. 190: 382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., USDapartment of Health and Human Services, NIH Publication No. 91-3242 (1991)) and the North numbering convention (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, Vol. 406: 228-256 (2011)). The CDRs of the antibodies of the present invention were determined according to the methods described above.

[0125] The antibodies of the present invention are monoclonal antibodies ("mAbs"). Monoclonal antibodies can be produced, for example, by hybridoma technology, recombinant technology, phage display technology, synthetic technology, such as CDR grafting, or a combination of such techniques or other techniques known in the art. The monoclonal antibodies of the present invention are human or humanized. Humanized antibodies can be engineered to contain one or more human framework regions (or substantially human framework regions) surrounding CDRs derived from a non-human antibody. Human framework germline sequences can be obtained from ImmunoGeneTics (INGT) via its website http: / / imgt.cines.fr or The Immunoglobulin FactsBook by Marie-Paule Lefranc and Gerard Lefranc, Academic 25 Press, 2001, ISBN 012441351. Techniques for producing human or humanized antibodies are well known in the art. In another embodiment of the present invention, the antibody, or nucleic acid encoding the antibody, is provided in isolated form. As used herein, the term "isolated" refers to a protein, peptide, or nucleic acid that is free or substantially free of any other macromolecular species found in the cellular environment. "Substantially free," as used herein, means that the protein, peptide, or nucleic acid of interest contains more than 80% (on a molar basis), preferably more than 90%, and more preferably more than 95% of the macromolecular species present.

[0126] The anti-Aβ antibodies of the present invention are administered as pharmaceutical compositions. Pharmaceutical compositions containing the antibodies of the present invention can be administered to subjects at risk of or exhibiting the diseases or disorders described herein by any parenteral route (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular). Subcutaneous and intravenous routes are preferred. In some embodiments, the anti-N3pGlu Aβ antibodies are administered by intravenous infusion.

[0127] Terms such as "treatment," "treating," or "to treat" include inhibiting, slowing, or halting the progression or severity of an existing symptom, condition, disease, or disorder in a subject. The term "subject" refers to a human.

[0128] The term "prevention" refers to the prophylactic administration of an antibody of the invention to an asymptomatic subject or a subject suffering from preclinical Alzheimer's disease to prevent the onset or progression of Alzheimer's disease.

[0129] The terms "disease characterized by Aβ deposition" or "disease characterized by Aβ deposits" are diseases pathologically characterized by Aβ deposits in the brain or cerebral vasculature. This includes diseases such as Alzheimer's disease, Down's syndrome, and cerebral amyloid angiopathy. The clinical diagnosis, staging, or progression of Alzheimer's disease can be readily determined by the attending diagnostician or medical professional, such as one skilled in the art, by using known techniques and observing the results. This generally involves brain plaque imaging, mental or cognitive assessments (e.g., Clinical Dementia Rating - summary of boxes (CDR-SB), Mini-Mental State Exam (MMSE), or Alzheimer's Disease Assessment Scale - Cognitive). Cognitive and functional assessments can be used to determine changes in a patient's cognition (e.g., cognitive decline) and function (e.g., functional decline). As used herein, "clinical Alzheimer's disease" refers to a diagnosed stage of Alzheimer's disease. This includes conditions diagnosed as prodromal Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease, and severe Alzheimer's disease. The term "preclinical Alzheimer's disease" refers to a stage preceding clinical Alzheimer's disease, in which measurable changes in biomarkers (such as CSF Aβ42 levels by amyloid PET or deposited brain plaques) represent the earliest signs of a patient with Alzheimer's disease pathology that will progress to clinical Alzheimer's disease. This is usually before symptoms such as memory loss and confusion become noticeable. Preclinical Alzheimer's disease may also include the development of a mutation in one or two APOE This includes presymptomatic autosomal dominant carriers as well as patients who are at high risk of developing AD due to carrying the e4 allele.

[0130] A reduction or slowing of cognitive decline can be measured by a cognitive assessment such as the Clinical Dementia Assessment-Summary of Boxes, Mini-Mental State Examination, or Alzheimer's Disease Assessment Scale-Cognition. A reduction or slowing of functional decline can be measured by a functional assessment such as the ADCS-ADL.

[0131] As used herein, "mg / kg" refers to the amount of antibody or drug administered to a subject in milligrams based on the subject's body weight in kilograms. The dose is given at one time. For example, a 10 mg / kg dose of antibody to a subject weighing 70 kg is a single 700 mg dose of antibody administered in a single dose. Similarly, a 20 mg / kg dose of antibody to a subject weighing 70 kg is a 1400 mg dose of antibody administered in a single dose.

[0132] As used herein, 18 Using F-flortaucipir-based quantitative analysis, a human subject has an "ultra-low tau" burden if the tau burden is less than 1.10 SUVr (<1.10 SUVr), where quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain (Parametric Estimation of Reference Signal Intensity or PERSI, see Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med., 59:944-951 (2018)) when compared to a reference region (Multiblock Centroid Discriminant Analysis of Reference Signal Intensity or MUBADA, see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med., 59:937-943 (2018)).

[0133] As used herein, a human subject has a "very low to moderate tau" load if the tau load is 1.46 SUVr or less (i.e., ≦1.46 SUVr) using 18F-flortaucipir-based quantitative analysis, where quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain when compared to a reference region (see MUBADA, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med., 59:937-943 (2018)).

[0134] As used herein, 18Using F-flortaucipir-based quantitative analysis, a human subject has a "low to moderate tau" load if the tau load is between 1.10 and 1.46 (i.e., ≦1.10 SUVr and ≦1.46 SUVr), where quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain when compared to a reference region (see MUBADA, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med., 59:937-943 (2018)). (See, "Low-to-moderate tau load," J. Nucl. Med., 59:944-951 (2018)). "Low-to-moderate tau load" can also be referred to as "intermediate" tau load.

[0135] As used herein, 18 Using F-flortaucipir-based quantitative analysis, a human subject has a "high tau" burden if the tau burden is greater than 1.46 SUVr (i.e., >1.46 SUVr), where quantitative analysis refers to the calculation of SUVr, which represents counts within a specific target region of interest in the brain when compared to a reference region (see MUBADA, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med., 59:937-943 (2018)).

[0136] As used herein, a human subject is experiencing a slow decline if the human subject has not experienced a decline in the Integrated Alzheimer's Disease Rating Scale (iADRS) of greater than about -20 over the past 18 months. A human subject is experiencing a rapid decline if the human subject has experienced a decline in the iADRS of greater than about -20 over the past 18 months.

[0137] As used herein, the term "about" means up to ±10%, unless the meaning of the term "about" differs from this meaning in view of the context of its use.

[0138] The terms "human subject" and "patient" are used interchangeably in this disclosure.

[0139] As used herein, "method of treatment" is equally applicable to the use of a composition to treat a disease or disorder described herein and / or the use of a composition in and / or for use in the manufacture of a medicament for treating a disease or disorder described herein.

[0140] The following examples further illustrate the present invention, however, it should be understood that the examples are given by way of illustration and not limitation, and that various modifications may occur to those skilled in the art. [Example]

[0141] Example 1: Expression and purification of engineered N3pGlu Aβ antibodies An antibody against N3pGlu Aβ was selected as the exemplary antibody for this example. Antibodies against N3pGlu Aβ are known in the art. For example, U.S. Patent No. 8,679,498 and U.S. Patent No. 8,961,972 (incorporated herein by reference in their entireties) disclose anti-N3pGlu Aβ antibodies, methods for making the antibodies, antibody formulations, and methods for using the antibodies to treat diseases such as Alzheimer's disease.

[0142] An exemplary method for expressing and purifying an anti-N3pGlu Aβ antibody of the present invention is as follows: Suitable host cells, such as HEK293 EBNA or CHO, are either transiently or stably transfected with an expression system for secreting the antibody using an optimal predetermined HC:LC vector ratio, or with a single vector system encoding both the HC and LC. The clarified medium into which the antibody has been secreted is purified using any of a number of commonly used techniques. For example, the medium can be conveniently applied to a Protein A or G Sepharose FF column equilibrated with a compatible buffer, such as phosphate-buffered saline (pH 7.4). The column is washed to remove nonspecifically bound components. The bound antibody is eluted, for example, by a pH gradient (e.g., from 0.1 M sodium phosphate buffer (pH 6.8) to 0.1 M sodium citrate buffer (pH 2.5)). Antibody fragments are detected, for example, by SDS-PAGE and pooled. Depending on the intended use, further purification is optional. The antibody may be concentrated and / or sterile filtered using common techniques. Soluble aggregates and multimers can be effectively removed by common techniques including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The purity of the antibody after these chromatographic steps is greater than 99%. The product may be immediately frozen at -70°C or lyophilized.

[0143] Example 2: Evaluation of safety, tolerability, and efficacy of anti-N3pGlu Aβ antibodies Donanemab was selected as the exemplary antibody for this example. A multicenter, non-randomized, double-blind, placebo-controlled phase 2 clinical trial (NCT03367403; clinicaltrials.gov) was designed to evaluate the safety and efficacy of an N3pGlu Aβ antibody (also referred to herein as donanemab) in AD subjects with early symptomatic AD (prodromal AD and mild dementia due to AD). This phase 2 trial evaluated, among other things, whether removal of existing amyloid plaques could slow disease progression as determined by clinical measures and biomarkers of disease pathology and neurodegeneration over up to 72 weeks of treatment.

[0144] The study was a 133-week study, with a screening period of up to 9 weeks, a treatment period of up to 72 weeks, a final evaluation 4 weeks later at week 76, and a 48-week immunogenicity and safety follow-up period.

[0145] Figure 1 shows the study design of the clinical protocol. Treatment Groups and Duration: Approximately 1497 patients were screened and approximately 266 were non-randomized. Patients received the following treatments (medications) for up to 72 weeks: Donanemab: Intravenous donanemab (700 mg Q4WK for the first three doses, then 1400 mg Q4WK) for up to 72 weeks; or Placebo: Intravenous placebo Q4WK for up to 72 weeks. Primary and secondary endpoints: The primary endpoints of this study were: Cognitive and functional change as measured by change in Integrated Alzheimer's Disease Rating Scale (iADRS) score from baseline to 18 months. The secondary endpoints of this study were: ADAS-Cog 13 Cognitive change from baseline to 18 months as measured by change in score, change in Clinical Dementia Rating Scale-Sum of Boxes score (CDR-SB), change in Mini-Mental State Examination score (MMSE), and change in Alzheimer's Disease Cooperative Study-instrumental Activities of Daily Living scale (ADCS-iADL) score. ·[ 18 Change in cerebral amyloid plaque deposition from baseline to 18 months as measured by [F]-florbetapir PET scan. ·[ 18 Change in brain tau deposition from baseline to 18 months as measured by [F]-florbetapir PET scan. Change in volumetric MRI measurements from baseline to 18 months. Safety Endpoints: The safety endpoints of this study were: Standard safety assessments: spontaneously reported adverse events (AEs), clinical tests, vital signs and weight measurements, 12-lead electrocardiogram (ECG), physical and neurological examinations MRI (amyloid-related imaging abnormality (ARIA) and urgent radiographic findings) Columbia-Suicide Severity Rating Scale (C-SSRS) Statistical Analysis: Unless otherwise stated, all efficacy analyses followed the intent-to-treat (ITT) principle. An ITT analysis is the analysis of data by group to which subjects were assigned by random assignment, even if they did not receive their assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Unless otherwise stated, all pairwise tests of treatment effect were performed at a two-sided alpha (α) level of 0.05. Two-sided confidence intervals (CI) are presented at the 95% confidence level. Efficacy: The primary objective of this study was to test the hypothesis that intravenous infusion of donanemab slows cognitive and / or functional decline in AD compared with placebo, as measured by the composite iADRS scale, in patients with early symptomatic AD. Changes from baseline scores on the iADRS at each scheduled post-baseline visit during the treatment period were analyzed using a MMRM model. The MMRM model included the following terms: baseline score, pooled investigator, treatment, visit, interaction by visit, baseline by visit interaction, concomitant acetylcholinesterase inhibitor (AChEI) and / or memantine use at baseline (yes / no), and age at baseline. The primary time point for treatment comparison was the end of the double-blind treatment period (week 76). For the treatment comparison of donanemab versus placebo, least-squares mean progression and its associated p-value and 95% CI for treatment group contrasts were calculated. In addition, we calculated the Bayesian posterior probability that the dynamic treatment group was superior to placebo by at least the margin of interest (25% slowing of placebo progression).

[0146] ADAS-Cog 13 Changes from baseline at each scheduled post-baseline visit during the treatment period in secondary efficacy outcomes, including ADCS-iADL, CDR-SB, and MMSE, will be analyzed using the same MMRM model described for the primary analysis. Safety: Safety will be assessed by summarizing and analyzing AEs, laboratory analytes, vital signs, MRI scans, ECGs, and immunogenicity during the double-blind treatment period. Pharmacokinetics / Pharmacodynamics: Pharmacokinetic or pharmacodynamic (PK / PD) relationships between plasma donanemab concentrations and SUVr, cognitive endpoints, ARIA incidence, or other markers of PD activity were examined graphically. The relationship between the presence of antibodies to donanemab and PK, PD, safety, and / or efficacy may also be evaluated graphically. If warranted, additional analyses may be investigated to evaluate potential interactions between anti-drug antibodies, PD, and other endpoints (PET scan, ARIA-E, etc.). Additional modeling may be performed based on the results of graphical analysis. Dosing and Dose Justification: Donanemab (700 mg or 1400 mg) will be administered as an approximately 140 mL IV infusion over a minimum of 30 minutes every 4 weeks. The 700 mg and 1400 mg donanemab doses, administered intravenously once every 4 weeks, will be selected based on current preclinical pharmacology and toxicology data, as well as clinical PK, PD, and safety data. Upfront and ongoing exposures include 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg, 20 mg / kg, and 40 mg / kg, with single-dose and / or multiple-dose dosing schedules. Data from Study AACC (NCT01837641, clinicaltrials.gov) suggest that the PK of donanemab is linear when doses are 10 mg / kg or higher. When doses are ≥10 mg / kg, minimal accumulation in plasma PK is expected for Q4 weekly IV dosing of 700 mg and 1400 mg, as the mean half-life is approximately 9-11 days. 18 F]-florbetapir PET signal reduction was observed with a single dose of 20 mg / kg and with a 10 mg / kg Q2-weekly dosing schedule at 3 months [ 18F-florbetapir PET reduction is comparable. Additionally, based on the reduced patient burden and comparable safety profile of a 4-weekly dosing schedule compared with a 2-weekly dosing schedule, 1400 mg Q4-weekly administration is selected as the highest dosing regimen for robust amyloid plaque reduction. The lowest rate of ARIA-E is observed with a monthly dosing of 10 mg / kg. For this reason, a titration schedule (700 mg Q4-weekly for the first three doses, followed by 1400 mg Q4-weekly) has been proposed to reduce the incidence of ARIA while allowing patients to achieve high PD efficacy. Additionally, dose reduction rules have been established for incident ARIA-E. Inclusion Criteria: Patients aged 60-85 years, including both men and women, at the time of informed consent were eligible for enrollment in the study. Patients may present with gradual and progressive changes in memory function as reported by the patient or study partner (informant) over a 6-month period. In some instances, patients must have an MMSE score of 20-28 (global) at Visit 1 or an acceptable historical [number of years] within the 6 months prior to Visit 1 that meets the central lead criteria. 18 Patients may also have a [F]-flourtaucipir PET scan. 18 F]-Flortaucipil scan (central reading) criteria and / or [ 18 F]-flourtaucipil scan (central reading) criteria can be met. Exclusion Criteria: Patients will be excluded from study enrollment if they meet any of the following criteria: have a Modified Hachinski Ischemia Scale (MHIS; Hachinski et al., 1975) score of 4 or greater; lack, in the investigator's opinion, adequate pre-morbid literacy, adequate vision, or adequate hearing to complete the required psychometric testing; have a central nervous system disorder other than AD that may affect cognition or ability to complete the study, including, but not limited to, other dementias, serious infection of the brain, Parkinson's disease, multiple concussions, or epilepsy or recurrent seizures (excluding febrile childhood seizures). significant neurological disease affecting the CNS; current serious or unstable illness, including cardiovascular, hepatic, renal, gastrointestinal, respiratory, endocrine, neurological (other than AD), psychiatric, immunological, or hematological disorders, and other conditions that, in the investigator's opinion, may interfere with the analysis in this study; or life expectancy less than 24 months; history of cancer within the past 5 years, except for nonmetastatic basal cell and / or squamous cell carcinoma of the skin, in situ cervical cancer, non-aggressive prostate cancer, or other cancers with a low risk of recurrence or spread; psychiatric disorders or symptoms that, in the investigator's judgment, confound interpretation of drug effects or affect cognitive assessment; or any current primary psychiatric diagnosis other than AD if it is likely to affect the patient's ability to complete the study; patients with a history of schizophrenia or other chronic psychosis; patients with a history of long QT syndrome; clinically determined by the investigator to be at serious risk for suicide as assessed by medical history, examination, or C-SSRS; a history of alcohol or drug use disorder (excluding tobacco use disorder) within 2 years prior to the screening visit; a history of clinically significant multiple or severe drug allergies or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, and / or exfoliative dermatitis);or known positive serology for human immunodeficiency virus (HIV) antibodies. Local laws and regulations may apply as to whether testing is required; any clinically significant abnormalities at screening as determined by the investigator in physical or neurological examination, vital signs, ECG, or laboratory test results that may be harmful to the patient, interfere with the study, or show evidence of another etiology of dementia; screening MRI showing evidence of significant abnormalities suggesting another potential etiology of progressive dementia or clinically significant findings that may affect the patient's ability to safely participate in the study; claustrophobia or contraindicated metal (ferromagnetic) implants / Have any contraindications to MRI, including the presence of a cardiac pacemaker; have a focused-read MRI demonstrating the presence of ARIA-E, more than four cerebral microbleeds, more than one area of ​​superficial hemosiderosis, any large hemorrhage, or severe white matter disease; have a mean (triplicate ECG) corrected QT (QTcF) interval measurement >450 msec (men) or >470 msec (women) at screening (as determined by the clinical trial site); patients with a history of hepatitis B should undergo HBsAg testing at screening and will be excluded if HBsAg is positive; patients with a history of hepatitis C should undergo HCV testing at screening RNA PCR testing should be performed, and a positive HCV RNA PCR result will exclude patients; calculated creatinine clearance <30 mL / min at screening (Cockcroft-Gault formula; Cockcroft and Gault, 1976); alanine transaminase (ALT) ≥ 2 × upper limit of normal (ULN) of the laboratory performing the screening, aspartate aminotransferase (AST) ≥ 2 × ULN, total bilirubin level (TBL) ≥ 1.5 × ULN, or alkaline phosphatase (ALP) ≥ 1.5 × ULN at screening;Have received treatment with stable doses of AChEI and / or memantine for less than 2 months before non-randomization; changes in concomitant medications that could potentially affect cognition and their dosing should be stable for at least 1 month before screening and between screening and non-randomization (does not apply to medications discontinued due to exclusion or with a limited duration of use, such as antibiotics); current use of medications known to significantly prolong the QT interval; have received previous treatment with passive anti-amyloid immunotherapy for less than 5 half-lives before non-randomization; have undergone active immunization against Aβ in any other study; have a known allergy to donanemab, related compounds, or any component of the formulation; or have a history of significant atopy; have an allergy to any monoclonal antibody, diphenhydramine, epinephrine, or methylprednisolone; [; 18 F]-florbetapir or [ 18 sensitivity to [F]-flortaucipir; contraindication to MRI; contraindication to PET; existing or planned exposure to ionizing radiation that, in combination with the planned administration of the test PET ligand, results in a cumulative exposure exceeding the local recommended exposure limit. Dose Modifications for ARIA-E: Dose modifications of donanemab will be adjusted for the occurrence of ARIA-E, with examples shown in Table A below. If a dose reduction is necessary, reduce the dose of donanemab to the next lower dose (1400 mg to 700 mg or 700 mg to placebo).

[0147] [Table 1] a The investigator may choose to temporarily discontinue donanemab after discussion with the sponsor. b If a patient has a second occurrence of ARIA-E and previously had the dose of donanemab reduced or donanemab temporarily discontinued, then donanemab will be permanently discontinued.

[0148] All cases of ARIA-E require unscheduled MRI scans every 4 to 6 weeks until the ARIA-E resolves. Discontinuation of Study Treatment: Reasons that may lead to permanent discontinuation of study treatment: Subject decision (subject, or subject's designee; e.g., legal guardian requests discontinuation of investigational drug) or discontinuation due to a hepatic event or abnormal liver test. Subjects who discontinue investigational drug due to a hepatic event or abnormal liver test should have additional liver safety data collected via CRF / electronic data entry.

[0149] Interruption of investigational drug for abnormal liver tests will be considered if the subject meets one of the following conditions: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 x upper limit of normal (ULN); ALT or AST >5 x ULN; ALT or AST >3 x ULN and total bilirubin level (TBL) >2 x ULN for more than 2 weeks; or international normalized ratio (IMR) >1. INR) >1.5; ALT or AST >3 x ULN with the occurrence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%); alkaline phosphatase (ALP) >3 x ULN; ALP >2.5 x ULN and TBL >2 x ULN; or ALP >2.5 x ULN with the occurrence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%).

[0150] In addition, subjects will be discontinued from investigational drug in the following circumstances: Donanemab treatment should be permanently discontinued in the following patients: The incidence of a second ARIA-E after a previous dose reduction or temporary interruption of donanemab; Any increase in ARIA-H accompanied by clinically significant symptoms; More than four new microbleeds, more than one new area of ​​superficial hemosiderosis or significant worsening of pre-existing superficial hemosiderosis, or any macrobleed regardless of symptoms; or - ARIA-E events reported as significant adverse events (SAEs), regardless of the severity of symptoms or MRI findings. Donanemab treatment should also be permanently discontinued in the following patients: persistent acute infusion reaction (i.e., unresponsive to medications such as antihistamines, nonsteroidal anti-inflammatory drugs, and / or narcotics, and / or brief interruption of the infusion); or Adverse events or clinically significant laboratory test values, ECG results, physical examination findings, MRI findings (such as symptomatic ischemic stroke),

[0151] Temporary interruption of donanemab study treatment due to ARIA-E A temporary interruption from donanemab treatment is permitted for an ARIA-E if the ARIA-E meets the interruption criteria set forth in Table A. In the case of an ARIA-E where the protocol indicates continued dosing or a dose reduction rather than an interruption, administration of donanemab may be temporarily interrupted.

[0152] Donanemab may be resumed after the first occurrence of ARIA-E, for example, if dosing is temporarily interrupted due to ARIA-E and symptoms and radiological findings completely resolve within 16 weeks after temporary drug discontinuation. If ARIA-E symptoms and radiological findings do not completely resolve within 16 weeks, the patient will be permanently discontinued from donanemab treatment.

[0153] Study drug may be restarted at either 700 mg or placebo in a double-blind fashion, depending on the original study arm to which the patient is non-randomized. An unscheduled safety MRI scan is required 4-6 weeks after resumption of medication. Efficacy Assessment: Cognitive and functional testing will be conducted using the eCOA tablet. Audio recordings of the assessor's questions and the patient's and research partner's responses will also be collected via the eCOA tablet during the administration of cognitive and functional tests for centralized monitoring of assessor-scale administration. Each patient's cognitive and functional testing should be conducted at approximately the same time each day to reduce potential variability. Note that the ADAS-Cog and MMSE must be administered by different assessors than the ADCS-ADL and CDR. These two assessors should continue to administer the same scales on the same patients throughout the study. If possible, each assessment should be conducted for a given patient by the same assessor at each visit. The principal investigator (PI) is responsible for selecting the assessors who will administer the instruments on-site, provided that all training requirements are met by these assessors.

[0154] When administered, cognitive and functional testing should be performed first before any medical procedures that may be stressful for the patient (e.g., blood draws). 18 F]-Flortaucipir PET tau imaging, 18 Note that [F]-flourtaucipir PET amyloid imaging) can be performed on other days within the visit window. Primary efficacy endpoints: The Integrated Alzheimer's Disease Rating Scale (iADRS; see Wessels et al., "A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS)," J Prev Alzheimers Dis, Vol. 2(4):227-241 (2015), which is incorporated herein by reference in its entirety. The iADRS represents a composite developed using both a theory-driven approach (incorporating measures of both cognition and function) and a data-mining approach (identifying the most sensitive combination of scales through analysis of data from the Alzheimer's Disease Neuroimaging Initiative). The iADRS measures core domains of AD, including ADAS-Cognitive Assessment Score (ADAS-Cognitive Assessment Score). 13 The iADRS score is a simple linear combination of scores from two well-established, treatment-sensitive, and widely accepted measures: the ADAS-Cognitive Assessment and Learning Disorders (ADCS-iADL). All items from these two scales are included without additional item weighting, providing face validity and ease of interpretation of the composite relative to its components. The iADRS score is a linear combination of the ADAS-Cognitive Assessment and Learning Disorders (ADCS-iADL). 13 and ADCS-iADL, and is the primary validity measure. 13 and ADCS-ADL are the actual scales administered to patients. Secondary efficacy evaluations: Additional clinical outcome measures were ADAS-Cog 13 The doses should be administered in the same order at each visit, immediately after the assessment of the serotonin receptor agonist (SNR). To minimize missing data, the assessor should include each oral measurement (as specified in the instructions) with the patient or study partner and record responses appropriately. The same study partner should be used as the informant at all visits. Alzheimer's Disease Assessment Scale-Cognitive Subscale: ADAS-Cog 13The ADAS-Cog is a rater-administered instrument designed to assess the severity of impairments in cognitive and non-cognitive behaviors characteristic of individuals with AD (see Rosen et al., "A New Rating Scale for Alzheimer's Disease," Am J Psychiatry. 141(11):1356-1364 (1984), which is incorporated herein by reference in its entirety). 13 The cognitive subscale of the ADAS, the ADAS-Cog, should be administered by the same assessor from visit to visit to reduce potential variability. 13 The ADAS-Cognitive Assessment Scale (ADAS) consists of 13 items that assess the areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit cancellation, and a maze-completion measure (Mohs et al., "Development of Cognitive Instruments for Use in Clinical Trials of Antidementia Drugs: Additions to the Alzheimer's Disease Assessment Scale that Broaden its Scope," The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord., Vol. 11 (Suppl. 2): S13-S21 (1997), which is incorporated herein by reference in its entirety). 13 The ADAS-Cog allows for better discrimination between mildly affected patients than the ADAS-Cog11 and is included as a secondary outcome. 13 The scale ranges from 0 to 85, with higher scores indicating greater disease severity. Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory: The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire completed by the patient's research partner (Galasko et al., "An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer's Disease," The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord., 1997; Vol. 11 (Suppl. 2): S33-S39; Galasko et al., "Galantamine Maintains Ability to Perform Activities of Daily Living in Patients with Alzheimer's Disease," J Am Geriat Soc., Vol. 52 (No. 7): 1070-1076 (2004), which are incorporated herein by reference in their entireties). The ADCS-ADL should be administered by the same rater from visit to visit to reduce potential variability. The ADCS-ADL subset (items 7–23) for instrumental activities of daily living (iADL) is used as a secondary efficacy measure. The focus in the early symptomatic AD population is on iADL, rather than basic activities of daily living (bADL), which are thought to be affected in more severe stages of the disease. iADL scores range from 0 to 56, with lower scores indicating greater disease severity. For each specific item, the research partner is first asked whether the patient has attempted an ADL in the past 4 weeks. If the patient has attempted an ADL, the research partner is asked to rate the patient's performance level based on a set of performance descriptors. Scores for each item and an overall score for the tool are calculated. The total ADCS-ADL score ranges from 0 to 78, with higher scores indicating greater levels of functional impairment. A separate score for bADL (0–22) is also calculated. Clinical Dementia Rating Scale: The CDR is a semi-structured interview conducted with the patient and research partner (informant) that provides a comprehensive measure of functioning (see Berg et al., "Mild Senior Dementia of the Alzheimer's Type 4. Evaluation of Intervention," Ann Neurol., Vol. 31(3):242-249 (1992), incorporated herein by reference in its entirety). The CDR should be administered by the same assessor from visit to visit to reduce potential variability. Informants are asked questions about the patient's memory, orientation, judgment, and problem-solving, community issues, home and hobbies, and personal care. The scale assesses the patient's memory, orientation, judgment, and problem-solving abilities. Higher scores indicate greater disease severity. Assigning severity scores to each of the six domains results in a total score known as the sum of the boxes, hence the abbreviation CDR-SB. The CDR-SB ranges from 0 to 18, with higher scores indicating greater functional impairment. The Mini-Mental State Examination (MMSE) is a brief instrument used to assess a patient's cognitive function (see Folstein et al., "Mini-Mental State: A Practical Method for Grading the Cognitive State of Patients for the Clinician," J Psychiatr Res., Vol. 12(13):189-198 (1975), which is incorporated herein by reference in its entirety). The MMSE should be administered by the same assessor from visit to visit to reduce potential variability. The instrument is divided into two sections. The first section measures orientation, memory, and attention. The maximum score for the first section is 21. The second section tests the patient's ability to name objects, follow verbal and written commands, write sentences, and copy figures. The maximum score for the second section is 9. Total MMSE scores range from 0 to 30, with lower scores indicating greater levels of impairment. Biomarker efficacy measurement (double-blind period) 18 F]-florbetapir PET scan: baseline, Week 52 [Visit 15] and Week 76 [Visit 21], or early discontinuation (ED) 18 Changes in amyloid burden ([ F]-florbetapir PET scans in donanemab-treated and placebo-treated patients 18 F]-florbetapir PET signal). [ 18 F]-Flortaucipir PET scan: baseline and endpoint (Visit 21 [Week 76] or ED) 18 Changes in tau burden ([ F]-flourtaucipir scans) in donanemab-treated and placebo-treated patients 18 F]-flortaucipir PET signal). Volumetric MRI: Brain magnetic resonance imaging may be performed between visits 2 and 14. The effects of donanemab treatment and placebo treatment on volumetric MRI will be evaluated and compared to assess the brain volume loss that occurs in patients with AD. Amyloid deposit clearance: baseline, Visit 8 (Week 24), Visit 15 (Week 52), and endpoint Visit 21 (Week 76), or ED[ 18 For patients undergoing [F]-florbetapir PET scans, the clearance of amyloid deposits ([ 18 F]-florbetapir PET signal). Accumulation of tau deposits: ([ 18 The extent of tau PHF deposit accumulation (assessed by [F]-flortaucipir PET signal) was assessed at baseline and endpoint visit 21 (week 76), or at ED[ 18 Patients undergoing [F]-flourtaucipir PET scans will be compared between donanemab-treated and placebo-treated patients. Biomarkers: Biomarker studies are conducted to address questions of drug disposition, target engagement, PD, mechanism of action, variability in patient response (including safety), and correlation with clinical outcomes. Sample collection is integrated into clinical studies to enable examination of these questions through the measurement of biomolecules, including deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, lipids, and other cellular elements. Serum, plasma, and whole blood RNA samples for biomarker studies are collected between visits 2 and 14, as local regulations permit.

[0155] Example 3: Safety, Tolerability, and Efficacy Study Results Donanemab was selected as the exemplary antibody for this example. This example provides results from the safety, adverse events, and efficacy of donanemab in participants with early symptomatic AD. Enrollment was based on florbetapir and flortaucipir positron emission tomography (PET) scans, which demonstrated tau and amyloid plaque pathology, respectively. Participants received either intravenous placebo or donanemab (700 mg for doses 1-3, then 1400 mg) every 4 weeks for up to 72 weeks. The primary outcome measure was the change from baseline at week 76 in the integrated AD Rating Scale (iADRS; range 0-144, lower scores indicate greater cognitive deficits and impairment in activities of daily living). Secondary outcome measures included the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; range 0-18, higher scores indicate greater impairment), the AD Rating Scale-Cognitive (ADAS-Cognitive), and the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; range 0-18, higher scores indicate greater impairment). 13 ; range 0-85, higher scores indicate greater disease severity), AD Collaborative Study-Instrumental Activities of Daily Living (ADCS-iADL; range 0-59, lower scores indicate greater functional impairment), Mini-Mental State Examination (MMSE; range 0-30, lower scores indicate greater functional impairment), florbetapir and [ 18 These include amyloid and tau burden assessed by [F]-florbetapir PET, and volumetric magnetic resonance imaging MRI (vMRI), respectively. Patient Population and Study Design: This study is a multicenter, non-randomized, double-blind, placebo-controlled trial evaluating the safety, adverse events, and efficacy of donanemab in participants aged 60-85 years with early symptomatic AD (a combination of prodromal AD, symptomatic pre-dementia phase of AD with overt MCI [MCI-AD], and mild AD dementia [symptoms severe enough to meet dementia and AD diagnostic criteria]) (Dubois et al., "Research Criteria for the Diagnosis of Alzheimer's Disease: Revising the NINCDS-ADRDA Criteria," The Lancet Neurology, 6:734-46 (2007), which is incorporated herein by reference in its entirety). Screening procedures include the Mini-Mental State Examination (MMSE; range 0-30, lower scores indicate greater impairment, Folstein et al., "Mini-mental state. A Practical Method for Grading the Cognitive State of Patients for the Clinician," J. Psychiatr. Res., Vol. 12:189-98 (1975), which is incorporated herein by reference in its entirety), 18 F]-florbetapir PET scan, magnetic resonance imaging (MRI), and [ 18 F]-florbetapir PET scan. 18[F]-florbetapir PET scans were reviewed by a centralized PET imaging facility to assess patient eligibility. All eligible patients were required to have evidence of pathological tau on PET scan and quantitative tau levels below a specified upper threshold. The latter criterion addressed concerns that anti-amyloid treatments have limited efficacy in advanced disease, as indicated by the presence of widespread tau pathology. Tau images were obtained using published methods (Pontecorvo et al., "A Multicentre Longitudinal Study of Flortaucipir (18F) in Normal Aging, Mild Cognitive Impairment and Alzheimer's Disease Dementia," Brain, Vol. 142: 1723-35 (2019); Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," Journal of Nuclear Medicine, Vol. 59: 937-43 (2018); Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity,” J. Nucl. Med., 59:944-51 (2018), which is incorporated herein by reference in its entirety), and to visually assess, for example, whether a patient has an AD pattern (Fleisher et al., “Positron Emission Tomography Imaging With 18 [F]-flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes,” JAMA Neurology, 77:829-39 (2020), incorporated herein by reference in its entirety.

[0156] Any image with an SUVr > 1.46 was excluded as having high tau. For images not excluded as having high tau, images with an SUVr value < 1.10 or visually interpreted as having a negative AD pattern were excluded as having implausible tau levels, except that images visually interpreted as having a severe tau AD pattern but with an SUVr value < 1.10 were still included. With the exception of MRI, each patient underwent a screening [ 18 All other Visit 1 eligibility criteria had to be met before the [F]-florbetapir PET scan.

[0157] Participants who met the inclusion criteria were nonrandomized 1:1 to receive either intravenous (IV) donanemab every 4 weeks (700 mg for the first three doses, then 1400 mg) or IV placebo every 4 weeks for up to 72 weeks. Nonrandomization of participants was stratified by study site for comparability between groups for site factors. There was no stratification by entry criteria. Participants treated with donanemab had their dose reduced to 700 mg if amyloid clearance in centimeters (CL) measured by florbetapir scan (weeks 24 and 52) was ≥11 but <25, or switched to placebo if either measure was <11, or if two consecutive scans were ≥11 but <25. Cases of amyloid-related imaging abnormalities - edema / exudation (ARIA-E; signal hyperintensity on MRI in fluid-attenuated inversion recovery imaging sequences due to parenchymal fluid accumulation or sulcal fluid exudation; Sperling et al., "Amyloid-related Imaging Abnormalities in Amyloid-Modifying Therapeutic Trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup," Alzheimer's & Dementia, Vol. 7:367-85 (2011), which is incorporated herein by reference in its entirety) occurred during the first three dose escalations of 700 mg, and this dose was not escalated. Final endpoint measurements and safety assessments were performed at Week 76, 4 weeks after the last infusion. Clinical and Biomarker Outcome Measures: The primary outcome measure was the change from baseline to 76 weeks in the iADRS score compared to placebo (range 0-144, with lower scores indicating greater cognitive deficits and impairment in daily living functioning; see Wessels et al., "A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS)," J. Prev. Alzheimer's Dis., Vol. 2:227-41 (2015), which is incorporated herein by reference in its entirety). The iADRS is a linear combination of its individual components, the AD Assessment Scale-Cognitive (ADAS-Cognitive). 13ranges from 0 to 85, with higher scores indicating greater disease severity; Mohs et al., "Development of Cognitive Instruments for Use in Clinical Trials of Antidementia Drugs: Additions to the Alzheimer's Disease Assessment Scale that Broaden its Scope. The Alzheimer's Disease Cooperative Study," Alzheimer Dis Assoc Disord, Vol. 11, Suppl. 2: S13-21 (1997), which is incorporated herein by reference in its entirety) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL; ranges from 0 to 59, with lower scores indicating greater functional impairment; Galasko et al., "An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer's Disease," Alzheimer Disease and Associated Disorders, Vol. 11, S33-S9 (1997), and Galasko et al., "Galantamine Maintains Ability to Perform Activities of Daily Living in Patients with Alzheimer's Disease,” Journal of the American Geriatrics Society, 52:1070-6 (2004), which are incorporated herein by reference in their entireties.

[0158] The iADRS was developed using theoretical constructs intended to measure core disease processes, and clinical trial data was used to identify items / scales that best function against those constructs. 13All items from the total score and ADCS-iADL score are included without item weighting, providing face validity and ease of interpretation of both the composite and its components. The iADRS allows for an overall measure of AD impairment (total score) and individual subscores (cognitive and functional). Validation of the iADRS has been established, and statistical properties of composite performance have been described.

[0159] Secondary outcome measurement methodologies included the Clinical Dementia Rating Scale-Sum-of-Boxes (CDR-SB; range 0-18, higher scores indicate greater impairment; Morris, "The Clinical Dementia Rating (CDR)," Current Version and Scoring Rules, Vol. 43:2412-a (1993) which is incorporated herein by reference in its entirety), ADAS-Cog, assessed by florbetapir and [18F]-flortaucipir PET, respectively. 13 The ADCS-iADL, MMSE, amyloid and tau burden, and volumetric MRI are detailed in the protocol. Comprehensive tau load assessment was performed using the Tau Scale, which takes into account the spatiotemporal distribution of tau. IQ This was performed using an algorithm (Whittington et al., "TauIQ-A Canonical Image Based Algorithm to Quantify Tau PET Scans," J. of Nuclear Medicine (2021), which is incorporated herein by reference in its entirety). Sample Size and Statistical Analysis Determination: Enrolling 250 participants non-randomized 1:1 into the two treatment groups, with 200 participants expected to complete treatment, was determined to provide approximately 84% power to demonstrate that the dynamic treatment group had a posterior probability of 0.6 or greater of slowing iADRS progression by at least 25% compared with placebo. Assumptions for power calculations were mean progression levels in the placebo and donanemab groups of approximately 12 and 6 points (50% slowing), respectively, over 18 months, with a common standard deviation of 17. Efficacy analyses were conducted on a modified intention-to-treat basis (unless otherwise specified), with participants having baseline and at least one post-baseline iADRS measurement. Unless otherwise specified, all pairwise tests of treatment effect were performed at a two-sided alpha level of 0.05.

[0160] Baseline characteristics were summarized by treatment group and overall, using descriptive statistics for continuous and categorical measures. The primary outcome was analyzed using mixed-model repeated-measures (MMRM) analysis, with the change from baseline in iADRS score at each scheduled post-baseline time point as the dependent variable. The fixed-effects model included the following terms: baseline score, investigator, treatment, visit, interaction by visit, baseline by visit interaction, use of acetylcholinesterase inhibitors and / or memantine (yes / no) at baseline, and age at baseline. Visit was considered a categorical variable. Secondary efficacy outcomes were assessed using MMRM analysis. Bretz's graphical approach (Bretz et al., "A Graphical Approach to Sequentially Rejective Multiple Test Procedures," Statistics in Medicine, Vol. 28(4):586-604 (2009), which is incorporated herein by reference in its entirety) was used to obtain study-wise type I error rate control for the primary and significant secondary hypotheses at an alpha level of 0.05. Assuming the primary analysis was significant, the MMRM analysis described for the primary analysis was performed on the CDR-SB, ADAS-Cog, and MMRM-Cog groups. 13 Significance was determined based on the ADCS-iADL and MMSE scores, and multiplicity graphs of hypotheses. Long-term clinical outcomes were obtained using point estimates and error bars. For post-baseline categorical data, Fisher's exact test was used for treatment group comparisons. For post-baseline continuous data collected at endpoint, analysis of covariance (ANCOVA) with independent factors for treatment and age was used. Each primary site investigator was responsible for selecting raters who met the training requirements to administer the instruments at the site. Raters were blinded to treatment assignment.

[0161] A Bayesian disease progression model (DPM) was used to assess the rate of decline in iADRS between the donanemab and placebo groups over the 76-week study period, as prespecified in the protocol. This model assumes a proportional treatment effect compared to placebo and includes a diffuse prior distribution. A similar model was previously used, except that the prior distribution of the parameter representing placebo decline in the current model was not forced to be monotonic. The analysis yielded a posterior probability distribution of the disease progression ratio (DPR), defined as the proportional decline in the donanemab group relative to placebo. A DPR of less than 1 favors donanemab. The 95% confidence intervals and posterior mean disease progression ratios are presented. The posterior probability of a dynamic treatment group achieving at least a 25% slowing of disease progression compared to placebo was prespecified and calculated from the DPM. The DPM model was used to assess CDR-SB, ADAS-Cog, and variance in the CDR-SB and ADAS-Cog scores. 13 The rate of decline in ADCS-iADL and MMSE was assessed. As part of the pre-specified multiplicity testing strategy for secondary endpoints, the DPM model was not included.

[0162] Safety parameters (AEs, laboratory analytes, vital signs, electrocardiograms, and MRI) were summarized during the treatment period using descriptive statistics for continuous variables and frequencies, with percentages for categorical variables.

[0163] Missing data in the MMRM model were handled using a likelihood-based mixed-effects model for repeated measures. Model parameters were simultaneously estimated using restricted likelihood estimation incorporating all observed data. Estimates have been shown to be unbiased when missing data are missing at random and when there is negligible non-random missing data. Repeated measures analyses used only data from visits where data were scheduled to be collected. If participants discontinued the study early, there may be efficacy or safety data measurements at visits where variables were not scheduled to be collected. This data was used for all other analyses.

[0164] Population and Baseline Characteristics: Baseline demographic data for the placebo and donanemab monotherapy groups were as follows: mean age 75.4 and 75.0 years, 51.6% and 51.9% women, 96.0% and 93.1% white race, and 74.2% and 72.5% APOE4 carriers, respectively (Table B).

[0165] [Table 2] * Note: Includes multiple American Indian or Alaska Native groups. † Includes participants in combined groups. # the number of participants with non-missing data, used as a common factor; a Donanemab monotherapy N=130, b Total N=271, c Placebo N=121, d Donanemab monotherapy N=126, e Total N=261, f Placebo N=124, g Donanemab monotherapy N=130, h Total N = 269. APOE 4 = apolipoprotein E allele 4; AChEI = acetylcholinesterase inhibitor; ADAS-Cog 13 = AD Rating Scale-Cognitive 13-item subscale; ADCS-ADL = Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory; ADCS-iADL = Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory; iADRS = Integrated Alzheimer's Disease Rating Scale; MMSE = Mini-Mental State Examination; CDR-SB = Clinical Dementia Rating Scale-Box Sum; PET = Positron Emission Tomography; N / n = number of participants; SD = standard deviation;

[0166] At the start of the study, the trial consisted of three arms, including a combination arm of donanemab and a BACE 1 inhibitor. This arm was discontinued early in the study, and 15 participants were randomized to that arm. In the modified intention-to-treat population, of the 1,955 participants screened, 126 were randomized to placebo and 131 were randomized to donanemab. The mean baseline scores on the iADRS were 105.9 for placebo and 106.2 for donanemab; for MMSE, they were 23.7 and 23.6, respectively; and the CDR-SB scores were 3.4 and 3.6. 18 The global tau loads for [F]-flortaucipir PET were 0.46 and 0.47; amyloid PET values ​​were 101.1 and 107.6 (Table B). Primary Outcome: Donanemab demonstrated a significant slowing of decline in a composite measure of cognition and daily functioning compared with placebo in patients with early-symptomatic Alzheimer's disease. Donanemab met the primary endpoint of change from baseline to 76 weeks on the Integrated Alzheimer's Disease Rating Scale (iADRS), which slowed the decline by 32% compared with placebo (Figure 2A), a statistically significant improvement. The iADRS is a composite of two commonly used measures of Alzheimer's disease: the cognitive scale ADAS-Cognitive Assessment Scale (ADAS-Cognitive Assessment Scale) and the cognitive scale ADAS-Cognitive Assessment Scale (ADAS-Cognitive Assessment Scale). 13 and the ADCS-iADL functional scale. The change from baseline in iADRS at 76 weeks was -10.06 in placebo and -6.86 in donanemab-treated patients (treatment difference: 3.20, 95% confidence interval [CI]: 0.12, 6.27; p = 0.04) (Figure 2A and Table C).

[0167] Figures 2A to 2F show the results of the primary iADRS and the secondary CDR-SB and ADAS-Cog 13Clinical outcomes for the CDR-SB (Figure 2C), ADAS-iADL, and MMSE are shown. Figure 2A shows the results of the LS mean change from baseline to week 76 for the primary outcome, iADRS score, analyzed with MMRM. Figure 2B shows percent slowing estimates from the MMRM model at the 18-month endpoint and the Bayesian DPM model throughout the 18-month study. 95% confidence intervals are shown. Figures 2C-2F show the results of the CDR-SB (Figure 2C), ADAS-Cog, and MMSE, analyzed with MMRM. 13 Results are shown for the secondary outcome, LS mean change from baseline to 76 weeks in ADCS-iADL (Figure 2D), ADCS-iADL (Figure 2E), and MMSE scores (Figure 2F). In Figures 2A-2F, Δ = difference; W = weeks; iADRS = Integrated Alzheimer's Disease Assessment Scale; ADAS-Cog 13 = Alzheimer's Disease Assessment Scale-Cognitive Subscale; ADCS-iADL = Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale; CDR-SB = Clinical Dementia Rating Scale-Sum of Boxes; MMSE = Mini-Mental State Examination; MMRM = Mixed Model for Repeated Measures; DPM = Disease Progression Model; LS = Least Squares; CI = Confidence Interval; n = Number of Participants; SE = Standard Error.

[0168] [Table 3] Primary iADRS and secondary ADAS-Cog analyzed with MMRM 13 Results of mean change from baseline for ADCS-iADL, CDR-SB, and MMSE clinical outcomes. iADRS = Integrated Alzheimer's Disease Assessment Scale; ADAS-Cog 13 = Alzheimer's Disease Assessment Scale-Cognitive Subscale; ADCS-iADL = Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale; CDR-SB = Clinical Dementia Rating Scale-Sum of Boxes; MMSE = Mini-Mental State Examination; MMRM = Mixed Models for Repeated Measures; LS = Least Squares; CI = Confidence Interval; SE = Standard Error

[0169] Estimates of percent slowing of disease progression compared to placebo from the MMRM model at the 18-month endpoint and from Bayesian DPM over the entire 18-month period showed a slowing of iADRS decline with both methods (Figure 2B). The posterior probability of at least a 25% slowing of disease progression compared to placebo on the iADRS was calculated as 0.78 from Bayesian DPM. Secondary Outcomes: Donanemab also demonstrated consistent improvements compared with placebo in all prespecified secondary endpoints measuring cognition and function, although not all secondary endpoints reached nominal statistical significance. In the donanemab group, the observed differences from placebo in change from baseline at 76 weeks were -0.36 (95% CI: -0.83 to 0.12) for CDR-SB and -0.36 (95% CI: -0.83 to 0.12) for ADAS-Cog. 13 The mean scores for ADCS-iADL were −1.86 (95% CI: −3.63 to −0.09), for ADCS-iADL were 1.21 (95% CI: −0.77 to 3.20), and for MMSE were 0.64 (95% CI: −0.40 to 1.67) (Figures 2C to 2F and Table D).

[0170] [Table 4] Primary iADRS and secondary ADAS-Cog analyzed with MMRM 13 Results of mean change from baseline for ADCS-iADL, CDR-SB, and MMSE clinical outcomes. iADRS = Integrated Alzheimer's Disease Assessment Scale; ADAS-Cog 13 = Alzheimer's Disease Assessment Scale-Cognitive Subscale; ADCS-iADL = Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale; CDR-SB = Clinical Dementia Rating Scale-Sum of Boxes; MMSE = Mini-Mental State Examination; MMRM = Mixed Models for Repeated Measures; LS = Least Squares; CI = Confidence Interval; SE = Standard Error By targeting the biomarker N3pGlu Aβ, donanemab treatment has been shown to rapidly result in high levels of amyloid plaque clearance, as measured by amyloid imaging. For PET amyloid, participants treated with donanemab demonstrated a reduction in 85CL amyloid plaques at week 76 compared to placebo (placebo = 0.93, donanemab = -84.13) (Figure 3A). Separation of 68CL reductions was evident in the donanemab group by week 24 compared to placebo (placebo = -1.82, donanemab = -69.64; a 65% reduction from baseline in the donanemab group). At weeks 24, 52, and 76, the proportions of participants in the donanemab group who were "amyloid-negative," defined as amyloid plaques less than 24.1 cm, were 40.0%, 59.8%, and 67.8%, respectively (Figure 3A). Approximately 27% and 55% of donanemab participants receiving the drug at weeks 28 and 56, respectively, achieved adequate amyloid reduction to reduce to placebo infusion. In this study, patients discontinued donanemab and switched to placebo when amyloid plaque levels were less than 25 cm on two consecutive measurements or less than 11 cm on any measurement.

[0171] [ 18 Comprehensive tau loading assessment by [F]-flortaucipir PET revealed no differences between groups from baseline to 76 weeks (Figure 3B-1). However, Figure 3B-2 shows significant slowing of tau for the globally measured MUBADA / cerebellar peduncle reference region. Unlike other analyses that focus on individual lobes or regions, this figure shows the effect of donanemab on total tau (neurofibrillary tangles measured by flortaucipir PET) progression throughout the brain. The MUBADA region represents a comprehensive region throughout the brain that corresponds to typical areas with neurofibrillary tangle accumulation consistent with Alzheimer's disease. Treatment with donanemab has a statistically significant effect on slowing the progression of neurofibrillary tangles throughout the brain. In Figure 3B-2, " *" indicates p<0.05, BL = baseline; LS = least squares; MUBADA = multiblock centroid discriminant analysis; N = number of participants; SE = standard error; SUVr = standardized uptake value ratio.

[0172] Hippocampal volume changes assessed by vMRI showed no differences between groups (Figure 3E). Participants treated with donanemab had greater decreases in total brain volume and increases in ventricular volume compared with placebo (Figures 3C and 3D).

[0173] Figures 3A-3E show secondary biomarker outcomes. Figure 3A shows the [ 18 Figure 3B shows the results for the secondary outcome, change from baseline to 76 weeks, in cerebral amyloid plaque deposition, as measured by [F]-florbetapir PET scan. "Amyloid negative" / <24.1 CL = mean CL level in otherwise healthy, similar elderly individuals. 18 Figure 3 shows global tau loading measured by [F]-flortaucipir PET scan. Figures 3C-E show vMRI of the whole brain (Figure 3C), ventricles (Figure 3D), and hippocampus (Figure 3E). In Figures 3A-E, Δ = difference; W = weeks; LS = least squares; CI = confidence interval; CL = centimeter; n = number of participants; SE = standard error. Adverse Events: There was no difference in the incidence of death or serious adverse events (SAEs) between the donanemab and placebo groups. A total of 113 (90.4%) of 125 participants in the placebo group and 119 (90.8%) of 131 participants in the donanemab group had at least one treatment-emergent adverse event (TEAE) during the double-blind period in the safety population. The incidence of ARIA-E was significantly higher in the donanemab group (27%) compared with placebo (0.8%). Symptomatic ARIA-E was reported by 6.1% of all participants in the donanemab group (22% of participants with ARIA-E) compared with 0.8% in the placebo group. Most ARIA-E cases occurred within 12 weeks of treatment initiation. Severe symptomatic ARIA-E requiring hospitalization occurred in two participants treated with donanemab (1.5%). Both participants had symptoms of confusion, and one reported difficulty expressing himself; all completely resolved. ARIA-E completely resolved in both cases, with a mean ARIA-E resolution time of 18 weeks. The incidence of central nervous system superficial hemosiderosis (a type of ARIA with hemorrhage (ARIA-H)), nausea, and infusion-related reactions (IRRs) were all significantly higher in the donanemab group compared with placebo. Treatment discontinuation due to ARIA-E occurred in seven participants (5.3%) in the donanemab group, and two participants (1.5%) discontinued the study due to ARIA-E. No cerebral macrohemorrhages were observed in either group. IRRs were reported in 7.6% of donanemab participants and 0% of placebo participants. Serious IRR or hypersensitivity reactions occurred in 3 participants (2.3%) treated with donanemab. The incidence of treatment-emergent anti-drug antibodies (TE-ADAs) in participants treated with donanemab was approximately 90%.

[0174] These results demonstrate that amyloid clearance in donanemab, an amyloid plaque-specific intervention in patients with early symptomatic AD, was accompanied by a slowing of disease progression compared with placebo. This treatment difference of 3.20 on the iADRS scale at 76 weeks should be interpreted in the context of not only the score range across the entire disease spectrum (0-144), but also, importantly, the dynamic range of the iADRS within the participant population (26 points) and the decline in the placebo group (-10.06).

[0175] The results provided herein are unexpected and surprising in several respects. The dosing regimen of donanemab provided extensive amyloid clearance early in the study, with nearly 60% of participants having "amyloid-negative" scans by week 52. This is 18 This is the first trial to screen all participants with [F]-flourtaucipir PET scanning, which is likely to narrow the scope of underlying pathology and thus reduce the variance in clinical decline.

[0176] Tau PET screening of patients excluded subjects with high tau, who are less responsive to anti-amyloid treatment or have disease that is more resistant to anti-amyloid treatment.

[0177] Using a relatively novel disease progression model as proposed by the European Prevention of Alzheimer's Dementia project, we have developed a model for the iADRS, ADAS-Cog 13Analysis of treatment differences in ADCS-iADL, CDR-SB, and MMSE scores was performed. This model may allow for a substantial increase in statistical power (Wang et al., "A Novel Cognitive Disease Progression Model for Clinical Trials in Autosomal-Dominant Alzheimer's Disease," Statistics in Medicine 37:3047-55 (2018)), which is incorporated herein by reference in its entirety, along with better sensitivity for detecting treatment effects (Solomon et al., "European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS): Study Protocol," BMJ Open 8:e021017 (2018)), which is incorporated herein by reference in its entirety), and this study revealed similar estimates of disease slowing to the single point estimate of the MMRM model.

[0178] Regarding the observed lack of treatment effect on comprehensive tau loading, it is believed that PET tau changes lag substantially behind amyloid changes, and that the 18-month time period is too short to detect imaging changes. Modeling in autosomal dominant subjects suggests a 10-20 year delay from the first detectable PET amyloid changes and the first detectable tau PET changes (see Barthelemy et al., "A Soluble Phosphorylated Tau Signature Links Tau, Amyloid, and the Evolution of Stages of Dominantly Inherited Alzheimer's Disease," Nat. Med., 26:398-407 (2020), which is incorporated herein by reference in its entirety). The lack of a comprehensive effect on tau may prompt questions about whether targeting amyloid-β reduction impacts biological disease progression. However, additional prespecified analyses of brain regions suggested reduced tau accumulation in the frontal and temporal lobe regions in the donanemab group compared to placebo (Figures 4A-4E).

[0179] A robust reduction or prevention of further increases in tau accumulation is seen, for example, in the frontal lobe of the brain. It is important to note that no statistical significance was seen in the occipital lobe of the brain. This lobe has some of the highest baseline signals and may therefore provide a ceiling effect on the ability to demonstrate reductions in increasing tau load.

[0180] Figures 4A-4E show regional SUVr analysis of tau accumulation relative to the cerebellar gray matter reference. Frontal lobe tau load, measured by flortaucipitin using the cerebellar reference region, correlates with changes in iADRS and CDR-SB over the following 76 weeks in symptomatic early AD subjects. In Figures 4A-4E, LS = least squares; SE = standard error; AAL region using the posterior cerebellar gray matter reference region. The frontal lobe shows a 59.1% slowing of tau accumulation (P value: 0.0020); the parietal lobe shows a 44.6% slowing of tau accumulation (P value: 0.0024); the occipital lobe shows a 21.0% slowing of tau accumulation (P value: 0.2036); and the lateral temporal lobe shows a 31.8% slowing of tau accumulation (P value: 0.0328).

[0181] 5A-5B show the change in baseline frontal tau SUVR versus placebo at 76 weeks and demonstrate that lower frontal tau burden is associated with less patient decline. Higher frontal tau burden is associated with more rapid patient decline. In other words, patients with lower frontal tau burden experience a slower decline (as measured by iADRS or CDR-SB) compared to patients with higher frontal tau burden.

[0182] This measurement reflects global changes in tau load, and further investigation may indicate subregions that may be more sensitive to changes. Optimal methods for region selection and analysis to quantify tau changes and response to treatment are still in their infancy.

[0183] In contrast to recent BACE inhibitor studies that showed significant volumetric changes, there were no significant changes in hippocampal volume (Wessels et al., "Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials," JAMA Neurology, Vol. 77:199-209 (2020), which is incorporated herein by reference in its entirety). The observation of greater total brain volume loss and greater ventricular volume increase with donanemab treatment compared to placebo may be interpreted as related to protein clearance rather than atrophy. Although global volumetric MRI changes are typically attributed to atrophy in natural history studies of AD, it remains unclear whether they represent true atrophy in the context of rapid structural clearance of protein aggregates, as seen in this study and another anti-amyloid treatment study (Sur et al., "BACE Inhibition Causes Rapid, Regional, and Non-progressive Volume Reduction in Alzheimer's Disease Brain," Brain 143:3816-26 (2020), which is incorporated herein by reference in its entirety).

[0184] ARIA-E and ARIA-H are associated with amyloid plaque removal therapy (Sperling et al., "Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's Association Research Roundtable Workgroup," Alzheimer's & Dementia, Vol. 7: 367-85 (2011); Sevigny et al., "The Antibody Aducanumab Reduces Aβ Plaques in Alzheimer's Disease," Nature, Vol. 537: 50-6 (2016); Ostrowitzki et al., "Mechanism of Amyloid Removal in Patients With Alzheimer's Disease Treated With Gantenerumab," Archives of Neurology, Vol. 69: 198-207 (2012); Salloway et al., "Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease," New England Journal of Neurology, Vol. 10: 198-207 (2012)). Journal of Medicine, Vol. 370: 322-33 (2014); Salloway et al., "A Phase 2 Multiple Ascending Dose Trial of Bapineuzumab in Mild to Moderate Alzheimer's Disease," Neurology, Vol. 73: 2061-70 (2009); and Sperling et al., "Amyloid-related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Bapineuzumab: A Retrospective Analysis," Lancet Neurol., Vol. 11: 241-9 (2012), which are incorporated herein by reference in their entireties.

[0185] In the phase 1b trial, the incidence of ARIA-E was 26.1% among participants treated with donanemab, where two participants reported symptomatic ARIA-E (4.3%). In this study, a similar incidence of ARIA-E was found in the donanemab group (27%), where 6.1% reported symptomatic ARIA-E. The incidence of ARIA-E was more prevalent in ApoE4 carriers, as seen in other trials of plaque-targeting antibodies (Sevigny et al., "The Antibody Aducanumab Reduces Aβ Plaques in Alzheimer's Disease," Nature, 2016; Vol. 537: 50-6; Ostrowitzki et al., "Mechanism of Amyloid Removal in Patients With Alzheimer's Disease Treated With Gantenerumab," Archives of Neurology, Vol. 69: 198-207; Salloway et al., "Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease," NEJM, 2014; Vol. 370: 322-33 (2014); and Sperling et al., "Amyloid-Related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Bapineuzumab: A Retrospective Analysis," Lancet Neurol., Vol. 11:241-9 (2012), which is incorporated by reference in its entirety.) The incidence of TE-ADAs in participants treated with donanemab (approximately 90%) was similar to the Phase 1 findings (>85%).

[0186] Taken together, these results demonstrate that in participants with early symptomatic AD, treatment with donanemab resulted in amyloid plaque clearance and slowing of cognitive and functional decline as measured by the iADRS scale.

[0187] Example 4: Efficacy Associated with Baseline Tau PET Patient Stratification Donanemab was selected as the exemplary antibody for this example. Donanemab, an anti-N3pGlu Aβ antibody, has been found to be most effective in subjects with the lowest baseline flortaucipitin levels, but may be less effective in subjects with high tau (>1.46 SUVr). In other words, subjects with high tau (>1.46 SUVr) may be less responsive to Aβ therapy.

[0188] Tau levels (e.g., for stratification of human subjects with AD) are determined based on an initial visual assessment of the flortaucipir scan, followed by quantitative analysis. Visual assessment relies on a three-stage readout (tAD-, tAD+, tAD++) based on the presence of tracer uptake in specific regions of the neocortex. Quantitative analysis refers to the calculation of SUVr, which represents counts within specific target regions of interest in the brain (e.g., multiblock centroid discriminant analysis or MUBADA) compared to a reference region (a parametric estimate of reference signal intensity or PERSI). Lower SUVr values ​​indicate lower tau burden, while higher SUVr values ​​indicate higher tau burden.

[0189] As shown in Table E, scans in the low to moderate tau group (e.g., with an SUVr of 1.10 or less to 1.46 or less) are eligible for administration of anti-N3pGlu Aβ antibodies. Visual Assessment: A method for visual assessment of human subjects is described by Fleisher et al., "Positron Emission Tomography Imaging With 18[F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes," JAMA Neurol., Vol. 77(7):829-839 (2020), which is incorporated herein by reference in its entirety. Briefly, a flortaucipir scan is negative (tAD-) if there is no increase in neocortical tracer activity in any region of the brain, or if activity is isolated to regions of the frontal lobe or temporal lobe that do not include the posterolateral temporal (PLT) region. Positive scans are classified into two categories based on the region of increased neocortical tracer activity. A flortaucipir scan in which neocortical tracer activity is limited to the posterolateral temporal (PLT) or occipital regions is classified as tAD+.

[0190] Finally, if a flortaucipir scan shows increased tracer activity in the parietal or precuneus regions, or activity in the frontal regions along with activity in the PLT or occipital regions, it is classified as tAD++. Quantitative analysis is performed on all tAD+ and tAD++ scans. Quantitative Analysis: Quantitative analysis is accomplished through an automated image processing pipeline. Previously developed neocortical target volumes of interest (VOIs) (see Mubada, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med., 2018; 59:937-943 (2018), which is incorporated herein by reference in its entirety) are applied to each scan, and derived counts are normalized to a patient-specific reference region (PERSI). Other target and reference regions are also extracted through the pipeline. PERSI reference regions are a subject-specific, data-driven technique that identifies voxels with nonspecific flortaucipir uptake within atlas-defined white matter regions (see, e.g., Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med., 59:944-951 (2018), which is incorporated herein by reference in its entirety). MUBADA target regions were developed using statistical methods to maximize separation of diagnostic groups based on image characteristics (see, Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med., 59:937-943 (2018), which is incorporated herein by reference in its entirety). When applied to flortaucipir images from a large dataset of 202 subjects (55Aβ-aged cognitively normal, 43Aβ-MCI, 54Aβ+MCI, 16Aβ-AD, and 34Aβ+AD), the analysis yielded two perspectives (a.k.a., components).The first perspective (explaining 95% of the variance) provided the greatest separation of groups by diagnosis and amyloid status and was converted into a VOI now referred to as the MUBADA VOI (see, e.g., Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med., 2018; 59:937-943 (2018), which is incorporated herein by reference in its entirety).

[0191] The MUBADA VOI ratios to the PERSI reference region were then applied to 204 subjects, and the resulting values ​​were divided into four tau burden quartiles: (1) very low; (2) low; (3) moderate; and (4) high. The cutoff SUVr values ​​separating very low from low were 1.10; low and moderate were 1.23; and moderate and high were 1.46. These values ​​are used to screen subjects according to the above algorithm.

[0192] Subjects with tAD+ and tAD++ scans with SUVr > 1.46 did not receive anti-N3pGlu Aβ antibodies based on the hypothesis that cognitive decline in high tau patients is primarily caused by tauopathy and therefore does not respond to anti-amyloid therapy.

[0193] [Table 5]

[0194] As shown in Figures 6A-6C, donanemab, an anti-N3pGlu Aβ antibody, is found to be most effective in the treatment subgroup with the lowest baseline flortau signal. Based on this trend, we can hypothesize that patients with high tau (>1.46 SUVr) are less likely to respond to treatment.

[0195] The data demonstrate that donanemab, an anti-N3pGlu Aβ antibody, is most effective in human subjects with tau levels of approximately 1.14 SUVr or less or approximately 1.27 SUVr or less (Figures 6A and 6B). In the rightmost graph, defined by baseline tau PET SUVr values ​​greater than 1.274 SUVr, the change in scale score was not statistically significant in the donanemab-treated group compared to placebo (Figure 6C). Figures 6A-6C show baseline tau subgroup analysis based on the iADRS (FTP = flortaucipitin).

[0196] Example 5: Comparison of neurological tau burden and cognitive changes Assessment of both global and frontal lobe neurological tau burden compared with cognitive change is measured substantially as described below. Subjects are assessed for both global and frontal lobe neurological tau burden at baseline using flortaucipir as described herein. In addition, at baseline, subjects are cognitively assessed using one of the iADRS or CDR-SB, as known in the art. Subjects may be cognitively reassessed at a given time point thereafter, for example, at 26 weeks, 52 weeks, 78 weeks, or 104 weeks, using either the iADRS or CDR-SB. Cognitive assessment versus change in neurological tau burden may be plotted as shown in Figures 5, 7, and 8. Figure 7 shows global tau burden at baseline versus iADRS change over 18 months. Figure 8 shows frontal lobe tau burden at baseline versus iADRS change over 18 months.

[0197] Figures 5, 7, and 8 demonstrate lower cognitive decline associated with lower tau burden at baseline. In addition, Figures 5, 7, and 8 demonstrate heterogeneity in cognitive decline among patients determined to have higher tau burden at baseline (e.g., greater than a SUVR of about 1.4).

[0198] Example 6: Treatment of subjects identified with high tau burden A subject may be determined to have high tau burden at baseline according to the methods described herein, including PET imaging, including the use of flortaucipir, and human pTau217 assessment. Tau burden may be assessed globally or based on regional (lobe-based) lobal burden, e.g., posterolateral temporal lobe, occipital lobe, parietal lobe, and / or frontal lobe. Patients determined to have high tau burden may be treated with an anti-Aβ antibody described herein and according to the dosing regimen described herein.

[0199] Additionally, subjects may be cognitively assessed at baseline by any of the modalities described herein, including one or more of the ADAS-Cog, iADL, CDR-SB, MMSE, APOE-4 genotyping, and / or iADRS. Following treatment with an anti-Aβ Ab described herein, and according to the dosing regimen described herein, subjects may be cognitively re-evaluated, for example, at 26, 52, 78, or 104 weeks. Patients who demonstrate slow or non-rapid cognitive decline, including those determined to have a high tau burden, may continue treatment with the anti-Aβ antibodies described herein.

[0200] Example 7: Efficacy and safety associated with carriers of the apolipoprotein E e4 (APOE e4) allele A Phase II clinical trial (NCT03367403; clinicaltrials.gov) (disclosed above in Example 2, Example 3, Example 4, and Example 5) also included testing the efficacy and safety of an anti-N3pGlu Aβ antibody (donanemab) in a subgroup of participants with one or two alleles of APOE e4.

[0201] This Phase 2 clinical trial was a randomized, placebo-controlled, double-blind, multicenter study evaluating the safety, tolerability, and efficacy of donanemab in patients with early symptomatic AD. Clinical change from baseline to 76 weeks was assessed in all enrolled patients with intermediate tau pathology levels using the Integrated AD Rating Scale (iADRS; primary endpoint), a composite tool measuring cognition and daily function, and the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; secondary endpoint). Baseline characteristics indicated that 72.5% and 74.2% of patients treated with donanemab or placebo, respectively, were ApoE4 carriers. Additional analyses of the iADRS and key secondary endpoints were conducted focusing on this subgroup population. Results: Compared to placebo, donanemab treatment resulted in a 49% slowing of cognitive decline as measured by the iADRS (p=0.004) (Figure 9A) and a 36% slowing of cognitive decline in the CDR-SB (p=0.038) in ApoE4 carriers at week 76 (Figure 9C).

[0202] The difference in donanemab treatment between carriers and non-carriers was significantly greater in carriers (iADRS: p=0.001, Figures 9A-9B; CDR-SB: p=0.046, Figures 9C-9D). Additional key secondary endpoints demonstrated consistent and robust efficacy of donanemab compared to placebo in ApoE4 carriers. See Tables F and G below.

[0203] [Table 6]

[0204] [Table 7]

[0205] The safety profile in ApoE4 carriers was consistent with the overall donanemab-treated population. Donanemab slowing of tau PET increases was numerically greater in donanemab-treated ApoE4 carriers than in non-carriers.

[0206] Amyloid-related imaging abnormalities (ARIA) with edema or exudates (mostly asymptomatic) were more common in ApoE4 carriers (33.7%) than in non-carriers (8.3%). ARIA with hemosiderin deposits such as microhemorrhages occurred in 34.5% of ApoE4 carriers receiving donanemab. Censoring carrier subjects with ARIA did not change the significance of the placebo treatment difference for iADRS (p=0.020) and CDR-SB (p=0.050).

[0207] Analysis of the study population demonstrated greater efficacy of donanemab in ApoE4 carriers than in non-carriers, as measured by a significant slowing of disease progression on both the iADRS and CDR-SB.

[0208] Figures 9A-9B show that donanemab exhibits greater efficacy in APOE e4 carriers than non-carriers. Figure 9A shows that donanemab exhibits greater efficacy in APOE e4 carriers than non-carriers on the iADRS scale. Figure 9B shows that donanemab exhibits greater efficacy in APOE e4 carriers than non-carriers on the CDR-SB scale. Figure 9E shows amyloid change (centiloid) by APOE e4 status for patients in the dose and placebo groups. Figure 9F shows change in tau PET SUVR by patient APOE e4 status. The left graph shows frontal lobe data for APOE e4 carriers (referred to as E4 carriers in Figure 9F) and non-carriers (referred to as E4 non-carriers in Figure 9F). The graphs on the right show lateral temporal lobe data for APOE e4 carriers (referred to in the figure as E4 carriers) and non-carriers (referred to in the figure as E4 non-carriers). Figures 9G-9I show baseline tau subgroup analysis based on the iADRS for APOE e4 carriers in both the donanemab-treated and placebo groups. The bottom third represents patients with a baseline flotausipir (FTP) SUVR ≤ 1.144 for both the placebo and donanemab groups. The middle third represents patients with a baseline FTP SUVR between 1.144 and 1.268 for both the placebo and donanemab groups. The top third represents patients with a baseline FTP SUVR > 1.268 for both the placebo and donanemab groups.

[0209] Sequence (underlined parts indicate CDRs)

[0210] [Table 8]

[0211] [Table 9]

[0212] [Table 10]

Claims

1. 1. A method for treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising: administering an effective amount of the anti-Aβ antibody to the human subject, wherein the human subject is (i) low to moderate tau burden; or (ii) low to moderate tau burden and one or two alleles of APOE e4 administering, Medications, including:

2. 1. A method for treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising: determining whether the human subject has a low to moderate tau burden; administering to the human subject an effective amount of the anti-Aβ antibody if the human subject has a low to moderate tau burden; Medications, including:

3. 1. A method for treating or preventing a disease characterized by amyloid beta (Aβ) deposits in the brain of a human subject, the method comprising: determining whether the human subject has a low to moderate tau burden and one or two alleles of APOE e4; administering to the human subject an effective amount of the anti-Aβ antibody, if the human subject has a low to moderate tau burden and one or two alleles of APOE e4; Medications, including:

4. The method of any one of claims 1 to 3, wherein the human subject is administered an effective amount of the anti-Aβ antibody for a period of time sufficient to treat or prevent the disease.

5. The agent according to any one of claims 1 to 3, wherein the treatment or prevention of the disease results in (i) a reduction in Aβ deposits in the brain of the human subject, and / or (ii) a slowing of cognitive or functional decline in the human subject.

6. 6. The method of claim 5, wherein the reduction in Aβ deposits in the brain of the human subject is determined by amyloid PET brain imaging or a diagnostic method that detects a biomarker of Aβ.

7. The method of claim 5 or 6, wherein the effective dose of the anti-Aβ antibody is administered to the human subject until Aβ deposits in the brain of the human subject are reduced by about 20 to 100%.

8. 8. The method of claim 7, wherein the Aβ deposits in the brain of the human subject are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%.

9. 9. The method of claim 1, wherein the effective dose of the anti-Aβ antibody is administered to the human subject until the Aβ deposits in the brain of the human subject are reduced by (i) about an average of about 25 centiloids to about 100 centiloids, (ii) about an average of about 50 centiloids to about 100 centiloids, (iii) about 100 centiloids, or (iv) about 84 centiloids.

10. 10. The method of claim 1, wherein the disease characterized by Aβ deposits in the brain of the human subject is selected from preclinical Alzheimer's disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy.

11. The method of any one of claims 1 to 10, wherein the human subject is an early symptomatic AD patient.

12. The method of claim 11, wherein the human subject has prodromal AD and mild dementia due to AD.

13. A drug described in any one of claims 1 to 3, wherein the human subject has a low to moderate tau load when the tau load measured by PET brain imaging is 1.10 SUVr to 1.46 SUVr.

14. The method of any one of claims 1 to 3, wherein the tau load of the human subject is determined using PET brain imaging or a diagnostic method that detects a tau biomarker.

15. 15. The method of claim 1, wherein administering comprises: (i) administering to the human subject one or more first doses of the anti-Aβ antibody of about 100 mg to about 700 mg, wherein each first dose is administered once about every four weeks; and (ii) about four weeks after administering the one or more first doses, administering to the subject one or more second doses of the anti-Aβ antibody of greater than about 700 mg to about 1400 mg, wherein each second dose is administered once about every four weeks.

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