Anti-N3pGlu amyloid beta antibodies and uses thereof

Abstract

The present invention relates to the treatment or prevention of diseases characterized by the deposition of Aβ in the brain using anti-N3pGlu 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, in some aspects, relates to doses and dosing regimens useful for such treatment. The present invention, in some aspects, also relates to human subjects that respond to the treatment or prevention of diseases characterized by the deposition of Aβ in the brain using anti-N3pGlu Aβ antibodies. The present invention also relates to human subjects that have one or two alleles of APOE4.

Description

[Technical field]

[0001] The present disclosure relates to methods of preventing or treating diseases with anti-N3pGlu Aβ antibodies, which diseases are characterized by the deposition of amyloid beta (Aβ) in a subject. The present disclosure also relates to doses and dosing regimens of anti-N3pGlu Aβ antibodies useful for treating or preventing diseases characterized by the deposition of Aβ. Some aspects of the present disclosure relate to treating or preventing diseases characterized by the deposition of Aβ in a subject, where the subject is selected based on i) tau levels / burden in the entire brain (global tau), ii) tau levels / burden in parts of the brain (e.g., different lobes of the brain), and / or iii) the presence of one or two alleles of APOE4 in the subject's genome. 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). The present disclosure also relates to slowing disease progression in subjects with early symptomatic Alzheimer's disease, optionally in the presence of intermediate brain tau load. The present disclosure also relates to slowing disease progression of AD. Treatment with the anti-N3pG Aβ antibody of the present disclosure can be optionally initiated in patients with evidence of AD neuropathology and mild cognitive impairment or mild dementia stage disease, in the presence of brain tau load. In some embodiments, the brain tau load is very low, low, intermediate, or high tau. [Background technology]

[0002] A cure for Alzheimer's disease is one of society's most important unmet needs. Accumulation of amyloid-β peptide in the form of cerebral amyloid plaques is an early and essential event in Alzheimer's disease, leading to neurodegeneration and, as a result, the onset of clinical symptoms such as cognitive and functional impairment (Selkoe, "The Origins of Alzheimer Disease: A is for Amyloid," JAMA 283:1615-7 (2000); Hardy et al., "The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics," Science 297:353-6 (2002); Masters et al., "Alzheimer's Disease," Nat. Rev. Dis. Primers 1:15056 (2015); and Selkoe et al., "The Amyloid Hypothesis of Alzheimer's Disease at 25 years," EMBO Mol. Med. 8:595-608 (2016)).

[0003] Amyloid beta 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 especially in neuronal synapses. APP is cleaved by γ-secretase to release Aβ peptides, which include a group of peptides ranging in size from 37 to 49 amino acid residues. Aβ monomers aggregate into various types of higher-order structures, including oligomers, prefibrils, and amyloid fibrils. Amyloid oligomers are soluble and can spread throughout the brain, while amyloid fibrils are larger, insoluble, and can further aggregate to form amyloid plaques. Amyloid plaques found in human patients contain a heterogeneous mixture of A® peptides, some of which contain N-terminal truncations and may further contain N-terminal modifications such as N-terminal pyroglutamic acid residues (pGlu).

[0004] The role of amyloid plaques 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)). In addition, the presence of amyloid plaques 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)). It is hypothesized that interventions or therapies aimed at removing Aβ plaques will slow the clinical progression of AD.

[0005] Some known anti-Aβ antibodies include bapineuzumab, gantenerumab, aducanumab, GSK933776, solanezumab, crenezumab, ponezumab, and lecanemab (BAN2401). Antibodies targeting Aβ have shown promise as treatments for Alzheimer's disease in both preclinical and clinical studies. Despite this promise, many amyloid-targeting antibodies have failed to achieve therapeutic endpoints in multiple clinical trials. The history of anti-amyloid clinical trials spans almost two decades, and in most cases, doubts have been cast on 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 7:146-151 (2020); Budd et al., “Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease,” The Journal of Prevention of Alzheimer's Disease 4(4):255-263 (2017); and Klein et al., “Gantenerumab Reduces Amyloid-β Plaques in Patients with Prodromal to Moderate Alzheimer's Disease: A PET Substudy Interim Analysis,” Alzheimer's Research & Therapy 11.1:1-12 (2019)).

[0006] Amyloid plaques found in human patients contain a heterogeneous mixture of Aβ peptides. N3pGlu Aβ (also called N3pG Aβ, N3pE Aβ, Aβ pE3-42, or Aβ p3-42) is a truncated form of Aβ peptide found exclusively in amyloid plaques. N3pGlu Aβ lacks the first two amino acid residues at the N-terminus of human Aβ and has a pyroglutamate derived from glutamic acid at the third amino acid position of Aβ. N3pGlu Aβ peptides are a minor component of Aβ deposited in the brain, but studies suggest that N3pGlu Aβ peptides have aggressive aggregation properties and accumulate early in the deposition cascade. Passive immunization by long-term chronic administration of antibodies against plaque-found Aβ, including N3pGlu Aβ, has been shown to disrupt Aβ aggregates and promote plaque removal in the brain in various animal models.

[0007] Antibodies against N3pGlu Aβ are known in the art. For example, U.S. Patent No. 8,679,498 (herein incorporated by reference in its entirety, including the anti-N3pGlu Aβ antibodies disclosed therein) discloses anti-N3pGlu Aβ antibodies and methods of using these antibodies to treat diseases such as Alzheimer's disease.

[0008] Donanemab (disclosed in U.S. Patent No. 8,679,498) is an antibody directed against the pyroglutamate modification of the third amino acid of the amyloid beta (N3pGlu Aβ) epitope, which is present only in brain amyloid plaques. Donanemab's mechanism of action is the targeting and removal of existing amyloid plaques, which are a key pathological feature of AD. A second neuropathological hallmark of AD is the presence of intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. It is possible that Aβ drives tau pathology, and that more complex and synergistic interactions between Aβ and tau appear at later stages and drive disease progression (Busche et al., “Synergy Between Amyloid-β and Tau in Alzheimer's disease”, Nature Neuroscience 23:1183-93 (2020)).

[0009] Donanemab's therapeutic and preventive strategies include, for example, targeting N3pGlu Aβ, which is specific to amyloid plaques in early symptomatic AD patients where cerebral amyloid load is present. The rationale is based on the amyloid hypothesis of AD, which states that Aβ production and deposition are an early and necessary event in the pathogenesis of AD. See, for example, Selkoe, “The Origins of Alzheimer Disease: A is for Amyloid,” JAMA 283:1615-1617 (2000). Clinical support for this hypothesis comes from the demonstration that parenchymal Aβ levels are elevated before AD symptoms appear, and is supported by genetic variants of AD that overproduce brain Aβ and genetic variants that prevent Aβ production. See, e.g., Jonsson et al., “A Mutation in APP Protects Against Alzheimer's Disease and Age-related Cognitive Decline,” Nature 488(7409):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. 72:316-24(2015).

[0010] However, there are significant problems with long-term chronic administration of Aβ antibodies, which have led to adverse events in humans, such as amyloid-related imaging abnormalities (ARIA), vasogenic edema and crevicular effusion (ARIA-E), microhemorrhages and hemosiderin deposits (ARIA-H), injection site reactions, and the risk of immunogenicity. For example, Piazza and Winblad, “Amyloid-Related Imaging Abnormalities (ARIA) in Immunotherapy Trials for Alzheimer's Disease:Need for Prognostic Biomarkers?” Journal of Alzheimer's Disease, 52:417-420 (2016); Sperling, et al., “Amyloid-related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Bapineuzumab: A Retrospective Analysis,”The Lancet Neurology 11.3:241-249(2012);Brashear et al.,“Clinical Evaluation of Amyloid-related Imaging Abnormalities in Bapineuzumab Phase III Studies,”J.of Alzheimer's Disease 66.4:1409-1424(2018);Budd et al.,“Clinical Development of Aducanumab,an Anti-Aβ Human Monoclonal antibody See “Being Investigated for the Treatment of Early Alzheimer’s Disease,” The Journal of Prevention of Alzheimer’s Disease 4.4:255 (2017).

[0011] The exact cause of such adverse events is unclear, but it is generally believed that antibody therapy disrupts the blood-brain barrier through interaction with cerebrovascular amyloid, which leads to a leaky barrier and the development of edema in patients. Several possible mechanisms of action have been hypothesized, such as removal of amyloid from the vessel wall destabilizing the neurovascular unit, localizing inflammation / infiltration in the neurovascular unit, and increasing the level of cerebrovascular amyloid due to higher levels of interstitial soluble Aβ, removal of parenchymal plaques, or localization of AQP-4 in the astrocyte end foot processes of the neurovascular unit.

[0012] Some therapeutic amyloid-targeting antibodies have shown a dose-response related increase in ARIA-E. See, e.g., Brashear et al., “Clinical Evaluation of Amyloid-related Imaging Abnormalities in Bapineuzumab Phase III Studies,” J. of Alzheimer's Disease 66.4:1409-1424 (2018); Budd et al., “Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease,” The Journal of Prevention of Alzheimer's Disease 4.4:255 (2017). In some cases, patients with the epsilon 4 allele of apolipoprotein E (referred to herein as APOE4, apoE4, or ApoE-ε4) have a higher incidence of ARIA-E.

[0013] To reduce the adverse event rate of ARIA-E while maintaining plaque clearance, some antibody treatment programs implement dose escalation schemes that include multiple dose escalations (3-4 steps) over a period of about 6 months before reaching an effective dose level. See, for example, Budd et al., “Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease,” The Journal of Prevention of Alzheimer's Disease 4.4:255 (2017) and Klein et al., “Gantenerumab Reduces Amyloid-β Plaques in Patients with Prodromal to Moderate Alzheimer's Disease: a PET Substudy Interim Analysis,” Alzheimer's Research & Therapy 11.1:101 (2019). Such treatment regimens may not completely remove amyloid plaques or may delay the removal of amyloid plaques.

[0014] Thus, a need exists for improved doses, dosing regimens, or methods that adequately treat subjects without causing or increasing problematic adverse events. Summary of the Invention

[0015] One aspect of the present disclosure provides doses and dosing regimens that avoid problematic adverse events such as ARIA with vasogenic edema that have been observed in patients receiving therapeutic antibodies that bind to deposited amyloid and are dose-limiting in some clinical development programs.

[0016] The antibodies of the present disclosure selectively bind to N3pGlu Aβ, which is found primarily in deposited amyloid plaques. The occurrence of N3pGlu Aβ peptide in deposited parenchymal plaques is very low (approximately 1-2%) relative to other Aβ peptide species, with the majority consisting of full-length Aβ. 1-42 Thus, the total number of binding sites for the disclosed antibodies is dramatically reduced relative to other plaque-binding Aβ antibodies. Biochemical analysis of CAA, the amyloid that deposits along CNS blood vessels, demonstrated a similarly low occurrence of N3pGlu peptides (approximately 2%).

[0017] Surprisingly, the antibodies of the present disclosure do not require multiple dose escalation over a long period of time. In some cases, the antibodies can reach effective dose levels without causing a high incidence of adverse events. Furthermore, in some cases, the anti-N3pGlu Aβ antibodies and dosing regimens of the present disclosure promote rapid brain amyloid clearance while minimizing the incidence and / or severity of ARIA adverse events observed with anti-amyloid antibodies, as described herein.

[0018] The beneficial effect of the improved doses, dosing regimens, and methods of the present disclosure may be, for example, because the antibodies have low total binding to vascular amyloid (e.g., due to low occurrence of N3pGlu peptides) while rapidly clearing parenchymal plaques. In other words, the beneficial effect of the improved doses, dosing regimens, and methods of the present disclosure may be due to a combination of i) their ability to target parenchymal / vascular plaques and achieve rapid reduction of amyloid plaques, and ii) the relative paucity of antibody binding sites found on both parenchymal and vascular amyloid deposits. Clinical studies have demonstrated that treatment of Alzheimer's disease patients using the improved doses, dosing regimens, and methods of the present disclosure results in rapid removal of deposited amyloid (such as amyloid plaques) from the subject's brain. Despite the sparse occurrence of the target epitopes of the antibodies of the present disclosure, the rate of amyloid clearance was significantly faster than published data from other amyloid-targeting therapeutic antibodies at a range of doses (Budd et al., The Journal of Prevention of Alzheimer's Disease 4.4:255 (2017) and Klein et al., Alzheimer's Research & Therapy 11.1:101 (2019)).

[0019] The dosing regimen described herein facilitates the antibodies of the present disclosure to rapidly clear brain amyloid while minimizing the incidence and / or severity of ARIA adverse events observed with this class of therapeutic antibodies. Furthermore, the dosing regimen disclosed herein provides early and extensive amyloid clearance (e.g., approximately 60% of subjects have "amyloid negative" scans by week 52). The dosing scheme described herein facilitates the anti-N3pGlu Aβ antibodies to rapidly clear parenchymal plaques while providing lower overall binding to vascular amyloid (due to the lower occurrence of N3pGlu peptides).

[0020] As mentioned above, 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 achieve therapeutic endpoints in multiple clinical trials. The history of anti-amyloid clinical trials spans almost two decades, and in most cases, the potential for such therapies to effectively treat AD has been questioned (Aisen et al., “The Future of Anti-amyloid Trials,” The Journal of Prevention of Alzheimer's Disease 7 146-151 (2020)). To date, only a handful of AD treatments have been approved. A challenge in treating Alzheimer's disease is that it is still primarily diagnosed and treated based on symptoms, e.g., psychiatric disorders, rather than based on brain pathology. Yet another challenge is the reproducibility crisis faced during clinical trials, where it is often difficult to obtain reproducible results, even when clinical trials are designed in a nearly identical way. This is caused by two main factors. First, most trials set enrollment criteria based on symptoms, not pathology, and therefore enroll heterogeneous populations with large variations in the level of underlying pathology, or even worse, patients with different underlying diseases. These patients will therefore progress to AD at very different rates, and the within-group variability, measured, for example, by the standard deviation of the mean, is very large in AD trials. The problem of population heterogeneity is also exacerbated by within-subject noise in outcome measurements.

[0021] It is very difficult to determine whether subjects with Aβ plaques will respond to anti-N3pGlu Aβ antibody treatment. This is partly due to the physiological and clinical heterogeneity among subjects with Aβ plaques, and because subjects are still diagnosed mainly on the basis of symptoms. For example, it remains a challenge for clinicians to determine whether patients with subtle cognitive symptoms, such as memory decline, suffer from prodromal or preclinical Alzheimer's disease and may progress to AD dementia in the near future.

[0022] Placebo populations in AD disease clinical trials vary widely in the trajectory 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 15.1:106-152 (2019)), which is believed to be due to the heterogeneity of the study populations (Devi et al., “Heterogeneity of Alzheimer's Disease: Consequence for Drug Trials?” Alzheimer's Research & Therapy 10.1:1-3 (2018)). This further increases the problem of identifying and treating subjects who may benefit from a particular treatment. Proper identification of patients who may respond to anti-N3pGlu Aβ antibody treatment is paramount, for example, for timely referral to memory clinics, accurate and early AD diagnosis, initiation of symptomatic treatment, future planning, and initiation of disease-modifying treatment.

[0023] Until now, test cohorts have been selected by clinical characteristics such as range of cognitive test scores and self-reported memory problems. After years of failure, experts in the field have advocated testing anti-amyloid disease-modifying therapies (DMTs) earlier in the progression of the disease (Aisen et al. 2020). However, several clinical studies of anti-amyloid DMTs have not achieved their endpoints, despite targeting patients at the early stages of Alzheimer's disease. For example, the Phase III clinical trial of crenezumab (Cread trial) recruited patients with prodromal to mild AD. The results of this study have been exclusively negative. No differences were found in both primary and secondary endpoints between treatment versus placebo groups or within prodromal versus mild AD subgroups (NCT03114657, Therapeutics:Crenezumab.Alzforum.AC Immune SA, Genentech, Hoffmann-La Roche;2019[cited 2020Sep7], available at clinicaltrials.gov.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 halted due to the low likelihood of efficacy in the primary and secondary endpoints of the study (Ostrowitzki et al., “A Phase III Randomized Trial of Gantenerumab in Prodromal Alzheimer's Disease,” Alzheimer's research & therapy 9.1:1-15(2017)).

[0024] Thus, there is a need for improved methods of appropriately identifying whether a subject will respond to an amyloid-targeted therapy.

[0025] Doody et al., “Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease,” NEJM, 370;4, 311-321 (2014) indicate that “no clear differential treatment effects on efficacy measures were observed between APOEε4 carriers and non-carriers.” It has now been found that administration of anti-N3pGlu Aβ antibodies to human subjects with one or two alleles of APOE4 (e.g., heterozygous or homozygous carriers of APOE4) results in unexpected and surprising benefits when compared to non-carriers of one or more of those alleles. Accordingly, some of the embodiments of the present disclosure include administering a dose of anti-N3pGlu Aβ antibodies to patients with that allele as a means of slowing their cognitive decline. Specifically, it has been found that there is a greater benefit in APOE4 carriers than in non-carriers when patients are administered anti-N3pGlu Aβ antibodies. This means that patients who receive anti-N3pGlu Aβ antibodies who have APOE4 have less cognitive decline than non-carriers, as measured using a variety of clinical measures and a variety of endpoints.

[0026] Across all therapeutic clinical trials selected for the presence of amyloid pathology, carriers are younger, have higher amyloid loads, and have higher tau pathology at baseline. Clinical decline across all scales in the placebo group does not differ by carrier status. For the placebo group, comparison of carrier status shows no significant longitudinal change in amyloid, however, a trend toward greater tau change in carriers vs. non-carriers. Relative longitudinal change in amyloid during therapy shows greater reductions in non-carriers than in carriers. One hypothesis to consider is the interaction of APOE with tau. Amyloid deposits are known to concentrate and contain APOE embedded within plaques. More recently, it has been shown that APOE can also be isolated from tau tangles. Animal data further suggest that there is an interaction of APOE with tau. In addition, rare mutations in APOE appeared to protect subjects with autosomal dominant PSEN1 mutations well beyond the time of typical disease onset, despite significant cerebral amyloid loads but relatively low tau burdens. In some embodiments, the present disclosure shows that APOE also affects tau beyond amyloid interactions, and the rate of tau change may be faster in carriers. Furthermore, the impact of treatment may have a greater impact on tau progression, which is more directly related to clinical progression. Tau progression and spread is associated with low-density lipoprotein receptor-related protein 1 (LRP1, also known as alpha-2-macroglobulin receptor, apolipoprotein E receptor, or cluster of differentiation 91). See Rauch et al., "LRP1 is a Master Regulator of Tau Uptake and Spread," Nature 580(7803):381-385 (2020), which is incorporated herein by reference in its entirety. Recent reports suggest that LRP1 promotes tau internalization and degradation via an APOE-mediated mechanism.See Cooper et al., “Regulation of Tau Internalization, Degradation, and Seeding by LRP1 Reveals Multiple Pathways for Tau Catabolism,” Journal of Biological Chemistry 100715 (2021), which is incorporated by reference in its entirety.

[0027] One aspect of the present disclosure is based on the discovery that Alzheimer's patients with low or moderate tau, very low to moderate tau, or no high tau are responsive to treatment with anti-N3pGlu Aβ antibodies, and patients with high tau levels may not be effectively treated with anti-N3pGlu Aβ antibodies, even if clinically classified as preclinical or early stage AD. Another aspect of the present disclosure is based on the discovery that Alzheimer's patients with one or two alleles of APOE4 are responsive to treatment with anti-N3pGlu Aβ antibodies. Yet another aspect of the present disclosure is based on the discovery that Alzheimer's patients with one or two alleles of APOE4 and low or moderate tau, very low to moderate tau, or no high tau are responsive to treatment with anti-N3pGlu Aβ antibodies.

[0028] Identifying subjects who are most responsive to treatment with anti-N3pGlu Aβ antibodies solves the over 20-year-old problem of finding clinically effective anti-amyloid treatments and reflects a significant advance in the art. Some aspects of the present disclosure 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 in clinical trials, reducing noise and ensuring more reproducible results, but also ensures proper identification of AD stage and its progression. Proper identification of AD stage allows, for example, timely referral to memory clinics, accurate and early AD diagnosis, initiation of symptomatic treatment, future planning, and initiation of disease-modifying treatment. [Brief description of the drawings]

[0029] (Not stated in the original text) DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Some aspects of the present disclosure provide a two-step dosing regimen of an anti-N3pGlu Aβ antibody to a human subject suffering from a disease characterized by Aβ plaques in the brain. In the first step, the human subject is administered one or more first doses (or low doses) of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, each first dose (low dose) being administered about once every four weeks (i.e., at a frequency of once every four weeks). About four weeks after administering the one or more first doses, in the second step, the human subject is administered one or more second doses (or high doses) of more than 700 mg to about 1400 mg, each second dose (high dose) being administered once every four weeks.

[0031] Some aspects of the present disclosure relate to identifying the stage / progression of AD in a subject based on i) the global or overall tau burden in the brain of a human subject, or ii) the spread of tau in the subject's brain or a portion thereof. In some aspects, an anti-N3pGlu Aβ antibody of the present disclosure may be administered to a subject i) without determining the stage / progression of AD in the subject, or ii) regardless of the stage / progression of AD in the subject.

[0032] In some embodiments, patients may be stratified / identified / selected / treated based on the amount of tau present in the subject's brain (e.g., whole brain or part of the brain). In some embodiments, patients may be stratified / identified / selected / treated based on the amount of tau present in the subject's brain (e.g., whole brain or part of the brain) and the presence of one or two alleles of APOE4.

[0033] 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). For example, during some stages, 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). Another stage of AD is where tau burden in AD patients is limited to the posterior lateral temporal (PLT) or occipital regions. Yet another stage of AD is when tau burden in AD patients is present in parietal or precuneus or frontal regions with tau burden in PLT or occipital regions. In some embodiments, patients can be stratified / identified / selected / treated based on the stage of AD progression (e.g., based on the spread of tau in the brain) and the presence of one or two alleles of APOE4.

[0034] Stratification of patients based on the amount of tau in the brain, the AD progression in the brain, and / or the presence of one or two alleles of APOE4 can be used to determine, for example, whether a patient will respond to anti-N3pGlu Aβ antibody treatment. Stratification / selection of patient populations based on the amount of tau in the brain, the AD progression in the brain, and / or the presence of one or two alleles of APOE4 also helps to solve the problems of patient heterogeneity and replicability encountered during the design and implementation of clinical trials.

[0035] Another aspect of the present disclosure provides a human subject that is responsive to the treatment or prevention of a disease characterized by amyloid beta plaques in the brain of the human subject.In some embodiments of this aspect of the present disclosure, the responsive human subject includes a human subject with low to moderate tau load, very low to moderate tau load, and / or one or two alleles of APOE4.In some embodiments of this aspect of the present disclosure, the responsive human subject excludes a human subject with high tau load.In some embodiments of this aspect of the present disclosure, the responsive human subject excludes a human subject with high tau load and / or one or two alleles of APOE4.

[0036] In some embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure are administered to a responsive human subject for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain of the human subject. In some embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure are administered to a human subject for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain of the human subject. In some embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure are administered to a human subject for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain of the human subject, regardless of brain tau levels.

[0037] In one aspect, the disclosure relates to a method of treating or preventing a disease characterized by Aβ plaques in the brain of a human subject, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, where each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, where each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), where the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments of this aspect of the invention, the anti-N3pGlu Aβ antibody is administered to the human subject regardless of brain tau levels. Some aspects of the present disclosure relate to methods of treating or preventing a disease characterized by Aβ plaques in the brain of a human subject, comprising administering to the subject an anti-N3pGlu Aβ antibody to reduce Aβ plaques in the brain.

[0038] In some embodiments, such treatment results in a reduction or reduction of amyloid deposits, amyloid beta plaques, or Aβ load in the brain of a patient having a disease characterized by Aβ plaques. In some embodiments, such treatment results in a reduction or reduction of tau levels in the brain of a patient having a disease characterized by Aβ plaques. In some embodiments, such treatment results in a reduction or reduction of plasma tau levels in a patient having a disease characterized by Aβ plaques. In some embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure slow the accumulation of tau pathophysiology as measured by brain tau PET and / or plasma p-tau.

[0039] In some embodiments, such treatment results in a decrease or reduction in neurofilament light chain (NfL) levels in the brain of patients with a disease characterized by Aβ plaques. In some embodiments, such treatment results in a decrease or reduction in Aβ levels in the plasma or cerebrospinal fluid (CSF) of patients with a disease characterized by Aβ plaques. 42 / 40 In some embodiments, such treatment results in a decrease or reduction in glial fibrillary acidic protein (GFAP) levels in the blood of patients with a disease characterized by Aβ plaques. In some embodiments, such treatment results in a decrease or reduction in P-tau217 levels in patients with a disease characterized by Aβ plaques.

[0040] Another aspect of the present disclosure relates to an anti-N3pGlu Aβ antibody for use in treating or preventing a disease characterized by Aβ plaques in the brain of a human subject, wherein the anti-N3pGlu Aβ antibody is for administration in one or more first doses of about 100 mg to about 700 mg, where each first dose is administered about once every four weeks, followed by one or more second doses of greater than 700 mg to about 1400 mg administered four weeks after the administration of the one or more first doses, where each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a LCVR and a HCVR, where the LCVR comprises the amino acid sequence of SEQ ID NO:1, and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0041] One aspect of the present disclosure relates to a method of reducing amyloid beta plaques in the brain of a human Alzheimer's Disease (AD) subject, comprising administering to the subject three 700 mg first doses of an anti-N3pG Aβ antibody, each first dose being administered once every four weeks, and four weeks after administration of the three first doses, administering to the subject one or more 1400 mg second doses of an anti-N3pG Aβ antibody once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO:1 and the HCVR consists of the amino acid sequence of SEQ ID NO:2.

[0042] Another aspect of the present disclosure relates to an anti-N3pGlu Aβ antibody for use in treating or preventing a disease characterized by Aβ plaques in the brain of a human subject, wherein one or more first doses of the antibody of about 100 mg to about 700 mg are administered, each first dose being administered about once every four weeks, followed by one or more second doses of greater than 700 mg to about 1400 mg administered four weeks after administration of the one or more first doses, each second dose being administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a LCVR and a HCVR, wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0043] Another aspect of the present disclosure relates to use of an anti-N3pGlu Aβ antibody in the manufacture of a medicament for the treatment or prevention of a disease characterized by Aβ plaques in the brain of a human subject, wherein one or more first doses of the antibody of about 100 mg to about 700 mg are administered, each first dose being administered about once every four weeks, followed by one or more second doses of greater than 700 mg to about 1400 mg administered four weeks after administration of the one or more first doses, each second dose being administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a LCVR and a HCVR, wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0044] Another aspect of the present disclosure relates to a method of treating or preventing clinical or preclinical Alzheimer's disease, Down's syndrome, or clinical or preclinical CAA in a subject, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, where each first dose is administered about once every four weeks; and ii) about four weeks after administration of the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, where each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), where the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0045] Another aspect of the present disclosure is a method of treating or preventing preclinical AD (cognitively intact subjects with evidence of AD pathology), prodromal AD (sometimes referred to as Aβ-related mild cognitive impairment, MCI, or MCI due to AD), mild AD, moderate AD, and severe AD, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks. The present invention relates to a method in which the Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0046] Another aspect of the present disclosure relates to a method of slowing cognitive or functional decline in a patient having a disease characterized by Aβ plaques, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administration of the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0047] Another aspect of the present disclosure relates to a method of reducing Aβ plaques or Aβ load in a patient having a disease characterized by Aβ plaques, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administration of the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0048] Another aspect of the present disclosure relates to a method of slowing functional decline in a patient having a disease characterized by Aβ plaques, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administration of the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0049] Another aspect of the present disclosure relates to a method of preventing memory loss, cognitive decline, or functional decline in a patient having a disease characterized by Aβ plaques, comprising: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0050] Another aspect of the disclosure relates to a method of slowing disease progression in a human Alzheimer's disease subject, comprising administering to the subject an anti-N3pGlu Aβ antibody, slowing disease progression by at least 15% as measured by integrated Alzheimer's Disease Rating Scale (iADRS), wherein the administering comprises: i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, each first dose being administered once every four weeks; and ii) four weeks after administration of the three first doses, administering one or more 1400 mg second doses of an anti-N3pGlu Aβ antibody once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO:1 and the HCVR consists of the amino acid sequence of SEQ ID NO:2.

[0051] Another aspect of the disclosure relates to a method of slowing disease progression in a human Alzheimer's disease subject comprising administering to the subject an anti-N3pGlu Aβ antibody, slowing disease progression by at least 20% as measured by Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), wherein the administering comprises: i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, each first dose being administered once every four weeks; and ii) four weeks after administration of the three first doses, administering one or more 1400 mg second doses of an anti-N3pGlu Aβ antibody once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO:1 and the HCVR consists of the amino acid sequence of SEQ ID NO:2.

[0052] Another aspect of the present disclosure relates to methods of i) reducing or preventing brain amyloid beta accumulation, ii) reducing or preventing tau accumulation, iii) preventing or delaying the onset of memory loss, iv) preventing or delaying cognitive decline, v) preventing or delaying functional decline, or vi) preventing or delaying the onset of a symptomatic stage of AD in clinically asymptomatic subjects or cognitively intact subjects with evidence of AD pathology. 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-N3pGlu Aβ antibody, where each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, where each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), where the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2. In some embodiments, three first doses of about 100 mg to about 700 mg of anti-N3pGlu Aβ antibody are administered to the patient once every four weeks, and about four weeks after the one or more first doses, six doses of more than 700 mg to about 1400 mg of anti-N3pGlu Aβ antibody are administered to the patient once every four weeks. In some embodiments, three first doses of about 700 mg of anti-N3pGlu Aβ antibody are administered to the patient once every four weeks, and about four weeks after the one or more first doses, six doses of about 1400 mg of anti-N3pGlu Aβ antibody are administered to the patient once every four weeks. In some embodiments, the subject has evidence of AD pathology and is cognitively intact. In some embodiments, the subject has evidence of AD pathology and is clinically asymptomatic.

[0053] Some aspects of the present disclosure relate to a method of treating or preventing a disease characterized by Aβ plaques in the brain of a clinically asymptomatic human subject, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, three first doses of about 100 mg to about 700 mg of anti-N3pGlu Aβ antibody are administered to the patient every four weeks, and about four weeks after the one or more first doses, six doses of greater than 700 mg to about 1400 mg of anti-N3pGlu Aβ antibody are administered to the patient every four weeks. In some embodiments, three first doses of about 700 mg of anti-N3pGlu Aβ antibody are administered to the patient every four weeks, and about four weeks after the one or more first doses, six doses of about 1400 mg of anti-N3pGlu Aβ antibody are administered to the patient every four weeks.

[0054] In some embodiments, the clinically asymptomatic subject is known to have a genetic mutation that causes Alzheimer's disease. In the present disclosure, a "clinically asymptomatic subject known to have a genetic mutation that causes Alzheimer's disease" includes a patient known to have the PSEN1 E280A Alzheimer's disease-causing genetic mutation (Paisa mutation), an autosomal dominant Alzheimer's disease-causing genetic mutation, or is at high risk of developing AD due to carrying one or two APOE4 alleles.

[0055] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have very low to moderate tau burden, or low to moderate tau burden, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administration of the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0056] Another aspect of the present disclosure is a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has one or two alleles of APOE4 and has been determined to have very low to moderate tau burden or low or moderate tau burden, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks. The present invention relates to a method in which the Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0057] Another aspect of the present disclosure is a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, 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 very low to moderate tau load or a very low to moderate tau load, then i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks. The present invention relates to a method in which the Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0058] Another aspect of the present disclosure is a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising: determining whether the human subject has a very low to moderate tau load or a low to moderate tau load and one or two alleles of APOE4; and if the human subject has a very low to moderate tau load or a very low to moderate tau load and one or two alleles of APOE4, then i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks. The present invention relates to a method in which the Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0059] Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to not have high tau burden, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administration of the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0060] Another aspect of the invention relates to a method of treating or preventing a disease characterized by high tau burden and amyloid beta plaques in the brain of a human subject who has been determined to not have one or two alleles of APOE4, comprising: i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administration of the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0061] Another aspect of the invention relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has high tau burden, and if the human subject does not have high tau burden, then i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks, and ii) four weeks after administration of the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO: 1 and the HCVR comprises the amino acid sequence of SEQ ID NO: 2.

[0062] Another aspect of the invention is a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising: determining whether the human subject has high tau burden and one or two alleles of APOE4; and if the human subject has one or two alleles of APOE4 and does not have high tau burden, then i) administering to the human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, wherein each second dose is administered about once every four weeks. The present invention relates to a method in which the Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0063] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody, wherein the human subject has been determined as having very low to moderate tau burden or low to moderate tau burden.

[0064] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody, wherein the human subject has been determined to have very low to moderate tau burden or low to moderate tau burden and one or two alleles of APOE4.

[0065] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has low to moderate tau load or very low to moderate tau load, and if the human subject has low to moderate tau load or very low to moderate tau load, then administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody.

[0066] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has one or two alleles of APOE4 and a low to moderate tau burden or a very low to moderate tau burden, and if the human subject has one or two alleles of APOE4 and a low to moderate tau burden or a very low to moderate tau burden, then administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody.

[0067] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody, wherein the human subject has been determined as not having high tau burden.

[0068] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody, wherein the human subject has been determined to have one or two alleles of APOE4 and does not have high tau burden.

[0069] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has high tau burden, and if the human subject does not have high tau burden, then administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody.

[0070] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has one or two alleles of APOE4 and high tau burden, and if the human subject has one or two alleles of APOE4 and does not have high tau burden, then administering to the human subject an effective amount of an anti-N3pGlu Aβ antibody.

[0071] In some aspects, anti-N3pGlu Aβ antibodies may be used to reduce, prevent further increase, or slow the rate of tau accumulation in different parts of the human brain, e.g., different lobes of the brain of a human subject. In some embodiments, anti-N3pGlu Aβ antibodies are used to reduce, prevent further increase, or slow the rate of tau load / accumulation in the frontal lobe of the human brain. In some embodiments, tau accumulation in the frontal lobe is slowed by at least 30-70% compared to an untreated subject. In some embodiments, tau accumulation in the frontal lobe is slowed by at least 50% compared to an untreated subject. In some embodiments, the subject has a negative tau PET imaging scan in the frontal lobe brain region prior to administration of the anti-N3pGlu Aβ antibody. In some embodiments, the subject has a brain tau level in the frontal lobe region of less than 0.4 SUVr 76 weeks after administration of the anti-N3pGlu Aβ antibody, the brain tau level being measured by a tau PET imaging scan.

[0072] In some embodiments, anti-N3pGlu Aβ antibodies are used to reduce the rate, prevent further increase, or slow down tau burden / accumulation in the parietal lobe of the human brain. In some embodiments, the subject has an increase in tau levels in the parietal lobe of less than 0.06 SUVr after 76 weeks of administration of an anti-N3pGlu Aβ antibody, where the brain tau levels are measured by a tau PET imaging scan.

[0073] In some embodiments, anti-N3pGlu Aβ antibodies are used to reduce, prevent further increase, or slow the rate of tau load / accumulation in the occipital lobe of a human brain. In some embodiments, anti-N3pGlu Aβ antibodies are used to reduce, prevent further increase, or slow the rate of tau load / accumulation in the temporal lobe of a human brain. In some embodiments, anti-N3pGlu Aβ antibodies are used to reduce, prevent further increase, or slow the rate of tau load / 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-N3pG Aβ antibody, each first dose being administered about once every four weeks, and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0074] One aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have tau load in the temporal lobe of the brain and / or one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject. Another aspect of the present invention relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has tau load in the temporal lobe of the brain and / or one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject has tau load in the posterior lateral temporal lobe and / or one or two alleles of APOE4. In some embodiments, the human subject is administered i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose being administered about once every four weeks, and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0075] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have tau load in the occipital lobe of the brain and / or one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has tau load in the occipital lobe of the brain and / or one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose being administered about once every four weeks, and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0076] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have tau load in the parietal lobe of the brain and / or one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has tau load in the parietal lobe of the brain and / or one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose being administered about once every four weeks, and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0077] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have tau load in the frontal lobe of the brain and / or one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has tau load in the frontal lobe of the brain and / or one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose being administered about once every four weeks, and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0078] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have tau burden in the posterolateral temporal (PLT) and / or occipital lobes of the brain and / or one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques 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 / or one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose being administered about once every four weeks, and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0079] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have i) tau burden in the parietal or precuneus regions, or ii) tau burden in the frontal regions, and / or iii) one or two alleles of APOE4, in conjunction with tau burden in the PLT or occipital regions of the brain, comprising administering an anti-N3pGlu Aβ to the human subject.Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has i) tau burden in the parietal or precuneus regions, or ii) tau burden in the frontal regions, and / or iii) one or two alleles of APOE4, in conjunction with tau burden in the PLT or occipital regions of the brain, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose being administered about once every four weeks, and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0080] Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject who has been determined to have i) tau burden in the frontal lobe or ii) a region of the temporal lobe that does not include the posterior lateral temporal region (PLT) of the brain, and / or iii) one or two alleles of APOE4, comprising administering an anti-N3pGlu Aβ to the human subject. Another aspect of the present disclosure relates to a method of treating or preventing a disease characterized by amyloid beta plaques in the brain of a human subject, comprising determining whether the human subject has i) tau burden in the frontal lobe or ii) a region of the temporal lobe that does not include the posterior lateral temporal region (PLT) of the brain, and / or iii) one or two alleles of APOE4, and administering an anti-N3pGlu Aβ to the human subject. In some embodiments, the human subject is administered i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose being administered about once every four weeks, and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0081] In some aspects, the present disclosure relates to a method for selecting a human subject for treatment or prevention of a disease characterized by amyloid beta plaques in the human subject's brain. In some embodiments, the human subject is selected based on the amount of global (overall) 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 plaques in the brain because the patient has very low to moderate tau in the brain and / or one or two alleles of APOE4. In another embodiment, the human subject is selected for treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has low to moderate tau (or intermediate tau) in the brain and / or one or two alleles of APOE4. In another embodiment, the human subject is excluded from treatment or prevention of a disease characterized by amyloid beta plaques 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, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has tau load and / or one or two alleles of APOE4 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 plaques in the brain because the patient has tau load and / or one or two alleles of APOE4 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 plaques in the brain because the patient has tau load and / or one or two alleles of APOE4 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 plaques in the brain because the patient has tau load and / or one or two alleles of APOE4 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 plaques in the brain because the patient has tau load present in the posterior lateral temporal (PLT) and / or occipital lobes of the brain and / or one or two alleles of APOE4. In some embodiments, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has tau load in the PLT or occipital regions of the brain, i) tau load in the parietal or precuneus regions, or ii) tau load in the frontal regions, and / or iii) one or two alleles of APOE4. In some embodiments, a human subject is selected for the treatment or prevention of a disease characterized by amyloid beta plaques in the brain because the patient has tau load in the brain i) isolated to the frontal lobe, ii) tau load in the temporal lobe region not including the posterior lateral temporal region (PLT), and / or iii) one or two alleles of APOE4. In some embodiments, the human subject is administered i) one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, each first dose being administered about once every four weeks, and ii) about four weeks after administering the one or more first doses, the human subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2.

[0082] In some embodiments, the subject described in various aspects of the present disclosure is determined to have a posterior lateral temporal lobe tau load and / or one or two alleles of APOE4. In some embodiments, the subject described in various aspects of the present disclosure is determined to have a posterior lateral temporal lobe and occipital lobe tau load and / or one or two alleles of APOE4. In some embodiments, the subject described in various aspects of the present disclosure is determined to have a posterior lateral temporal lobe, occipital lobe, and parietal lobe tau load and / or one or two alleles of APOE4. In some embodiments, the subject described in various aspects of the present disclosure is determined to have a lateral temporal lobe, occipital lobe, parietal lobe, and frontal lobe tau load and / or one or two alleles of APOE4. In some embodiments, the subject described in various aspects of the present disclosure is determined to have a posterior lateral temporal lobe, occipital lobe, parietal lobe, and / or frontal lobe tau load and / or one or two alleles of APOE4. In some embodiments, a subject described in various aspects of the disclosure has been determined to have a posterior lateral temporal, occipital, parietal and / or frontal lobe tau load corresponding to a neurological tau load of greater than 1.46 SUVr based on PET imaging. In some embodiments, an anti-N3pGlu Aβ antibody of the disclosure limits the increase in frontal lobe tau in the subject over 72 weeks to less than 0.04 SUVr as measured by tau PET imaging.

[0083] In some embodiments, the tau load in the human brain or a portion thereof (e.g., a lobe or the entire brain) may be used to determine whether administration of an anti-N3pGlu Aβ antibody should be discontinued. For example, a slowing of the rate of tau clearance in the brain, a cessation of reduction in tau levels, a prevention of further increase in tau levels, or a slowing of the rate of tau accumulation may be used as an indicator to determine the duration of administration of an anti-N3pGlu Aβ antibody. In some embodiments, an anti-N3pGlu Aβ antibody is administered to a subject until a slowing of the rate of tau clearance, a cessation of reduction in tau levels, a prevention of further increase in tau levels, or a slowing of the rate of tau accumulation occurs in the temporal, occipital, parietal, or frontal lobe.

[0084] In some embodiments, the amyloid beta load in the human brain may be used to determine whether administration of an anti-N3pGlu Aβ antibody should be discontinued. For example, a slowing of the rate of Aβ clearance, a cessation of the reduction of Aβ levels, prevention of further increases in Aβ levels, or a slowing of the rate of Aβ accumulation in the brain may be used as an indicator to determine the duration of administration of an anti-N3pGlu Aβ antibody. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure is discontinued when Aβ plaques in the subject's brain reach normal levels by 24 weeks or when the reduction of Aβ plaque levels in the subject's brain stops. In some embodiments, the level of Aβ plaques in the subject's brain is maintained at normal levels for at least 52 weeks after administration of the anti-N3pGlu Aβ antibody is discontinued. In some embodiments, administration of an anti-N3pGlu Aβ antibody reduces the level of Aβ plaques in the subject's brain to normal levels by 24 weeks. In some embodiments, the level of Aβ plaques in the subject's brain is maintained at normal levels for at least another 52 weeks.

[0085] In some embodiments, the tau burden present in a portion of the brain of a human subject may be used to select an optimal treatment regimen or administer a therapy in combination with an anti-N3pGlu Aβ antibody. For example, the presence of tau burden in the frontal lobe of the brain of an amyloid-positive human subject may be used as an indicator to determine whether the human subject will benefit from administration of an anti-N3pGlu Aβ antibody alone or in combination with an anti-tau antibody. In some embodiments, an anti-N3pGlu Aβ antibody in combination with an anti-tau antibody may be used to reduce, prevent an increase in, or slow the rate of tau accumulation in different portions of the human brain, e.g., different lobes of the human subject's brain. In some embodiments, the tau burden in different portions of the human brain, e.g., different lobes of the human subject's brain, may be used i) to follow a patient's response to a treatment, or ii) when therapy needs to be restarted. In some embodiments, the antibodies, methods, or dosing regimens described in various aspects of the present disclosure cause i) a reduction in Aβ plaques in the brain of the human subject, and / or ii) a slowing of cognitive decline or functional decline in the human subject. In some embodiments, the antibodies, methods, or dosing regimens described herein result in a reduction of amyloid plaques.

[0086] Anti-N3pGlu Aβ antibodies according to various aspects of the present disclosure include, i) can be substituted with, or iii) are used together with anti-N3pGlu Aβ antibodies such as: 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, and 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 with light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 5, an amino acid sequence having at least 95% homology with light chain complementarity determining region 2 (LCDR2) of SEQ ID NO: 6, and an amino acid sequence having at least 95% homology with 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, and 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 with heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 8, an amino acid sequence having at least 95% homology with heavy chain complementarity determining region 2 (HCDR2) of SEQ ID NO: 9, and an amino acid sequence having at least 95% homology with heavy chain complementarity determining region 3 (HCDR3) of SEQ ID NO: 10; light chain complementarity determining region 1 (LCDR1) having the amino acid sequence of SEQ ID NO:5, light chain complementarity determining region 2 (LCDR2) having the amino acid sequence of SEQ ID NO:6, light chain complementarity determining region 3 (LCDR3) having the amino acid sequence of SEQ ID NO:7, heavy chain complementarity determining region 1 (HCDR1) having the amino acid sequence of SEQ ID NO:8, heavy chain complementarity determining region 2 (HCDR2) having the amino acid sequence of SEQ ID NO:9, and heavy chain complementarity determining region 3 (HCDR3) having the amino acid sequence of SEQ ID NO:10, or an amino acid having at least 95% homology to light chain complementarity determining region 1 (LCDR1) of SEQ ID NO:5. an anti-N3pGlu Aβ antibody comprising an amino acid sequence having at least 95% homology with light chain complementarity determining region 2 (LCDR2) of SEQ ID NO: 6, an amino acid sequence having at least 95% homology with light chain complementarity determining region 3 (LCDR3) of SEQ ID NO: 7, an amino acid sequence having at least 95% homology with heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 8, an amino acid sequence having at least 95% homology with heavy chain complementarity determining region 2 (HCDR2) of SEQ ID NO: 9, and an amino acid sequence having at least 95% homology with heavy chain complementarity determining region 3 (HCDR3) of SEQ ID NO: 10; LCVR and HCVR, wherein the LCVR comprises LCDR1, LCDR2 and LCDR3, and the HCVR comprises HCDR1, HCDR2 and HCDR3, selected from the group consisting of LCDR1 being SEQ ID NO:5, LCDR2 being SEQ ID NO:6, LCDR3 being SEQ ID NO:7, HCDR1 being SEQ ID NO:8, HCDR2 being SEQ ID NO:9, and HCDR3 being SEQ ID NO:10; or LCVR and HCVR, wherein the LCVR comprises LCDR1, LCDR2 and LCDR3, and H The CVR comprises HCDR1, HCDR2 and HCDR3, which are selected from the group consisting of LCDR1 having at least 95% homology with SEQ ID NO:5, LCDR2 having at least 95% homology with SEQ ID NO:6, LCDR3 having at least 95% homology with SEQ ID NO:7, HCDR1 having at least 95% homology with SEQ ID NO:8, HCDR2 having at least 95% homology with SEQ ID NO:9, and HCDR3 having at least 95% homology with 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 a 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 the LC comprises an amino acid sequence having at least 95% homology with SEQ ID NO:3 and the HC comprises an amino acid sequence having at least 95% homology with 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 having 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 having at least 95% homology to SEQ ID NO:4. an N3pGlu Aβ antibody comprising 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 N3pGlu Aβ antibody comprising a HCVR 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 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.

[0087] In some embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure include a kappa LC and an IgG HC. In certain embodiments, the anti-N3pGlu Aβ antibodies of the present disclosure are of the human IgG1 isotype.

[0088] In some embodiments, a human subject is administered one or more first doses of about 100 mg to about 700 mg of an anti-N3pGlu Aβ antibody described herein. In some embodiments, one or more first doses are administered to a human subject such that each first dose is administered once every four weeks. In certain embodiments, the first dose is administered once to the subject. In some embodiments, the first dose is administered twice to the subject, with each first dose being administered once every four weeks. In some embodiments, the first dose is administered three times to the subject, with each first dose being administered once every four weeks.

[0089] In some embodiments, the subject is administered one first dose, two first doses, or three first doses of about 100 mg to about 700 mg, each first dose being administered about once every four weeks. In certain embodiments, the human subject is administered three first doses of about 700 mg, each first dose being administered about once every four weeks. In some embodiments, the human subject is administered one, two, or three first doses before administering the second dose.

[0090] 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.

[0091] 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, about 700 mg. In some embodiments, the first dose is about 1 mg / kg to about 10 mg / kg of anti-N3pGlu 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 one first dose, two first doses, or three first doses of about 1 mg / kg to about 10 mg / kg. In one particular 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.

[0092] In certain embodiments, the first dose is administered once every four weeks or once a month. In one particular embodiment, the subject is administered a first dose of about 10 mg / kg, three times, once every four weeks. In some embodiments, the first dose of anti-N3pGlu Aβ antibody is administered to the subject for about one month, about two months, or about three months.

[0093] In some embodiments, the subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody. In some embodiments, the subject is administered one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pGlu Aβ antibody, each second dose being administered about once every four weeks. In some embodiments, the second dose is administered four weeks after the one or more first doses.

[0094] In certain embodiments, the subject is administered one or more second doses of more 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 more than 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, or about 1400 mg. In certain embodiments, the second dose is administered once every four weeks. In one particular embodiment, the subject is administered one or more second doses of more than 700 mg once every four weeks. In one particular embodiment, the subject is administered one or more second doses of about 1400 mg once every four weeks.

[0095] A brain MRI scan may be performed on the human subject to monitor / assess the human subject (e.g., for ARIA-E or ARIA-H). In some embodiments, a brain MRI scan may be performed on the human subject to diagnose / assess / monitor adverse events caused by administration of an anti-N3pGlu Aβ antibody. In some embodiments, the human subject undergoes a brain MRI scan between administration of doses of anti-N3pGlu Aβ antibody (e.g., once every 4 weeks). In some embodiments, a baseline brain MRI is obtained before initiating treatment with an anti-N3pGlu Aβ antibody. In some embodiments, the human subject undergoes a brain MRI scan before increasing the dose of anti-N3pGlu Aβ antibody, e.g., to 700 mg to 1400 mg. In some embodiments, the human subject undergoes a brain MRI scan after the first dose of anti-N3pGlu Aβ antibody. In some embodiments, the human subject undergoes a brain MRI scan after three doses of anti-N3pGlu Aβ antibody. In some embodiments, the human subject undergoes a brain MRI scan after the first 4 weeks of initiating treatment. In some embodiments, the human subject undergoes a brain MRI scan after the first 12 weeks of treatment. In some embodiments, the human subject undergoes a brain MRI scan before administering a 1400 mg dose. In some embodiments, the brain MRI scan is performed before starting administration of one or more 1400 mg second doses. In some embodiments, the human subject undergoes a brain MRI scan before administering a 20 mg / kg dose. In some embodiments, the human subject undergoes a brain MRI scan after the last dose of a 700 mg dose. In some embodiments, the human subject undergoes a brain MRI scan after the last dose of a 10 mg / kg dose. In some embodiments, the method of the present disclosure includes evaluating the subject's brain MRI scan for amyloid-related imaging abnormalities (ARIA) after administration of three first doses and before administration of one or more second doses.

[0096] In some embodiments, the disclosure provides a method of treating Alzheimer's disease in a subject in need thereof, comprising: i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, where each first dose is administered at a frequency of once every four weeks; ii) evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for amyloid-related imaging abnormalities (ARIA) after administration of the three first doses and prior to administration of one or more second doses, where if symptoms consistent with ARIA occur, administration of the one or more second doses is temporarily withheld; and iii) four weeks after administration of the three first doses, administering one or more 1400 mg second doses of an anti-N3pGlu Aβ antibody at a frequency of once every four weeks. The method relates to an Aβ antibody comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, administration of one or more second doses is resumed after resolution of ARIA symptoms or stabilization of MRI radiographs. In some embodiments, the one or more second doses are withheld and a corticosteroid is administered to the subject.

[0097] In some embodiments, the disclosure provides a method of treating Alzheimer's disease in a subject in need thereof, comprising: i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, where each first dose is administered at a frequency of once every four weeks; ii) evaluating a magnetic resonance imaging (MRI) scan of the subject's brain for amyloid-related imaging abnormalities (ARIA) after administration of the three first doses and prior to administration of one or more second doses, where if symptoms consistent with severe or symptomatic ARIA occur, administration of the one or more second doses is discontinued; and iii) four weeks after administration of the three first doses, administering one or more 1400 mg second doses of an anti-N3pGlu Aβ antibody at a frequency of once every four weeks, The method relates to a method in which the Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, administration of the one or more second doses is discontinued and a corticosteroid is administered to the subject.

[0098] In some embodiments, the disclosure relates to a method of treating Alzheimer's disease in a subject in need thereof until symptoms consistent with ARIA-E occur, comprising: i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, each first dose being administered once every four weeks; and ii) four weeks after administration of the three first doses, administering one or more 1400 mg second doses of an anti-N3pGlu Aβ antibody once every four weeks, wherein the anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR consists of the amino acid sequence of SEQ ID NO: 1 and the HCVR consists of the amino acid sequence of SEQ ID NO: 2. In some embodiments, symptoms of ARIA are detected by MRI or are present in the subject.

[0099] In some embodiments, the disclosure relates to a method for treating a patient with donanemab, the patient having Alzheimer's disease, the method comprising: a) administering (or having been administered) 700 mg of donanemab every 4 weeks for the first three doses; b) determining whether the patient has symptoms of ARIA-E i) by performing or having performed an MRI prior to dose escalation or ii) if clinical symptoms consistent with ARIA-E occur; c) temporarily discontinuing treatment with donanemab if the patient has symptoms of moderate ARIA-E; and d) if the patient does not have symptomatic ARIA-E, administering donanemab to the patient in an amount of 1400 mg every 4 weeks until brain amyloid is cleared, negative, or <24.1 CL.

[0100] In some embodiments, the disclosure relates to a method for treating a patient with donanemab, wherein the patient is suffering from Alzheimer's disease, the method comprising: a) administering (or having been administered) 700 mg of donanemab every 4 weeks for the first three doses; and b) determining whether the patient has symptoms of ARIA-E by i) performing or having performed an MRI prior to dose escalation or ii) if clinical symptoms consistent with ARIA-E occur; and if the patient does not have symptomatic ARIA-E, administering donanemab to the patient in an amount of 1400 mg every 4 weeks until brain amyloid is cleared, negative, or <24.1 CL.

[0101] In some embodiments, the disclosure provides an improved method of treating a patient with donanemab for a patient suffering from Alzheimer's disease, the improvement comprising: a) administering or having been administered 700 mg of donanemab every 4 weeks for the first three doses; b) determining if the patient has symptoms of ARIA-E by i) performing or having performed an MRI prior to dose escalation or ii) if clinical symptoms consistent with ARIA-E occur; c) temporarily discontinuing treatment with donanemab if the patient has symptoms of moderate ARIA-E; and d) if the patient does not have symptomatic ARIA-E, administering donanemab orally to the patient in an amount of 1400 mg every 4 weeks until brain amyloid is cleared, negative, or <24.1 CL.

[0102] In some embodiments, the disclosure provides an improved method of treating a patient with donanemab for a patient suffering from Alzheimer's disease, the improvement comprising: a) administering or having been administered 700 mg of donanemab every 4 weeks for the first three doses; and b) determining if the patient has symptoms of ARIA-E by i) performing or having an MRI prior to dose escalation or ii) if clinical symptoms consistent with ARIA-E occur; and if the patient does not have symptomatic ARIA-E, administering donanemab orally to the patient in an amount of 1400 mg every 4 weeks until brain amyloid is cleared, negative, or <24.1 CL.

[0103] In some embodiments, the disclosure relates to a method for treating a patient with donanemab, the patient suffering from Alzheimer's disease, the method comprising: a) administering or having been administered 700 mg of donanemab every 4 weeks for the first 3 doses, b) discontinuing treatment if the patient has moderate ARIA-E symptoms, and c) upon resolution of ARIA-E, continuing treatment by administering donanemab to the patient in an amount of 1400 mg every 4 weeks until brain amyloid is cleared, negative, <24.1 CL, or ARIA-E symptoms recur. In some embodiments, the symptoms or ARIA-E are confirmed or determined by an MRI scan.

[0104] In some embodiments, the disclosure relates to a method for treating a patient with donanemab, the patient having Alzheimer's disease, the method comprising: a) administering or having been administered 700 mg of donanemab every 4 weeks for the first 3 doses; and b) administering donanemab to the patient in an amount of 1400 mg every 4 weeks until brain amyloid is cleared, negative, or <24.1 CL, unless the patient has symptomatic ARIA-E. In some embodiments, symptoms or ARIA-E are confirmed or determined by an MRI scan.

[0105] In some embodiments, a brain MRI of the patient is obtained prior to dose escalation (e.g., from 700 mg to 1400 mg) or if symptoms consistent with ARIA-E occur. In some embodiments, treatment with an anti-N3pGlu Aβ antibody is withheld or discontinued due to or upon severe or symptomatic ARIA-E. In some embodiments, treatment with an anti-N3pGlu Aβ antibody may be temporarily interrupted upon mild or moderate asymptomatic ARIA-E in a patient. In some embodiments, the dose of an anti-N3pGlu Aβ antibody may be temporarily reduced to 1400 mg to 700 mg upon mild or moderate asymptomatic ARIA-E in a patient. In some embodiments, supportive care including corticosteroids may be administered to the patient upon ARIA-E. In some embodiments, treatment with an anti-N3pGlu Aβ antibody may be resumed following resolution of symptoms or stabilization of abnormal brain MRI radiographs.

[0106] If symptoms of ARIA-H occur, they are often in the presence of ARIA-E and are managed similarly to ARIA-E. In some embodiments, a brain MRI of the patient is obtained before increasing the dose or if symptoms consistent with ARIA-H occur. In some embodiments, treatment with the anti-N3pGlu Aβ antibody is withheld or discontinued due to or upon the occurrence of ARIA-H. In some embodiments, treatment with the anti-N3pGlu Aβ antibody may be temporarily interrupted if ARIA-H occurs in the patient, for example, if the ARIA-H symptoms are mild or moderate. In some embodiments, the dose of the anti-N3pGlu Aβ antibody may be temporarily reduced to 1400 mg to 700 mg if the patient experiences mild or moderate asymptomatic ARIA-H. In some embodiments, supportive care including corticosteroids may be administered to the patient if ARIA-H occurs. In some embodiments, treatment with the anti-N3pGlu Aβ antibody may be temporarily discontinued until symptoms of ARIA-E or ARIA-H improve.

[0107] In some embodiments, the subject is administered one or more second doses of greater than 10 mg / kg to about 20 mg / kg of an anti-N3pGlu Aβ antibody. In some embodiments, the second dose is greater than 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or 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 certain embodiments, the first dose is administered once a month. In one embodiment, the subject is administered one or more second doses of greater than 10 mg / kg, each second dose being administered once every four weeks or once a month. In one embodiment, the subject is administered one or more second doses of about 20 mg / kg, with each second dose being administered once every four weeks or once a month.

[0108] In some embodiments, a first dose of an anti-N3pGlu Aβ antibody is administered to a subject once, followed by one or more second doses, the second dose being administered 4 weeks after the one or more first doses and once every 4 weeks thereafter. In some embodiments, a first dose of an anti-N3pGlu Aβ antibody is administered to a subject twice (once every 4 weeks), followed by one or more second doses 4 weeks after the first dose and once every 4 weeks thereafter. In some embodiments, a first dose of an anti-N3pGlu Aβ antibody is administered to a subject three times (once every 4 weeks), followed by one or more second doses 4 weeks after the first dose and once every 4 weeks thereafter.

[0109] In some embodiments, the 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 particular embodiment, the 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.

[0110] In some embodiments, anti-N3pGlu Aβ antibodies slow disease progression in patients with early symptomatic Alzheimer's disease and intermediate brain tau burden. In some embodiments, patients receive 700 mg of anti-N3pG Aβ antibody every 4 weeks for the first three doses, followed by 1400 mg of anti-N3pG Aβ antibody every 4 weeks until brain amyloid plaques reach normal range. In some embodiments, an MRI is performed on the patient before increasing the dose of anti-N3pG Aβ antibody from 700 mg to 1400 mg.

[0111] In some embodiments, anti-N3pGlu Aβ antibodies slow disease progression in patients with early symptomatic Alzheimer's disease (i.e., patients with mild cognitive impairment or mild dementia due to AD). In some embodiments, anti-N3pGlu Aβ antibodies show clinical benefit in patients who are amyloid positive and have intermediate brain tau burden. In some embodiments, patients receive 700 mg of anti-N3pGlu Aβ antibody every 4 weeks for the first 3 doses, followed by 1400 mg of anti-N3pGlu Aβ antibody every 4 weeks until brain amyloid plaques are cleared. In some embodiments, a brain MRI is performed on the patient before increasing the dose of anti-N3pG Aβ antibody from 700 mg to 1400 mg. In some embodiments, a baseline brain MRI is obtained before starting treatment.

[0112] In some embodiments, anti-N3pGlu Aβ antibodies slow disease progression in patients with early symptomatic Alzheimer's disease (mild cognitive impairment or mild dementia due to AD) with biomarker evidence consistent with AD neuropathology. In some embodiments, patients receive 700 mg of anti-N3pGlu Aβ antibody every 4 weeks for the first 3 doses, followed by 1400 mg of anti-N3pGlu Aβ antibody every 4 weeks until brain amyloid plaques are cleared. In some embodiments, a brain MRI is performed on the patient before increasing the dose of anti-N3pG Aβ antibody from 700 mg to 1400 mg. In some embodiments, a baseline brain MRI is obtained before starting treatment. In some embodiments, if a dose / infusion of anti-N3pGlu Aβ antibody is missed, administration of anti-N3pGlu Aβ antibody is resumed on the same dosing schedule as needed.

[0113] In some embodiments, the dosing regimen of the present disclosure 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 the third dose). In some embodiments, the third dose is administered to the subject to reduce deposition of Aβ in the subject's brain, prevent further deposition of Aβ 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 or the same antibodies are used in the first dose, the second dose, and the third dose. In some embodiments, a different Aβ-targeting antibody is administered in the third dose. For example, some embodiments of the present disclosure include: i) administering to a human subject one or more first doses of about 100 mg to about 700 mg of an anti-N3pG Aβ antibody, where each first dose is administered about once every four weeks; ii) about four weeks after administering the one or more first doses, administering to the human subject one or more second doses of greater than 700 mg to about 1400 mg of an anti-N3pG Aβ antibody, where each second dose is administered about once 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-N3pGlu Aβ antibody, where the anti-N3pGlu Aβ antibody comprises a LCVR and a HCVR, where the LCVR comprises the amino acid sequence of SEQ ID NO:1 and the HCVR comprises the amino acid sequence of SEQ ID NO:2. In some embodiments, one or more third doses of an anti-N3pGlu Aβ antibody of the present disclosure may be administered to a subject every 2 or 4 weeks, every month, every year, every 2 years, every 3 years, every 4 years, every 5 years, or every 10 years. In some embodiments, the third dose is given every 2 weeks. In some embodiments, the third dose is given every 4 weeks. In some embodiments, the third dose is given annually. In one embodiment, the third dose is given every 2 years. In another embodiment, the third dose is given every 3 years. In another embodiment, the third dose of antibody is given every 5 years. In another embodiment, the third dose of antibody is given every 10 years.In another embodiment, the third dose of the antibody is given every 2 to 5 years. In another embodiment, the third dose of the antibody is given every 5 to 10 years.

[0114] In some embodiments, the anti-N3pGlu Aβ antibody is administered to the subject for a period sufficient to treat or prevent the disease. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject for a period of up to about 72 weeks, optionally once every 4 weeks or once a month. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject for a period of up to about 98 weeks, optionally once every 4 weeks or once a month. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject for a period of up to about 124 weeks, optionally once every 4 weeks or once a month. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a 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 antibody is administered to the subject until brain amyloid plaque reaches normal range or is eliminated. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until brain amyloid plaque reaches normal range or is eliminated. In some embodiments, the antibody is administered to the subject until the level of brain amyloid plaque stops decreasing. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until the level of brain amyloid plaque stops decreasing. In some embodiments, the antibody is administered to the subject until the subject is amyloid negative. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until the subject is amyloid negative. In some embodiments, if the amyloid plaque level in the subject's brain is less than 24.1 CL, the subject is considered to be amyloid negative. In some embodiments, the level of brain amyloid plaque in the subject can be measured by amyloid PET imaging scan.

[0115] In some embodiments, the dose of anti-N3pGlu Aβ antibody is 700 mg every 4 weeks for the first 3 doses, followed by 1400 mg every 4 weeks for up to 72 weeks or until brain amyloid plaques reach normal range or are cleared. In some embodiments, the dose of anti-N3pGlu Aβ antibody is 700 mg every 4 weeks for the first 3 doses, followed by 1400 mg every 4 weeks until brain amyloid plaques stop reducing.

[0116] In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject, optionally once every 4 weeks or once a month, for a period of up to about 18 months. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject, optionally once every 4 weeks or once a month, for a period of up to about 24 months. In some embodiments, the anti-N3pGlu Aβ antibody (comprising a first dose of antibody and a second dose of antibody) is administered to the subject, optionally once every 4 weeks or once a month, for a period of up to about 30 months.

[0117] In one embodiment, a subject is administered a first dose of 700 mg three times every four weeks, followed by a second dose of 1400 mg once every four weeks for a period of up to 72 weeks. In some embodiments, an anti-N3pGlu Aβ antibody (e.g., comprising a first dose of antibody and a second dose of antibody) is administered to a 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-N3pGlu 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.

[0118] In certain embodiments, the anti-N3pGlu 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. In some embodiments, the antibody of the present disclosure is administered to the subject for a period of 72 weeks or less.

[0119] In some embodiments, the anti-N3pGlu 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 1 month to about 18 months. In some embodiments, the anti-N3pGlu Aβ antibody is administered to the subject for 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-N3pGlu Aβ antibody is administered to the subject for 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.

[0120] In some embodiments, the antibody is administered to the subject until brain amyloid plaques reach normal range, hi some embodiments, the antibody is administered to the subject until brain amyloid plaques are cleared.

[0121] 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.

[0122] In some embodiments, a human subject is administered an anti-N3pGlu Aβ antibody for a period of time sufficient to treat or prevent a disease characterized by amyloid beta plaques in the human subject's brain. In some embodiments, a human subject is administered an anti-N3pGlu Aβ antibody (e.g., including a first dose and / or a second dose) for a period of time sufficient to bring amyloid plaques in the subject's brain to normal range (or until brain amyloid plaques are cleared). A normal range of amyloid plaques is defined as two consecutive PET scans at least six months apart that demonstrate amyloid plaque levels of 25 centiloids or less, or a single PET scan that demonstrates amyloid plaque levels 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.

[0123] In some embodiments, the antibody of the present disclosure is administered to the 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, the antibody of the present disclosure is administered to the subject until the amyloid plaque level in the subject is about 25 centiloids or less in two consecutive PET imaging scans. In some embodiments, the two consecutive PET imaging scans are at least 6 months apart. In some embodiments, the antibody of the present disclosure is administered to the subject until the amyloid plaque level in the subject is about 11 centiloids or less when measured by one PET imaging.

[0124] In certain embodiments, a subject is administered three 700 mg first doses of an antibody of the present disclosure, where each first dose is administered once every four weeks, and then one or more 1400 mg second doses 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.

[0125] In other embodiments, a subject is administered three 700 mg first doses of an antibody of the present disclosure, each first dose administered once every four weeks, and then a 1400 mg second dose of the antibody, each second dose administered once every four weeks until the patient has amyloid plaque levels of about 25 centiloids or less on two consecutive PET imaging scans, or 11 centiloids or less on one PET imaging scan. In some embodiments, the two consecutive PET imaging scans are at least six months apart.

[0126] In some embodiments, the subject is not administered an anti-N3pGlu Aβ antibody dose after the amyloid plaque level in the patient is about 25 centiloids or less in two consecutive PET imaging scans, or about 11 centiloids or less in one PET imaging scan, in some embodiments, the two consecutive PET imaging scans are at least 6 months apart.

[0127] In some embodiments, a subject may be administered one or more 700 mg doses of an anti-N3pGlu Aβ antibody after the amyloid plaque level in the patient is about 25 centiloids or less in two consecutive PET imaging scans, or about 11 centiloids or less in one PET imaging scan.

[0128] In some embodiments, an antibody of the disclosure 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 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 14.12:1565-1571 (2018), which are incorporated by reference in their entireties.

[0129] In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ deposits in the subject's brain are reduced by about 50 to about 150 centiloids. In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ deposits in the subject's brain are reduced by about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, or about 150 centiloids. In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ plaques in the subject's brain are reduced by about 50 centiloids. In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ plaques in the subject's brain are reduced by about 60 centiloids. In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ plaques in the subject's brain are reduced by about 70 centiloids. In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ plaques in the subject's brain are reduced by about 80 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 84 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 90 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 100 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 110 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 120 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 130 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 140 centiloids. In some embodiments, an antibody of the disclosure is administered to a subject until there is about a 150 centiloid reduction in Aβ plaques in the subject's brain.

[0130] In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ deposits in the subject's brain are reduced by an average of about 25 to about 100 centiloids. In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ deposits in the subject's brain are reduced by an average of about 50 to about 100 centiloids. In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ deposits in the subject's brain are reduced by an average of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, about 100 centiloids. In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ plaques in the subject's brain are reduced by an average of about 50 centiloids. In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ plaques in the subject's brain are reduced by an average of about 60 centiloids. In some embodiments, the antibody of the present disclosure is administered to the subject until Aβ plaques in the subject's brain are reduced by an average of about 70 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 80 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 84 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 90 centiloids. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by an average of about 100 centiloids.

[0131] In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ deposits in the brain of the subject are reduced by about 25 to about 150 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ deposits in the brain of the subject are reduced by about 50 to about 150 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ deposits in the brain of the subject are reduced by about 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 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 50 centiloids. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ plaques in the brain of the subject are reduced by about 60 centiloids. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ plaques in the brain of the subject are reduced by about 70 centiloids. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ plaques in the brain of the subject are reduced by about 80 centiloids. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ plaques in the brain of the subject are reduced by about 84 centiloids. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ plaques in the brain of the subject are reduced by about 90 centiloids. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ plaques in the brain of the subject are reduced by about 100 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 110 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 120 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 130 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 140 centiloids.In some embodiments, a second dose of an antibody of the disclosure is administered to the subject until Aβ plaques in the subject's brain are reduced by about 150 centiloids.

[0132] In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ deposits in the subject's brain are reduced by an average of about 25 to about 100 centiloids. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ deposits in the subject's brain are reduced by an average of about 50 to about 100 centiloids. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ deposits in the subject's brain are reduced by an average of about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 84, about 90, about 100 centiloids. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ plaques in the subject's brain are reduced by an average of about 50 centiloids. In some embodiments, a second dose of the antibody of the present disclosure is administered to the subject until Aβ plaques in the subject's brain are reduced by an average of about 60 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until the Aβ plaque in the brain of the subject is reduced by an average of about 70 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until the Aβ plaque in the brain of the subject is reduced by an average of about 80 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until the Aβ plaque in the brain of the subject is reduced by an average of about 84 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until the Aβ plaque in the brain of the subject is reduced by an average of about 90 centiloids. In some embodiments, a second dose of an antibody of the present disclosure is administered to a subject until the Aβ plaque in the brain of the subject is reduced by an average of about 100 centiloids.

[0133] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a reduction of Aβ plaques in the brain of a human subject. In certain embodiments, Aβ plaques are reduced by about 20-100% after treatment. In some embodiments, the antibodies of the present disclosure are administered to the subject until Aβ plaques are reduced by about 20-100% in the brain of the subject. In some embodiments, the antibodies of the present disclosure are administered to the subject until Aβ plaques are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100% in the brain of the human subject. In some embodiments, the antibodies of the present disclosure are administered to the subject until Aβ plaques are reduced by about 20% in the brain of the subject. In some embodiments, the antibodies of the present disclosure are administered to the subject until Aβ plaques are reduced by about 25% in the brain of the subject. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 30%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 35%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 40%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 50%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 75%. In some embodiments, an antibody of the present disclosure is administered to a subject until Aβ plaques in the subject's brain are reduced by about 100%.

[0134] In some embodiments, the first and / or second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 20-100%. In certain embodiments, the second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 20-100%. In some embodiments, the second dose of an antibody of the present disclosure is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75% or about 100%. In some embodiments, the second dose is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 20%. In some embodiments, the second dose is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 25%. In some embodiments, the second dose is administered to a subject until Aβ plaques in the brain of the subject are reduced by about 30%. In some embodiments, the second dose is administered to the subject until Aβ plaques in the subject's brain are reduced by about 35%. In some embodiments, the second dose is administered to the subject until Aβ plaques in the subject's brain are reduced by about 40%. In some embodiments, the second dose is administered to the subject until Aβ plaques in the subject's brain are reduced by about 50%. In some embodiments, the second dose is administered to the subject until Aβ plaques in the subject's brain are reduced by about 75%. In some embodiments, the second dose is administered to the subject until Aβ plaques in the subject's brain are reduced by about 100%.

[0135] In some embodiments, the percentage reduction of Aβ plaques 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. In some embodiments, the Aβ plaque levels in the subject are reduced by at least 60% within 24 weeks of administration (including both the first and second doses) of an anti-N3pGlu Aβ antibody of the invention.

[0136] In some embodiments, centiloid reduction of Aβ plaques 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.

[0137] In some embodiments, the mean centiloid reduction of Aβ plaques 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.

[0138] In some embodiments, the disclosure provides for about a 15 to about 45 percent slowing of decline in a composite cognitive-functional endpoint from baseline. In some embodiments, the disclosure provides for about a 15 to about 45 percent slowing of decline in a composite cognitive-functional endpoint from baseline over 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.

[0139] In some embodiments, the present disclosure provides about 15 to about 45 percent slowing of decline in the composite cognitive-functional endpoint from baseline over a 76 week period. In some embodiments, the slowing of decline in the composite cognitive-functional endpoint from baseline is provided from a mixed model repeated measures (MMRM) model or a Bayesian disease progression model (DPM). In some embodiments, an antibody of the present disclosure is administered to a subject until about 15 to about 45 percent slowing of decline in the composite cognitive-functional endpoint from baseline is reached. In some embodiments, a first dose or a second dose of the present disclosure is administered to a subject until about 15 to about 45 percent slowing of decline in the composite cognitive-functional endpoint from baseline is reached.

[0140] In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 15% to about 45% compared to an untreated subject, where the disease progression is measured by DPM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 15% compared to an untreated subject, where the disease progression is measured by DPM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 20% compared to an untreated subject, where the disease progression is measured by DPM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 25% compared to an untreated subject, where the disease progression is measured by DPM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% compared to an untreated subject, where disease progression is measured by DPM.

[0141] In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 15% to about 45% compared to an untreated subject, where the disease progression is measured by MMRM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 15% compared to an untreated subject, where the disease progression is measured by MMRM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 20% compared to an untreated subject, where the disease progression is measured by MMRM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by about 25% compared to an untreated subject, where the disease progression is measured by MMRM. In some embodiments, administration of an anti-N3pGlu Aβ antibody of the present disclosure to a subject slows disease progression by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 45% compared to an untreated subject, where disease progression is measured by MMRM.

[0142] In some embodiments, the disclosure provides a slowing of decline or disease progression on an integrated Alzheimer's Disease Rating Scale (iADRS) of about 15 to about 60 percent from baseline or compared to untreated subjects. In some embodiments, the disclosure provides a slowing of decline or disease progression on an integrated Alzheimer's Disease Rating Scale of about 15 to about 60 percent from baseline or compared to untreated subjects over 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 slowing of decline measured by iADRS is provided from a mixed model repeated measures (MMRM) model or a Bayesian disease progression model (DPM).

[0143] In some embodiments, the disclosure results in a slowing of decline in the Unified Alzheimer's Disease Rating Scale or disease progression of about 20 percent, about 25 percent, about 30 percent, about 32 percent, about 35 percent, about 40 percent, about 45 percent, about 50%, about 55%, or about 60% from baseline or compared to untreated subjects.

[0144] In some embodiments, the disclosure provides for about a 15 to about 60 percent slowing of decline on the Unified Alzheimer's Disease Rating Scale over a 76 week period, compared to baseline or untreated subjects. In certain embodiments, the disclosure provides for about a 32 percent slowing of decline on the Unified Alzheimer's Disease Rating Scale over a 76 week period, compared to baseline or untreated subjects. In some embodiments, an antibody of the disclosure is administered to a subject until a slowing of decline on the Unified Alzheimer's Disease Rating Scale of about 15 to about 60 percent is reached, compared to baseline or untreated subjects. In some embodiments, a first or second dose of the disclosure is administered to a subject until a slowing of decline on the Unified Alzheimer's Disease Rating Scale of about 15 to about 60 percent is reached, compared to baseline or untreated subjects.

[0145] In some embodiments, the disclosure provides a slowing of decline or disease progression on the Integrated Alzheimer's Disease Rating Scale (iADRS) by about 3 to about 6 from baseline or compared to untreated subjects. In some embodiments, the disclosure provides a slowing of decline or disease progression on the Integrated Alzheimer's Disease Rating Scale by about 3 to about 6 from baseline or compared to untreated subjects over 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.

[0146] In some embodiments, the disclosure provides a slowing of decline or disease progression on the Unified Alzheimer's Disease Rating Scale by about 3, about 4, about 5, or about 6 points from baseline or compared to untreated subjects. In some embodiments, the disclosure provides a slowing of decline or disease progression on the Unified Alzheimer's Disease Rating Scale by 3 to about 6 points from baseline or compared to untreated over a 76 week period.

[0147] In some embodiments, the slowing of disease progression as measured by the iADRS is provided by a mixed model repeated measures (MMRM) model or a Bayesian disease progression model (DPM).

[0148] In some embodiments, a subject's composite cognitive function 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.

[0149] In some embodiments, the disclosure provides about a 20 to about 40 percent slowing of decline in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) or disease progression from baseline or compared to untreated subjects. In some embodiments, the disclosure provides about a 20 to about 40 percent slowing of decline in CDR-SB or disease progression from baseline or compared to untreated subjects over 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.

[0150] In some embodiments, the disclosure results in a slowing of decline in CDR-SB or disease progression of about 20 percent, about 25 percent, about 30 percent, about 35 percent, or about 40 percent from baseline or compared to untreated subjects.

[0151] In some embodiments, the disclosure provides about a 20 to about 40 percent slowing of the decline in CDR-SB from baseline or compared to untreated subjects over a 76 week period. In some embodiments, an antibody of the disclosure is administered to a subject until about a 20 to about 40 percent slowing of the decline in CDR-SB is reached from baseline or compared to untreated subjects. In some embodiments, a first or second dose of the disclosure is administered to a subject until about a 20 to about 40 percent slowing of the decline in CDR-SB is reached from baseline or compared to untreated subjects. In some embodiments, the slowing of disease progression as measured by CDR-SB is provided by a mixed model repeated measures (MMRM) model or a Bayesian disease progression model (DPM).

[0152] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the disclosure do not result in a reduction in hippocampal volume in a subject. In some embodiments, administration of the antibody does not result in a reduction in hippocampal volume in a subject.

[0153] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a reduction or reduction of tau levels in the brain of a human subject. In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a reduction or reduction of plasma tau levels in patients with a disease characterized by Aβ plaques. In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a reduction or reduction of P-tau 217 levels in patients with a disease characterized by Aβ plaques. In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a rapid and sustained reduction of P-tau 217 levels in patients with a disease characterized by Aβ plaques. In some embodiments, P-tau 217 levels are reduced by about 5% to about 40% from baseline. In some embodiments, P-tau 217 levels are reduced by about 10% to about 30% from baseline. In some embodiments, P-tau 217 levels are reduced by about 20% to about 30% from baseline. In some embodiments, P-tau 217 levels are reduced by about 25% to about 30% from baseline. In some embodiments, P-tau 217 levels are reduced by 5%, 10%, 15%, 20%, 24%, 25%, 29%, 30%, 35%, or 40% from baseline. In some embodiments, P-tau 217 levels are reduced by about 5% to about 40% from baseline after treatment with an anti-N3pG antibody. In some embodiments, P-tau 217 levels are reduced by about 10% to about 30% from baseline after treatment with an anti-N3pG antibody. In some embodiments, P-tau 217 levels are reduced by about 20% to about 30% from baseline after treatment with an anti-N3pG antibody. In some embodiments, P-tau 217 levels are reduced by about 25% to about 30% from baseline after treatment with an anti-N3pG antibody. In some embodiments, P-tau 217 levels are reduced by 5%, 10%, 15%, 20%, 24%, 25%, 29%, 30%, 35%, or 40% from baseline after treatment with an anti-N3pG antibody. In some embodiments, P-tau 217 levels are reduced by about 5% to about 40% from baseline at one or more time points during or after treatment with an anti-N3pG antibody of the present disclosure.

[0154] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in a decrease or reduction in neurofilament light chain (NfL) levels in the brain of patients with a disease characterized by Aβ plaques. In some embodiments, NfL levels are reduced by about 1% to about 20% compared to placebo. In some embodiments, NfL levels are reduced by about 5% to about 15% compared to placebo. In some embodiments, NfL levels are reduced by about 10% to about 15% compared to placebo. In some embodiments, NfL levels are reduced by 2%, 3%, 4%, 5%, 10%, 15%, or 20% compared to placebo. In some embodiments, NfL levels are reduced by about 1% to about 20% compared to placebo after treatment with an anti-N3pG antibody. In some embodiments, NfL levels are reduced by about 5% to about 15% compared to placebo after treatment with an anti-N3pG antibody. In some embodiments, NfL levels are reduced by about 10% to about 15% after treatment with an anti-N3pG antibody compared to placebo. In some embodiments, NfL levels are reduced by 2%, 3%, 4%, 5%, 10%, 15%, or 20% after treatment with an anti-N3pG antibody compared to placebo. In some embodiments, NfL levels are reduced by 2%, 3%, 4%, 5%, 10%, 15%, or 20% after treatment with an anti-N3pG antibody compared to placebo. In some embodiments, NfL levels are reduced by about 1% to about 20% compared to placebo at one or more time points during or after treatment with an anti-N3pG antibody of the present disclosure.

[0155] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the present disclosure result in an increase in the Aβ42 / 40 ratio in the plasma or cerebrospinal fluid (CSF) of patients with a disease characterized by Aβ plaques. 42 / 40 In some embodiments, the ratio of Aβ in plasma is increased by about 1% to about 10% compared to baseline. 42 / 40 In some embodiments, the ratio of Aβ in plasma is increased by about 1% to about 5% compared to baseline. 42 / 40The ratio is increased by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% compared to baseline. 42 / 40 The ratio is increased by about 1% to about 10% after treatment with an anti-N3pG antibody compared to baseline. 42 / 40 The ratio is increased by about 1% to about 5% compared to baseline after treatment with an anti-N3pG antibody. 42 / 40 The ratio increases by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% compared to baseline after treatment with an anti-N3pG antibody. In some embodiments, the plasma Aβ42 / 40 ratio increases by about 1% to about 10% compared to baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure.

[0156] In some embodiments, the antibodies, methods, dosing regimens, and / or uses of the disclosure result in a reduction or decrease in glial fibrillary acidic protein (GFAP) in the blood of patients with a disease characterized by Aβ plaques. In some embodiments, GFAP levels are reduced by about 5% to about 40% from baseline. In some embodiments, GFAP levels are reduced by about 10% to about 30% from baseline. In some embodiments, GFAP levels are reduced by about 10% to about 20% from baseline. In some embodiments, GFAP levels are reduced by about 10% to about 15% from baseline. In some embodiments, GFAP levels are reduced by 5%, 10%, 12%, 15%, 20%, 24%, 25%, 29%, 30%, 35%, or 40% from baseline. In some embodiments, GFAP levels are reduced by about 5% to about 40% from baseline after treatment with an anti-N3pG antibody. In some embodiments, GFAP levels are reduced from baseline by about 10% to about 30% after treatment with an anti-N3pG antibody. In some embodiments, GFAP levels are reduced from baseline by about 10% to about 20% after treatment with an anti-N3pG antibody. In some embodiments, GFAP levels are reduced from baseline by about 10% to about 15% after treatment with an anti-N3pG antibody. In some embodiments, GFAP levels are reduced by 5%, 10%, 12%, 15%, 20%, 24%, 25%, 29%, 30%, 35%, or 40% after treatment with an anti-N3pG antibody. In some embodiments, GFAP levels are reduced from baseline by about 5% to about 40% at one or more time points during or after treatment with an anti-N3pG antibody of the present disclosure. In some embodiments, GFAP levels are reduced from baseline by about 5% to about 30% at one or more time points during or after treatment with an anti-N3pG antibody of the present disclosure. In some embodiments, GFAP levels are reduced by about 5% to about 20% from baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure, hi some embodiments, GFAP levels are reduced by about 5% to about 15% from baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure.In some embodiments, GFAP levels are reduced by 5%, 10%, 14%, 15%, 20%, 25%, 30%, 35%, or 40% from baseline at one or more time points during or after treatment with an anti-N3pG antibody of the disclosure.

[0157] In some embodiments, the antibody of the present disclosure may be administered simultaneously, separately, or sequentially in combination with an effective amount of a symptomatic agent for treating Alzheimer's disease. The symptomatic agent may be selected from a cholinesterase inhibitor (ChEI) and / or an N-methyl-D-aspartic acid (NMDA) partial antagonist. In a preferred embodiment, the agent is a ChEI. In another preferred embodiment, the agent is an NMDA antagonist, or a combination agent comprising a ChEI and an NMDA antagonist.

[0158] In some embodiments, the dosing regimen or method described herein comprises administering solanezumab or an antibody comprising a portion of solanezumab to a human patient. In some embodiments, the anti-N3pGlu Aβ antibody is administered simultaneously, separately, or sequentially in combination with an effective amount of an antibody having a light chain of SEQ ID NO: 15. In some embodiments, the anti-N3pGlu Aβ antibody is administered simultaneously, separately, or sequentially in combination with an effective amount of an antibody having a heavy chain of SEQ ID NO: 16. In some embodiments, the anti-N3pGlu Aβ antibody is administered simultaneously, separately, or sequentially in combination with an effective amount of an antibody having two heavy chains of SEQ ID NO: 16 and two light chains of SEQ ID NO: 15. In some embodiments, the anti-N3pGlu Aβ antibody of the present disclosure may be administered simultaneously, separately, or sequentially in combination with an effective amount of solanezumab.

[0159] Additional information about solanezumab, including its CDR sequences, LCVR, HCVR sequences, and methods of making and using it, can be found in the following patent documents, which are incorporated by reference herein in their entireties: ●U.S. Patent No. 7,195,761 ● U.S. Patent Application Publication No. 2006 / 0039906 ●U.S. Patent No. 7,195,761 ●U.S. Patent No. 8,591,894 ●U.S. Patent No. 7,771,722 ●U.S. Patent Application Publication No. 2007 / 0190046.

[0160] Information about using solanezumab in combination with other antibodies can be found in U.S. Patent Application Publication No. 2019 / 03824, which is incorporated by reference in its entirety.

[0161] In some embodiments, solanezumab or an antibody comprising a portion of solanezumab is administered to a human subject to maintain amyloid beta levels within the normal range. In embodiments, solanezumab or an antibody comprising a portion of solanezumab is administered to a human subject to prevent an increase in amyloid plaque levels. In embodiments, solanezumab or an antibody comprising a portion of solanezumab is administered to a human subject to reduce the rate of increase in amyloid plaque levels.

[0162] In some embodiments, a human subject may receive a dose or dosing regimen of an anti-N3pGlu Aβ antibody described herein in combination with a dose or dosing regimen of solanezumab or an antibody comprising a solanezumab moiety. In some embodiments, the dose of solanezumab is 400 mg every 4 weeks, 800 mg every 4 weeks, 1200 mg every 4 weeks, or 1600 mg every 4 weeks. In some embodiments, the dosing regimen of solanezumab includes an initial dose of 400 mg and either maintaining the patient at 400 mg or escalating to 800 mg every 4 weeks or escalating to 1200 mg every 4 weeks, or escalating to 1600 mg over time. Other embodiments may include giving an initial dose of 1600 mg and then maintaining the dose or escalating to 400 mg, 800 mg, or 1200 mg. One of ordinary skill in the art would understand how to titrate up or down the dosage, or how to maintain a patient on a particular dosage (and the associated timing for dosing changes).

[0163] In some embodiments, administration of solanezumab causes a reduction in available soluble Aβ in the brain, which can be 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, or about 80 weeks.

[0164] In some embodiments, administration of solanezumab results in a 5% decrease in soluble Aβ concentrations. In other embodiments, administration of solanezumab results in a 10% decrease in soluble Aβ concentrations. In other embodiments, administration of solanezumab results in a 15% decrease in soluble Aβ concentrations. In other embodiments, administration of solanezumab results in a 20% decrease in soluble Aβ concentrations. In other embodiments, administration of solanezumab results in a 25% decrease in soluble Aβ concentrations. In other embodiments, administration of solanezumab results in a 30% decrease in soluble Aβ concentrations. In other embodiments, administration of solanezumab results in a 35% decrease in soluble Aβ concentrations. In other embodiments, administration of solanezumab results in a 40% decrease in soluble Aβ concentrations. In other embodiments, administration of solanezumab results in a 45% decrease in soluble Aβ concentrations. In other embodiments, administration of solanezumab results in a 50% decrease in soluble Aβ concentrations. In other embodiments, administration of solanezumab results in a greater than 50% decrease in soluble Aβ concentrations. One of ordinary skill in the art would know how to measure soluble Aβ concentrations. See Siemers et al., "Safety and Changes in Plasma and Cerebrospinal Fluid Amyloid β After a Single Administration of an Amyloid β Monoclonal Antibody in Subjects with Alzheimer Disease." Clinical Neuropharmacology 33.2(2010):67-73 and Farlow et al., "Safety and Biomarker Effects of Solanezumab in Patients with Alzheimer's Disease," Alzheimer's & Dementia 8.4(2012):261-271, each of which is incorporated herein by reference in its entirety.

[0165] One of ordinary skill in the art will appreciate that modifications in the dosage of solanezumab or another antibody may be based on a variety of factors, including PET scans, clinical observations, the performance of the patient in various "tests," and the like.

[0166] In some embodiments, the disease characterized by Aβ deposition in the brain of the subject 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.

[0167] The present disclosure includes the use of biomarkers for diseases characterized by Aβ plaques 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 who are destined to be affected or who are in the "preclinical" stage of the disease; 2) reducing disease heterogeneity in clinical trials or epidemiological studies; 3) reflecting the natural history of the disease, including stages of induction, latency, and detection; and 4) targeting subjects for clinical trials or treatment / prevention of the disease.

[0168] In some embodiments, biomarkers may be used to assess whether a subject can be treated using the antibodies, dosing regimens, or methods described herein. In some embodiments, biomarkers may be used to assess whether a disease (as described herein) can be prevented in a subject using the antibodies, dosing regimens, or methods described herein. In some embodiments, biomarkers may be used to assess whether a subject will respond to a treatment or prevention of a disease (as described herein) using the antibodies, dosing regimens, or methods described herein. In some embodiments, biomarkers may be used to stratify or classify subjects into groups and identify which groups of subjects will respond to a treatment / prevention of a disease (as described herein) using the antibodies, dosing regimens, or methods described herein. In some embodiments, biomarkers may be used to assess a subject's condition and / or the duration of administration of an antibody or a dose thereof to a subject, as described herein.

[0169] In some embodiments, the subject has a genetic mutation that causes autosomal dominant Alzheimer's disease or has an increased risk of developing AD due to carrying one or two APOE4 alleles. In certain embodiments, the subject carries one or two APOE4 alleles, i.e., the patient is heterozygous or homozygous.

[0170] In some embodiments, the subject has a baseline MMSE (Mini-Mental State Examination) score of 20-28 prior to administration of the anti-N3pGlu Aβ antibody.

[0171] In some embodiments, the subject has low to moderate tau burden or has been determined to have low to moderate tau burden. 18A subject has low to moderate tau burden if the 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 low to moderate tau burden or has been determined to have low to moderate tau burden and carries one or two APOE4 alleles.

[0172] In some embodiments, the subject has very low tau burden or has been determined to have very low tau burden. 18 A subject has very low tau burden if the tau burden, as measured by F-Flortaucipir, is less than 1.10 SUVr. In some embodiments, the subject has, or has been determined to have, very low tau burden and carries one or two APOE4 alleles.

[0173] 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 has very low to moderate tau burden if the tau burden, as measured by F-Flortaucipir, is <1.46 SUVr. In some embodiments, the subject has very low to moderate tau burden, or has been determined to have very low to moderate tau burden, and carries one or two APOE4 alleles.

[0174] In some embodiments, the subject does not have high tau burden or has been determined to not have high tau burden. 18A human subject has high tau burden if the tau burden, as measured by F-flourtaucipir, is greater than 1.10 SUVr. In some embodiments, a subject with high tau is not administered an antibody of the present disclosure. In some embodiments, the subject does not have, or has been determined not to have, high tau burden and carries one or two APOE4 alleles.

[0175] In some embodiments, the anti-N3pGlu Aβ antibodies, dosing regimens, or methods described herein are effective in human subjects with very low to moderate tau. In some embodiments, the anti-N3pGlu Aβ antibodies, dosing regimens, or methods described herein are effective in human subjects with low to moderate tau. In some embodiments, the antibodies of the present disclosure are most effective in human subjects with tau levels i) about 1.14 SUVr or less, or ii) about 1.14 SUVr to about 1.27 SUVr. In some embodiments, the anti-N3pGlu Aβ antibodies, dosing regimens, or methods described herein are effective in human subjects regardless of tau levels.

[0176] In some embodiments, the anti-N3pGlu Aβ antibodies, dosing regimens, or methods described herein are effective in human subjects with very low to moderate tau and one or two APOE4 alleles. In some embodiments, the anti-N3pGlu Aβ antibodies, dosing regimens, or methods described herein are effective in human subjects with low to moderate tau and one or two APOE4 alleles. In some embodiments, the antibodies of the present disclosure are most effective in human subjects with one or two APOE4 alleles and tau levels i) about 1.14 SUVr or less, or ii) about 1.14 SUVr to about 1.27 SUVr.

[0177] In some embodiments, the methods of the present disclosure are such that the level of Aβ plaques in the subject's brain is maintained at normal levels for at least 52 weeks after completion of administration of the second dose.

[0178] Tau levels in human subjects may be determined by techniques and methods familiar to the diagnosing physician or one of skill in the art. In some embodiments, human subjects suffering from a disease characterized by amyloid beta plaques are determined to have very low to moderate tau, low to moderate tau, or no high tau using techniques and methods familiar to the diagnosing physician or one of skill in the art. In some embodiments, such methods may also be used to pre-screen, screen, diagnose, evaluate the increase or reduction of brain tau burden, and / or evaluate progress achieved in the treatment or prevention of a disease described herein. In some embodiments, the methods may also be used to stratify subjects into groups and / or identify which groups of subjects will respond to treatment / prevention of a disease (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 human subjects may be used to pre-screen or screen subjects using the antibodies, dosing regimens, or methods described herein to determine which subjects will respond to treatment / prevention of a disease (described herein).

[0179] In some embodiments, tau levels in a human subject may be determined, for example, using techniques or methods that detect or quantify i) brain tau deposits, ii) tau in plasma, or iii) tau in cerebrospinal fluid. In some embodiments, brain tau load, tau in plasma, or tau in cerebrospinal fluid may be used to stratify subjects into groups and / or identify which groups of subjects will respond to disease treatment / prevention (as described herein) using the antibodies, dosing regimens, or methods described herein.

[0180] Tau levels in the brain of a human subject can be determined using methods such as 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 77.8:955-965 (2020); Ossenkoppele et al., “Discriminative Accuracy of F18-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 by reference in their entireties.

[0181] In some embodiments, the PET ligand biomarker F18-Flortaucipir may be used for purposes of this disclosure. For example, PET tau images may be quantitatively assessed to estimate SUVr (Standardized Uptake Value Ratio) by published methods (Pontecorvo et al., "A Multicentre Longitudinal Study of Flortaucipir ( 18F) in Normal Aging, Mild Cognitive Impairment and Alzheimer's Disease Dementia,” Brain 142:1723-35 (2019); Devous et al., “Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18,” Journal of Nuclear Medicine 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 are incorporated by reference in their entireties) and / or visually assess the patient, e.g., to determine whether the patient has an AD pattern (Fleisher et al., “Positron Emission Tomography Imaging With F18-flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic (Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018), which is incorporated by reference in its entirety). Lower SUVr values ​​indicate lower tau burden, and higher SUVr values ​​indicate higher tau burden. In one embodiment, quantitative assessment from flortaucipir scans is achieved by an automated image processing pipeline as described below (Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018), which is incorporated 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 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,” J. Nucl. Med. 59:944-951 (2018), which is incorporated by reference in its entirety). The preferred method of determining tau burden is quantitative analysis reported as standardized uptake value ratio (SUVr), which represents counts within a specific target region of interest in the brain when compared to a reference region (e.g., using PERSI), as compared to a reference region (e.g., MUBADA, ).

[0182] In some embodiments, phosphorylated tau (P-tau, phosphorylated at either threonine 181 or 217) may be used to measure tau loading / burden for purposes of the present disclosure (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. 12, 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 6, eaaz2387 (2020), which are incorporated herein by reference in their entirety). In certain embodiments, an antibody against human tau phosphorylated at threonine residue 217 may be used to measure tau load / burden in a subject for purposes of this disclosure (see International Patent Application Publication No. 2020 / 242963, which is incorporated by reference in its entirety). The present disclosure includes, in some embodiments, measuring tau load / burden in a subject using an anti-tau antibody disclosed in WO2020 / 242963. The anti-tau antibody disclosed in WO2020 / 242963 is directed against an isoform of human tau expressed in the CNS (e.g., recognizes an isoform expressed in the CNS, but not an isoform of human tau expressed only outside the CNS).Such antibodies against isoforms of human tau expressed in the CNS may be used in methods to identify / select patients as one or more of the following: (i) having a disease disclosed herein, (ii) at risk for a disease disclosed herein, (iii) in need of treatment for a disease disclosed herein, or (iv) in need of neurological imaging.

[0183] In some embodiments, a subject is positive for amyloid plaques if amyloid is detected in the brain by methods such as amyloid imaging with a radiolabeled PET compound, or by using a diagnostic agent that detects Aβ or a biomarker of Aβ. Exemplary methods that can be used in the present disclosure to measure brain amyloid load / burden include, for example, the use of 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 53.4:387 (2009), which is incorporated by reference in its entirety), florbetaben (Syed et al., "[ 18 F]Florbetaben: A Review in β-Amyloid PET Imaging in Cognitive Impairment,” CNS Drugs 29, 605-613 (2015), which is incorporated by reference in its entirety), and flutemetamol (Heurling et al., “Imaging β-amyloid Using [ 18F]Flutemetamol Positron Emission Tomography: From Dosimetry to Clinical Diagnosis,” European Journal of Nuclear Medicine and Molecular Imaging 43.2:362-373 (2016), which is incorporated herein by reference in its entirety.

[0184] F18-Florbetapir can provide qualitative and quantitative measurements of brain plaque load in patients, including those with prodromal AD or mild AD dementia. For example, the absence of significant F18-Florbetapir signal when visually read indicates sparse to no amyloid plaques in patients who clinically exhibit cognitive impairment. Thus, F18-Florbetapir also provides confirmation of amyloid pathology (see, e.g., Clark, et al., "Use of Florbetapir-PET for Imaging β-amyloid Pathology," JAMA 305.3:275-283 (2011), which is incorporated herein by reference in its entirety). F18-Florbetapir PET also provides a quantitative assessment of fibrillar amyloid plaques in the brain, and in some embodiments can be used to assess the reduction of amyloid plaques from the brain by the antibodies of the present disclosure. The F18-Florbetapir method can also be automated (see, e.g., Joshi, et al., “A Semiautomated Method for Quantification of F18 Florbetapir PET Images,” J. Nuclear Medicine 56.11:1736-1741 (2015), which is incorporated by reference in its entirety).

[0185] Amyloid imaging with radiolabeled PET compounds can be used to determine whether Aβ deposits are reduced or increased 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 % reduction in Aβ deposits in the brain of a patient before and after treatment. SUVr values ​​can be converted to standardized centiloid units, with 100 being the mean for AD and 0 being the mean for young controls, allowing comparisons between amyloid PET tracers and calculation of reductions according to centiloid units (Klunk et al., "The Centiloid Project: Standardizing Quantitative Amyloid Plaque Estimation by PET," Alzheimer's & Dementia 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 14.12:1565-1571 (2018), which are incorporated herein by reference in their entireties). In some embodiments, the change in cerebral amyloid plaque deposition from baseline is measured by F18-florbetapir PET scan.

[0186] Cerebrospinal fluid or plasma-based assays of β-amyloid may also be used to measure amyloid load / burden for the purposes of this disclosure. 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), incorporated herein by reference in its entirety). In some embodiments, the ratio of Aβ42 / Aβ40 or Aβ42 / Aβ38 can be used as amyloid beta biomarkers (Janelidze et al., “CSF Abeta42 / Abeta40 and Abeta42 / Abeta38 Ratios: Better Diagnostic Markers of Alzheimer Disease,” Ann Clin Transl Neurol 3, 154-165 (2016), incorporated herein by reference in its entirety).

[0187] In some embodiments, deposited cerebral amyloid plaques or Aβ in the CSF or plasma may be used to stratify subjects into groups and identify which groups of subjects will respond to disease treatment / prevention (as described herein) using the antibodies, dosing regimens, or methods described herein.

[0188] As used herein, "anti-N3pGlu Aβ antibody", "anti-N3pG antibody", or "anti-N3pE antibody" are used interchangeably and refer to an antibody that preferentially binds to N3pGlu Aβ over Aβ1-40 or Aβ1-42. 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. Pat. No. 8,679,498 B2, which is incorporated herein by reference in its entirety. See, for example, Table 1 in U.S. Pat. No. 8,679,498 B2. Each of the antibodies disclosed in U.S. Pat. No. 8,679,498 B2, including the "hE8L", "B12L" and "R17L" antibodies, may be used as the anti-N3pGlu Aβ antibody of the present disclosure or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure. Other representative types of anti-N3pGlu Aβ antibodies include, but are not limited to, those disclosed in U.S. Pat. No. 8,961,972, U.S. Pat. No. 10,647,759, U.S. Pat. No. 9,944,696, WO2010 / 009987A2, WO2011 / 151076A2, WO2012 / 136552A1 and equivalents thereof, such as antibodies disclosed under 35 U.S.C. § 112(f).

[0189] Those skilled in the art will understand and appreciate that "anti-N3pGlu Aβ antibodies" and several specific antibodies are identified and disclosed (along with methods of making and using such antibodies) in U.S. Patent No. 8,961,972 (hereby incorporated by reference in its entirety), U.S. Patent No. 10,647,759 (hereby incorporated by reference in its entirety), and U.S. Patent No. 9,944,696 (hereby incorporated 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 may be used as the anti-N3pGlu Aβ antibody of the present disclosure or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure.

[0190] 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," have been identified and disclosed (along with methods of making and using such antibodies) in WO2010 / 009987A2, 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") may be used as the anti-N3pGlu Aβ antibody of the present disclosure or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure.

[0191] Those skilled in the art will understand and appreciate that several specific antibodies, including "anti-N3pGlu Aβ antibodies," and "Antibody X" and "Antibody XI," have been 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 disclosure or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure.

[0192] 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," have been identified and disclosed (along with methods for making and using said 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") may be used as the anti-N3pGlu Aβ antibody of the present disclosure or in place of the anti-N3pGlu Aβ antibodies described in various aspects of the present disclosure.

[0193] As used herein, an "antibody" is an immunoglobulin molecule that contains two HCs and two LCs interconnected by disulfide bonds. The amino-terminal portion of each LC and HC contains a variable region that is 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. 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment 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, 406:228-256 (2011)). The CDRs of the antibodies of the present disclosure were determined according to the above methods.

[0194] The antibodies of the present disclosure 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 disclosure are human or humanized. Humanized antibodies can be engineered to include one or more human framework regions (or substantially human framework regions) surrounding the 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 from The Immunoglobulin FactsBook by Marie-Paule Lefranc and Gerard Lefranc, Academic 25 Press, 2001, ISBN 01244135. Techniques for generating human or humanized antibodies are well known in the art. In another embodiment of the present disclosure, the antibody or the nucleic acid encoding it 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 a cellular environment. "Substantially free," as used herein, means that the protein, peptide, or nucleic acid of interest contains greater than 80% (on a molar basis), preferably greater than 90%, and more preferably greater than 95% of the macromolecular species present.

[0195] The anti-N3pGlu Aβ antibodies of the present disclosure are administered as pharmaceutical compositions. Pharmaceutical compositions comprising the antibodies of the present disclosure can be administered to subjects at risk of or exhibiting a disease or disorder described herein by parenteral routes (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.

[0196] Terms such as "treatment," "treating," or "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.

[0197] The term "prevention" refers to the prophylactic administration of an antibody of the present disclosure to an asymptomatic subject or a subject with preclinical Alzheimer's disease to prevent the onset or progression of the disease.

[0198] The terms "disease characterized by Aβ deposition" or "disease characterized by Aβ plaques" are used interchangeably and refer to diseases pathologically characterized by Aβ plaques in the brain or cerebral vasculature. This includes diseases such as Alzheimer's disease, Down's syndrome, cerebral amyloid angiopathy, etc. Clinical diagnosis, staging, or progression of Alzheimer's disease can be readily determined by the attending diagnostician or medical professional, such as one of ordinary skill in the art, by using known techniques and observing the results. This will generally involve brain plaque imaging, psychiatric or cognitive assessments (e.g., Clinical Dementia Rating-Summary of Boxes (CDR-SB), Mini-Mental State Examination (MMSE) or Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog)), or functional assessments (e.g., Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). 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" is 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, characterized by measurable changes in biomarkers (e.g., CSF by amyloid PET). Preclinical Alzheimer's disease also includes presymptomatic autosomal dominant carriers, patients who carry one or two APOE4 alleles and therefore are at high risk of developing AD.

[0199] The reduction or slowing of cognitive decline can be measured by cognitive assessments such as the Clinical Dementia Rating-Summary of Boxes, Mini-Mental State Examination, or Alzheimer's Disease Assessment Scale-Cognition. The reduction or slowing of functional decline can be measured by functional assessments such as the ADCS-ADL.

[0200] As used herein, "mg / kg" refers to the amount of antibody or drug in milligrams administered to a subject based on body weight in kilograms. The dose is given at one time. For example, a 10mg / kg dose of antibody to a subject weighing 70kg is a single 700mg dose of antibody administered in a single dose. Similarly, a 20mg / kg dose of antibody to a subject weighing 70kg is a single 1400mg dose of antibody administered in a single dose.

[0201] In some embodiments, each dose of anti-N3pGlu Aβ antibody is administered intravenously to a subject over a period of at least 30 minutes at a concentration of about 4 mg / mL to about 10 mg / mL. In some embodiments, a 700 mg dose of anti-N3pGlu Aβ antibody is reconstituted to produce 40 mL of reconstituted solution, the reconstituted solution is further diluted to reach an antibody concentration of about 4 mg / mL to about 10 mg / mL, and the diluted solution is administered intravenously to a subject over a period of 30 minutes. In some embodiments, a 1400 mg dose of anti-N3pGlu Aβ antibody is reconstituted to produce 80 mL of reconstituted solution, the reconstituted solution is further diluted to reach an antibody concentration of about 4 mg / mL to about 10 mg / mL, and the diluted solution is administered intravenously to a subject over a period of 30 minutes.

[0202] As used herein, 18Using F-flortaucipir-based quantitative analysis, a human subject has a "very 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 when compared to a reference region (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)) (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)).

[0203] As used herein, 18 Using F-flortaucipir-based quantitative analysis, a human subject has a "very low to moderate tau" load if the tau load is below 1.46 SUVr (i.e., ≦1.46 SUVr), and 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 (MUBADA, see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)) (PERSI, see Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)).

[0204] As used herein,18 Using F-flortaucipir-based quantitative analysis, a human subject has a "low to moderate tau" burden if the tau burden is greater than or equal to 1.10 SUVr and less than or equal to 1.46 SUVr (i.e., ≥1.10 SUVr to ≤1.46 SUVr), and 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 (MUBADA, see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)) (PERSI, see Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)). "Low to moderate tau" load is also referred to as "intermediate" tau load.

[0205] 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), and 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 (MUBADA, see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J. Nucl. Med. 59:937-943 (2018)) (PERSI, see Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J. Nucl. Med. 59:944-951 (2018)).

[0206] As used herein, early symptomatic Alzheimer's disease encompasses the mild cognitive impairment stage of AD (also known as prodromal AD) and the mild dementia stage of AD. The National Institute on Aging and Alzheimer's Association (NIA-AA) has developed a framework to help define Alzheimer's disease (see Jack et al., "NIA-AA Research Framework: Toward a Biological Definition of Alzheimer's Disease," Alzheimer's & Dementia: The Journal of the Alzheimer's Association 14(4)535-562 (2018), which is incorporated herein by reference in its entirety).

[0207] As used herein, mild cognitive impairment is defined as cognitive performance below the expected range for the individual based on all available information. This may be based on clinical judgment and / or performance on cognitive testing. Cognitive performance is usually within the impaired / abnormal range based on population standards, but is not required as long as the performance is below the range expected for the individual. In addition to evidence of cognitive impairment, there must also be evidence of cognitive decline from baseline. This may be reported by the individual or observer, or observed by changes in longitudinal cognitive testing / behavioral assessments, or a combination of both. At this stage, the individual is independently performing activities of daily living, but cognitive difficulties may result in detectable but mild functional impacts on more complex activities of daily living, either by self-report or corroboration by a study partner. As used herein, mild dementia is defined as substantial progressive cognitive impairment and / or neurobehavioral impairment affecting several domains. This is documented by individual report or observer (e.g., study partner) report, or by changes in longitudinal cognitive testing. This stage involves clear functional impact on daily living, primarily affecting instrumental activities, where the individual is no longer fully independent and requires occasional assistance with activities of daily living. If AD has worsened to the point where a) there is impairment in basic activities and a significant functional impact on daily living, and b) the individual is no longer independent and requires frequent assistance with activities of daily living, the individual is considered not to have mild AD dementia.

[0208] As used herein, the term "about" means up to ±10%.

[0209] The terms "subject" and "patient" are used interchangeably in this disclosure.

[0210] The terms "first dose" and "low dose" may be used interchangeably in this disclosure. The terms "second dose" and "high dose" may be used interchangeably in this disclosure.

[0211] The phrases "slowing decline" and "slowing disease progression" are used interchangeably in this disclosure.

[0212] As used herein, "method of treatment" is equally applicable to the use of a composition to treat a disease or disorder as 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 as described herein.

[0213] The following examples further illustrate the present disclosure. However, it should be understood that the following examples are provided by way of illustration rather than limitation, and that various modifications may be made by those skilled in the art. EXAMPLES

[0214] Example 1: Expression and purification of engineered N3pGlu Aβ antibodies 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.

[0215] Exemplary methods for expressing and purifying anti-N3pGlu Aβ antibodies of the present disclosure are as follows: Suitable host cells, such as HEK293EBNA or CHO, can be either transiently or stably transfected with an expression system for secreting antibodies using an optimal predetermined heavy chain to light chain (HC:LC) vector ratio, or a single vector system encoding both HC and LC. The clarified medium, into which the antibodies are 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 that has been equilibrated with a compatible buffer, such as phosphate buffered saline (pH 7.4). The column is washed to remove non-specifically bound components. The bound antibody is eluted, for example, by a pH gradient (e.g., 0.1 M sodium phosphate buffer (pH 6.8) to 0.1 M sodium citrate buffer (pH 2.5)). Antibody fractions are detected, such as by SDS-PAGE, and pooled. Depending on the intended use, further purification is optional. The antibodies may be concentrated and / or sterile filtered using common techniques. Soluble aggregates and multimers may be effectively removed by common techniques including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The purity of the antibodies after these chromatography steps may be greater than 99%. The product may be immediately frozen at -70°C or lyophilized. The amino acid sequences of some of the anti-N3pGlu Aβ antibodies of the present disclosure are provided in the Sequence Listing.

[0216] Example 2: Evaluation of safety, tolerability, and efficacy of anti-N3pGlu Aβ antibodies The multicenter, randomized, double-blind, placebo-controlled, Phase 2 clinical study (NCT03367403, clinicaltrials.gov) (also known as TRAILBLZER-ALZ or AACG) was designed to evaluate the safety and efficacy of N3pGlu Aβ antibody (also referred to herein as donanemab) in AD subjects with early symptomatic AD (i.e., subjects with mild cognitive impairment or mild dementia due to AD). The study evaluated, among other things, whether removal of existing amyloid plaques over up to 72 weeks of treatment could slow disease progression as determined by clinical measurements and biomarkers of disease pathology and neurodegeneration.

[0217] This was a 133-week study, including a screening period of up to 9 weeks, a treatment period of up to 72 weeks with a final evaluation 4 weeks later at week 76, and 48 weeks of immunogenicity and safety follow-up (see Figure 1). Figure 1 shows the study design of the clinical protocol.

[0218] Treatment Groups and Duration: Approximately 1,497 patients were screened and approximately 266 were randomized. Patients received treatment for up to 72 weeks. Donanemab: Intravenous donanemab (700 mg Q4WK for the first 3 doses, then 1400 mg Q4WK) for up to 72 weeks, or ●Placebo: Intravenous placebo Q4WK for up to 72 weeks.

[0219] Primary and secondary endpoints: The primary endpoints of this study were: - Change in cognition and function as measured by change in Integrated Alzheimer's Disease Rating Scale (iADRS) score from baseline to 18 months.

[0220] Secondary endpoints of the study were: Cognitive change from baseline to 18 months as measured by: ADAS-Cog 13change 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. Change in cerebral amyloid plaque deposition from baseline to 18 months as measured by F18-florbetapir PET scan. Change in brain tau deposition from baseline to 18 months as measured by F18-flortaucipir PET scan. • Change in volumetric MRI measurements from baseline to 18 months.

[0221] Safety Endpoints: The safety endpoints of the study were: Standard safety assessments: spontaneously reported adverse events (AEs), clinical laboratory tests, vital signs and weight measurements, 12-lead electrocardiogram (ECG), physical and neurological examinations. ●MRI (Amyloid-Related Imaging Abnormalities [ARIA] and Emergency Radiological Findings) Columbia-Suicide Severity Rating Scale (C-SSRS)

[0222] Statistical Analysis: All efficacy analyses followed the intention-to-treat (ITT) principle unless otherwise specified. ITT analysis is the analysis of data by group to which subjects were assigned by random assignment, even if they did not receive the assigned treatment, did not receive the correct treatment, or did not otherwise follow the protocol. Pairwise tests of treatment effects were performed at a two-sided alpha (α) level of 0.05, unless otherwise stated. Two-sided confidence intervals (CIs) are presented at the 95% confidence level.

[0223] Efficacy: The primary objective of this study was to test the hypothesis that intravenous infusion of donanemab slows cognitive and / or functional decline associated with AD as measured by the composite scale iADRS compared to placebo in patients with early symptomatic AD. Changes from baseline score on the iADRS at each scheduled post-baseline visit during the treatment period were analyzed using a MMRM model, which included the following terms: baseline score, pooled investigator, treatment, visit, treatment-by-visit interaction, baseline-by-visit interaction, concomitant use of acetylcholinesterase inhibitors (AChEI) and / or memantine at baseline (yes / no), and age at baseline. The primary time point for treatment comparisons was the end of the double-blind treatment period (week 76). Treatment group contrasts in least-squares mean progression and associated p-values ​​and 95% CIs were calculated for the treatment comparison of donanemab versus placebo. In addition, we calculated the Bayesian posterior probability of the active treatment arm being superior to placebo by at least the margin of interest (slowing progression over placebo by 25%).

[0224] 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 in the primary analysis.

[0225] Safety: Safety will be assessed by summarizing and analyzing adverse events (AEs), clinical laboratory parameters, vital signs, MRI scans, ECGs, and immunogenicity during the double-blind treatment period.

[0226] Pharmacokinetics / Pharmacodynamics: Pharmacokinetic or pharmacodynamic (PK / PD) relationships between plasma donanemab concentrations and SUVr, cognitive function endpoints, ARIA incidence, or other markers of PD activity were investigated graphically. Relationships between the presence of antibodies to donanemab and PK, PD, safety, and / or efficacy may be evaluated graphically. If warranted, additional analyses may be considered 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.

[0227] Dosing and Dose Justification: Donanemab (700 mg or 1400 mg) will be administered every 4 weeks as an IV infusion of approximately 140 mL over a minimum of 30 minutes. The doses of 700 mg and 1400 mg of donanemab administered intravenously once every 4 weeks will be selected based on current preclinical pharmacology and toxicology data, and 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 in single 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 greater. At doses of 10 mg / kg or higher, the mean half-life is approximately 9-11 days, and plasma PK accumulation is predicted to be minimal with 700 mg and 1400 mg IV dosing every 4 weeks. A high level of F18-florbetapir PET signal reduction was observed with a single dose of 20 mg / kg, comparable to the F18-florbetapir PET signal reduction seen with a 10 mg / kg 2-weekly dosing schedule at 3 months. In addition to this, a 1400 mg 2-weekly dosing schedule is selected as the highest dosing regimen to robustly reduce amyloid plaques based on the reduced patient burden and comparable safety with a 4-weekly dosing schedule compared to a 2-weekly dosing schedule. The lowest rate of ARIA-E was observed with a 10 mg / kg monthly dosing. For this reason, an escalating schedule (700 mg 2-weekly for the first 3 doses, then 1400 mg 2-weekly) is proposed to reduce the incidence of ARIA while allowing patients to achieve high PD efficacy. In addition, dose reduction rules have been established for the ARIA-E accident.

[0228] Inclusion Criteria: Patients, both males and females, aged 60-85 years (inclusive) at the time of informed consent, were eligible to enroll in the study. Patients may show gradual and progressive changes in memory function as reported by the patient or study partner (informant) for 6 months or more. In some cases, patients may have an MMSE score of 20-28 (inclusive) at Visit 1 or an acceptable previous F18-flortaucipir PET scan within 6 months prior to Visit 1 meeting the central read criteria. Patients may also meet the F18-flortaucipir scan (central read) criteria and / or the F18-florbetapir scan (central read) criteria.

[0229] Exclusion Criteria: Patients will be excluded from study enrollment if they meet any of the following criteria: Modified Hachinski Ischemia Scale (MHIS, Hachinski et al. have a PTSD (Alzheimer's Disease) score of ≥ 4; lack sufficient premorbid literacy, vision, or hearing, in the opinion of the investigator, to complete the required psychometric testing; significant neurological disease affecting the central nervous system (CNS) other than AD that may affect cognition or ability to complete the study, including, but not limited to, other dementias, serious infections of the brain, Parkinson's disease, multiple concussions, or epilepsy or recurrent seizures (excluding childhood febrile convulsions); current serious or unstable illness, including cardiovascular, hepatic, renal, gastrointestinal, respiratory, endocrine, neurological (other than Alzheimer's disease), psychiatric, immunological, or hematological disorders, and other conditions that, in the opinion of the investigator, may interfere with the analysis of this study; or have a life expectancy of less than 24 months; excluding nonmetastatic basal cell and / or squamous cell carcinoma of the skin, cervical carcinoma in situ, nonadvanced prostate cancer, or other cancers with a low risk of recurrence or metastasis. , have a history of cancer within the past 5 years;patients with a current primary psychiatric diagnosis other than AD if, in the investigator's judgment, the psychiatric disorder or symptom may confound interpretation of drug effects, affect cognitive assessments, or affect the patient's ability to complete the study;patients with a history of schizophrenia or other chronic psychiatric illness;have a history of long QT syndrome;are clinically determined by the investigator to be at significant risk for suicide as assessed by medical history, examination, or C-SSRS;have a history of alcohol or drug use disorder (excluding smoking disorder) within 2 years prior to the screening visit;have a history of clinically significant multiple or severe drug allergies, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, and / or exfoliative dermatitis);or have known positive serology for human immunodeficiency virus (HIV) antibodies. Local laws and regulations may apply as to whether testing is required;At screening, having any clinically significant abnormalities in the physical or neurological exam, vital signs, ECG, or laboratory results that, as determined by the investigator, may be harmful to the patient, may interfere with the study, or show evidence of another etiology of dementia; a 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 / cardiac pacemakers have a contraindication to MRI, such as the presence of a manufacturer; have a central-read MRI showing the presence of ARIA-E, >4 cerebral microbleeds, >1 superficial siderosis, any macroscopic hemorrhage, or severe white matter disease; have a mean (3 ECGs) corrected QT (QTcF) interval measurement of >450 ms (males) or >470 ms (females) at screening (as determined by the clinical trial site); patients with a history of hepatitis B should have HBsAg testing at screening and will be excluded if HBsAg is positive; patients with a history of hepatitis C should have HCV RNA PCR testing at screening and will be excluded if HCV RNA PCR is positive; have a calculated creatinine clearance of <30 mL / min (Cockcroft-Gault formula, Cockcroft and Gault 1976); alanine transaminase (ALT) ≥ 2 × upper limit of normal (ULN) for the laboratory in question, aspartate aminotransferase (AST) ≥ 2 × ULN, total bilirubin level (TBL) ≥ 1.5 × ULN, or alkaline phosphatase (ALP) ≥ 1.5 × ULN at screening; receiving treatment with stable doses of AChEI and / or memantine for < 2 months prior to randomization; changes in concomitant medications that may affect cognition, which must have been stable for at least 1 month prior to screening and between screening and randomization (does not apply to medications that were discontinued due to exclusion or limited duration of use, such as antibiotics); current use of medications known to significantly prolong the QT interval; previous treatment with passive anti-amyloid immunotherapy with a half-life < 5 prior to randomization; receiving active immunization against Aβ in another study;Known allergy to donanemab, related compounds, or any component of the formulation;or history of significant atopy;allergy to either monoclonal antibodies, diphenhydramine, epinephrine, or methylprednisolone;sensitivity to F18-flobetapir or F18-flortaucipir;contraindication to MRI;contraindication to PET;current or planned exposure to ionizing radiation that, when combined with the planned administration of the investigational PET ligand, could result in cumulative exposure exceeding local recommended exposure limits;

[0230] Dosage Modifications for ARIA-E: Dosage modifications of donanemab will be adjusted for the occurrence of ARIA-E in the following cases as shown in Table A. If a dosage reduction is required, the dose of donanemab will be reduced to the next lower dose (1400 mg to 700 mg, or 700 mg to placebo). [Table 1]

[0231] All cases of ARIA-E require unscheduled MRI scans every 4 to 6 weeks until ARIA-E has resolved.

[0232] Discontinuation of Study Treatment: Reasons that may lead to permanent discontinuation of study treatment include: subject decision (e.g., request to discontinue investigational product by subject or subject's designee or legal guardian) or discontinuation due to hepatic event or abnormal liver test. Subjects who are discontinued from the study product due to a hepatic event or abnormal liver test will require collection of additional hepatic safety data via CRF / electronic data entry.

[0233] Discontinuation of investigational drug for liver test abnormalities will be considered if the subject meets any of the following conditions: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of normal (ULN); ALT or AST >5 × ULN for >2 weeks; ALT or AST >3 × ULN and total bilirubin level (TBL) >2 × ULN or international normalized ratio (INR) >1.5; ALT or AST >3 × ULN with the occurrence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%); alkaline phosphatase (ALP) >3 × ULN; ALP >2.5 × ULN and TBL >2 × ULN; or ALP >2.5 × ULN with the occurrence of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and / or eosinophilia (>5%).

[0234] In addition, subjects will be discontinued from the investigational product under the following circumstances: Treatment with donanemab is permanently discontinued in patients with: recurrence of ARIA-E after a previous dose reduction or temporary discontinuation of donanemab Any increase in ARIA-H with clinically significant symptoms, ○ >4 new microbleeds, >1 new superficial siderosis or significant worsening of existing superficial siderosis, or macrobleeds regardless of symptoms, or - ARIA-E events reported as serious adverse events (SAEs), regardless of symptom severity or MRI findings. Donanemab treatment should also be permanently discontinued in patients with: o Prolonged acute infusion reaction (i.e., unresponsive to medications such as antihistamines, nonsteroidal anti-inflammatory drugs, and / or narcotics, and / or short-term interruption of the infusion), or Adverse events or clinically significant laboratory values, electrocardiogram results, physical examination findings, MRI findings (e.g., symptomatic ischemic stroke),

[0235] Suspension of donanemab study treatment due to ARIA-E Temporary interruption of donanemab treatment is permitted if the ARIA-E meets the temporary interruption criteria shown in Table A. In the case of ARIA-E where the protocol indicates continued dosing or dose reduction rather than temporary interruption, administration of donanemab may be temporarily interrupted.

[0236] For example, if dosing is temporarily discontinued due to ARIA-E and symptoms and radiological findings completely resolve within 16 weeks after temporary drug discontinuation, donanemab may be resumed after the first episode of ARIA-E. If symptoms and radiological findings of ARIA-E do not completely resolve within 16 weeks, patients will be permanently discontinued from donanemab treatment.

[0237] The 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 was randomly assigned. An unscheduled safety MRI scan is required 4 to 6 weeks after dose restart.

[0238] Efficacy Assessment: Cognitive and functional testing will be performed using the eCOA tablet. Audio recordings of assessor questions and patient and study partner responses will also be collected via the eCOA tablet during the administration of cognitive and functional testing to centrally monitor the administration of the assessor scales. Cognitive and functional testing for each patient should be performed at approximately the same time each day that testing is performed to reduce potential variability. Note that the ADAS-Cog and MMSE should be administered by a different assessor than the ADCS-ADL and CDR. These two assessors should continue with the same scales for the same patients throughout the study. If possible, each assessment should be performed for a specific patient by the same assessor at each visit. The Principal Investigator (PI) is responsible for selecting the assessor who will administer the instruments on-site, provided that the assessor meets all training requirements.

[0239] If administered, cognitive and functional testing should be performed first prior to any potentially stressful medical procedures for the patient (e.g., blood draws). Note that some procedures (MRI, F18-flortaucipir PET tau imaging, F18-florbetapir PET amyloid imaging) may be performed on other days within the visit window.

[0240] Primary efficacy outcomes: The integrated Alzheimer's Disease Rating Scale (iADRS, 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. 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 via analysis of data from the Alzheimer's Disease Neuroimaging Initiative). The iADRS combines two well-established, treatment-sensitive and widely accepted scales in AD: the ADAS-Cognitive Assessment and Assessment for Cognitive Function (ADAS-Cognitive Assessment and Assessment for Cognitive Function), and the iADRS-Cognitive Assessment and Assessment for Cognitive Function (ADAS-Cognitive Assessment and Assessment for Cognitive Function). 13 The iADRS score is a simple linear combination of the ADAS-Cog and ADCS-iADL scores, which measure the core domains of AD. All items from these two scales were included without additional item weighting, allowing for face validity and ease of interpretation of the composite relative to its components. The iADRS score is a simple linear combination of the ADAS-Cog and ADCS-iADL scores, which measure the core domains of AD. 13 and ADCS-iADL, which are the primary efficacy measures. 13 and ADCS-ADL, which are the actual scales administered to patients.

[0241] Secondary efficacy assessment: ADAS-Cog 13Immediately following the assessment, additional clinical outcome measures should be administered in the same order at every visit. To minimize missing data, the assessor should include each measure verbally to the patient or study partner (as specified in the instructions) and record responses appropriately. The same study partner should be used as the informant at all visits.

[0242] Alzheimer's Disease Assessment Scale-Cognitive Subscale: ADAS-Cog 13 The ADAS-Cognitive Assessment Score (ADAS-Cognitive Assessment Scale) is a rater-administered instrument designed to assess the severity of cognitive and noncognitive behavioral impairment characteristic of individuals with AD (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 ADAS-Cognitive subscale should be administered by the same assessor at each visit to reduce potential variability. 13 The ADAS-Cognitive Assessment Scale (ADAS-Cognitive Assessment Scale) is a 13-item scale that assesses the areas of cognitive function most typically impaired in AD: orientation, verbal memory, language, praxis, delayed free recall, digit elimination, and maze completion (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. 11(Suppl 2):S13-S21 (1997), which is incorporated herein by reference in its entirety). 13は , is included as a secondary outcome because it is able to better discriminate between mildly affected patients than the ADAS-Cog11. 13The scale ranges from 0 to 85, with higher scores indicating greater severity of disease.

[0243] Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory: The ADCS-ADL is a 23-item inventory designed as an assessor-administered questionnaire that must be completed by the patient's study 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;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. 52(7):1070-1076 (2004), which are incorporated herein by reference in their entireties). The ADCS-ADL should be administered by the same assessor at each visit to reduce potential variability. The ADCS-ADL subset of items on instrumental activities of daily living (ADCS-iADL) (items 7–23) is used as a secondary validity measure. The focus in the early symptomatic AD population is on instrumental activities of daily living (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 0–56, with lower scores indicating greater disease severity. For each specific item, the study partner first asks whether the patient has attempted an ADL during the past 4 weeks. If the patient has attempted an ADL, the study partner is asked to rate the patient's level of ability based on a series of ability descriptions. Scores for each item and a total score for the tool are calculated. The total ADCS-ADL score ranges from 0–78, with higher scores indicating greater levels of impairment. A separate score for bADL (0–22) is also calculated.

[0244] Clinical Dementia Rating Scale: The CDR is a semi-structured interview administered to the patient and research partner (informant) to provide an index of global functioning (Berg et al., “Mild Senior Dementia of the Alzheimer's Type. 4. Evaluation of Intervention,” Ann Neurol. 31(3):242-249 (1992), which is incorporated herein by reference in its entirety). The CDR should be administered by the same assessor at each visit to reduce potential variability. Informants are asked about the patient's memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The patient's memory, orientation, judgment, and problem solving abilities are assessed. Higher scores indicate greater severity of disease. Assigning a severity score 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 values ​​indicating greater impairment.

[0245] Mini-Mental State Examination: The MMSE is a brief instrument used to assess a patient's cognitive function (Folstein et al., "Mini-Mental State". A Practical Method for Grading the Cognitive State of Patients for the Clinician," J Psychiatr Res. 12(13):189-198 (1975), which is incorporated herein by reference in its entirety). The MMSE should be administered by the same assessor at each 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 instructions, write sentences, and copy diagrams. 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.

[0246] Biomarker Efficacy Measures (Double-Blind Period) F18-Florbetapir PET Scan: Changes in amyloid burden (assessed by F18-Florbetapir PET signal) will be compared in donanemab- and placebo-treated patients for patients who underwent F18-Florbetapir PET scans at baseline, Week 52 [Visit 15], and Week 76 [Visit 21], or at the early discontinuation visit (ED).

[0247] F18-flortaucipir PET scans: Changes in tau burden (assessed by F18-flortaucipir PET signal) will be compared in donanemab- and placebo-treated patients for patients who underwent both baseline and endpoint (Visit 21 [Week 76] or ED) F18-flortaucipir scans.

[0248] Volumetric MRI: Magnetic resonance imaging of the brain may be performed during Visits 2-14. The effects of donanemab treatment and placebo treatment on volumetric MRI will be evaluated and compared to assess brain volume loss occurring in AD patients.

[0249] Amyloid Plaque Removal: Amyloid plaque removal (assessed by F18-florbetapir PET signal) will be compared in donanemab-treated and placebo-treated patients for patients who underwent F18-florbetapir PET scans at baseline, Visit 8 (Week 24), Visit 15 (Week 52) and endpoint Visit 21 (Week 76), or ED.

[0250] Accumulation of Tau Deposits: The extent of tau versus helical filament (PHF) plaque accumulation (assessed by F18-flortaucipir PET signal) will be compared in donanemab- and placebo-treated patients for patients who underwent baseline and endpoint Visit 21 (Week 76) or ED F18-flortaucipir PET scans.

[0251] Biomarkers: Biomarker studies are performed to address questions related to pharmacokinetics, target engagement, PD, mechanism of action, variability in patient response (including safety), and clinical outcomes. Specimen collection can be integrated into clinical studies to examine 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 will be collected during Visits 2-14, if local regulations permit.

[0252] Example 3: Safety, Tolerability, and Efficacy Study Results This example provides results from the safety, adverse events, and efficacy of donanemab in participants with early symptomatic AD. Enrollment was based on positron emission tomography (PET) scans of florbetapir and flortaucipir, which show tau and amyloid plaque pathology, respectively. Participants received either placebo or donanemab (700 mg for doses 1-3, 1,400 mg thereafter) intravenously every 4 weeks for up to 72 weeks. The primary outcome measure was the change from baseline in the integrated AD Rating Scale (iADRS, range 0-144, lower scores indicate greater cognitive deficits and greater impairment in activities of daily living) at 76 weeks. Secondary outcome measures included the Clinical Dementia Rating Scale sum of boxes (CDR-SB, range 0-18, higher scores indicate greater functional impairment), AD Assessment Scale-Cognitive (ADAS-Cognitive 13 , range 0-85, higher indicates greater disease severity), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-iADL, range 0-59, lower indicates greater impairment), Mini-Mental State Examination (MMSE, range 0-30, lower indicates greater impairment), amyloid and tau burden assessed with florbetapir and F18-flortaucipir PET, respectively, and volumetric magnetic resonance imaging MRI (vMRI).

[0253] Patient Population and Study Design: This study (TRAILBLAZER-ALZ) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the safety, adverse events, and efficacy of donanemab in participants aged 60-85 years with early symptomatic AD (a combination of prodromal AD, presymptomatic AD with overt MCI [MCI-AD], and mild AD dementia [symptoms severe enough to meet diagnostic criteria for dementia and AD]) (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 included the Mini-Mental State Examination (MMSE, range 0-30, lower scores indicating greater functional impairment; Folstein et al., “Mini-mental state. A Practical Method for Grading the Cognitive State of Patients for the Clinician,” J. Psychiatr. Res. 12:189-98 (1975), which is incorporated herein by reference in its entirety), F18-flortaucipir PET scan, magnetic resonance imaging (MRI), and F18-florbetapir PET scan. Flortaucipir and F18-florbetapir PET scans were examined by a centralized PET imaging laboratory to assess patient eligibility. All eligible patients were required to have evidence of pathological tau on PET scans and quantitative tau levels below a certain 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. Published methods (Pontecorvo et al., “A Multicentre Longitudinal Study of Flortaucipirvir ( 18F) in Normal Aging, Mild Cognitive Impairment and Alzheimer's Disease Dementia,” Brain 142:1723-35(2019); Devous et al., “Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18,” Journal of Nuclear Medicine 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 are incorporated by reference in their entireties), and visually assessed (Fleisher et al., “Positron Emission Tomography Imaging With F18-flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes,” JAMA Neurology 77:829-39 (2020), which is incorporated herein by reference in its entirety), SUVr (standardized uptake value ratio) was estimated.

[0254] Images with SUVr>1.46 were excluded as having high tau. For images that were not excluded as having high tau, images with SUVr values ​​<1.10 or images visually read as having a negative AD pattern were excluded as having inadequate tau levels, unless the image was visually read as having a progressive AD pattern but had an SUVr value <1.10, in which case it was still included. With the exception of MRI, each patient was required to meet all other Visit 1 eligibility criteria prior to the screening F18 florbetapir PET scan.

[0255] Participants who met the inclusion criteria were randomized 1:1 to receive either intravenous (IV) donanemab (first three doses 700 mg, then 1400 mg) or IV placebo every 4 weeks for up to 72 weeks. Participant randomization was stratified by study center to allow for comparability of center factors between groups. There was no stratification by inclusion criteria. Participants treated with donanemab were tapered to 700 mg if their amyloid clearance in centiloids (CL) measured by florbetapir scan (weeks 24 and 52) was ≥11 and <25, or switched to placebo if either measurement was <11, or ≥11 and <25 on two consecutive scans. If amyloid-related imaging abnormalities-edema / exudate (ARIA-E, signal hyperintensity on MRI in fluid-attenuated inversion recovery imaging sequences due to parenchymal fluid accumulation or cleft 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 7:367-85 (2011), which is incorporated herein by reference in its entirety) occurred during titration at the first three doses of 700 mg, the dose was not increased. Final endpoint measurements and safety assessments were performed at week 76, 4 weeks after the last infusion.

[0256] Clinical and Biomarker Outcome Measures: The primary outcome measure was the change from baseline to week 76 in the iADRS (range 0-144, lower scores indicate greater cognitive impairment and impairment in daily activities) compared with placebo. The iADRS is a multi-component scale that measures cognitive impairment in the ADAS-Cognitive (ADAS-Cognitive). 13, range 0-85, 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 11 Suppl 2:S13-21 (1997), which are incorporated herein by reference in their entireties) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL, range 0-59, with lower scores indicating greater impairment; Galasko et al., “An Inventory to Assess Activities of Daily Living for Clinical Trials in Alzheimer's disease,” Alzheimer Disease and Associated Disorders 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.

[0257] The iADRS was developed using theoretical constructs intended to measure core disease processes and used clinical trial data to identify items / scales that are optimal for implementing those constructs. 13All items from the total score and the ADCS-iADL score are included without item weighting, providing face validity and ease of interpretation of both the composite and its components. The iADRS is capable of measuring not only an overall measure of AD impairment (total score) but also the individual subscores (cognitive and functional). Validation of the iADRS has been established and the statistical properties of the composite performance have been described.

[0258] Secondary outcome measure methodology, 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 43:2412-a (1993), which is incorporated herein by reference in its entirety), ADAS-Cognitive Impairment Score (ADAS-Cognitive Impairment Score), and Cognitive Impairment Score (CDR-SB). 13 Amyloid and tau burden assessed by ADCS-iADL, MMSE, F18-florbetapir and F18-flortaucipir PET, respectively, and volumetric MRI are detailed in the clinical protocol. Assessment of global tau load includes tau volumetric analysis, which describes 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 by reference in its entirety).

[0259] Sample size determination and statistical analysis: Enrollment of 250 participants randomized 1:1 to the two treatment groups, with 200 participants expected to complete treatment, was determined to provide approximately 84% power to demonstrate that the active treatment group had a posterior probability of at least 0.6 of slowing the progression of the iADRS by at least 25% compared to placebo. Assumptions for the power calculation were mean 18-month progression levels of approximately 12 and 6 points (50% slowing) in the placebo and donanemab groups, respectively, with a common standard deviation of 17. Efficacy analyses were conducted on a modified intention-to-treat basis, with participants receiving baseline and at least one post-baseline iADRS measurement (unless otherwise specified). All pairwise tests of treatment effects were performed at a two-sided alpha level of 0.05, unless otherwise noted.

[0260] Baseline characteristics were summarized by treatment group and overall, with descriptive statistics for continuous and categorical measures. Primary outcomes were analyzed using mixed-model repeated measures (MMRM) analysis, with the change from baseline in iADRS score at each scheduled post-baseline time point used as the dependent variable. The fixed-effects model included the following terms: baseline score, investigator, treatment, visit, treatment-by-visit interaction, baseline-by-visit interaction, concomitant use of acetylcholinesterase inhibitors (AChEI) and / or memantine at baseline (yes / no), 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, 28(4):586-604 (2009), which is incorporated herein by reference in its entirety) was used to provide control for type I error rates for the study of the primary and key secondary hypotheses at an alpha level of 0.05. Assuming the primary analysis was significant, the MMRM analysis described for the primary analysis was consistent with the CDR-SB, ADAS-Cog 13, ADCS-iADL, and MMSE scores, and significance was determined based on multiplicity of hypotheses graphs. Long-term clinical outcomes are provided with point estimates and error bars. For post-baseline categorical data, Fisher's exact test was used to compare treatment groups. For post-baseline continuous data collected at endpoint, analysis of covariance (ANCOVA) with independent factors of treatment and age was used. Each lead site investigator was responsible for selecting assessors who met the training requirements to administer the instruments at the site. Assessors were blinded to treatment allocation.

[0261] 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. The model assumes a proportional treatment effect relative to placebo and includes a diffuse prior distribution. A similar model has been used previously, except that in the current model the prior distribution of the parameter representing placebo decline was not forced to be monotonic. This analysis generated a posterior probability distribution of the disease progression rate (DPR), defined as the proportional decline of the donanemab group relative to placebo. A DPR < 1 favors donanemab. The 95% confidence intervals and posterior means of the disease progression rates are displayed. The posterior probability of the active treatment group slowing disease progression by at least 25% relative to placebo was pre-specified and calculated from the DPM. The DPM model was used to assess the CDR-SB, ADAS-Cog 13 Rates of decline in ADCS-iADL, ADCS-iADL, and MMSE were assessed. The DPM model was not included as part of the prespecified multiplicity testing strategy for secondary endpoints.

[0262] Safety parameters (AEs, laboratory analytes, vital signs, ECG, MRI) were summarized using descriptive statistics for continuous variables and frequencies with percentages for categorical variables during the treatment period.

[0263] To handle missing data in the MMRM model, a repeated measures likelihood-based mixed effects model was used. Model parameters were estimated simultaneously 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 nonrandom missing data. In the repeated measures analysis, only data from visits where data collection was scheduled are used. If a participant discontinued the study early, efficacy or safety data measurements may have been taken at a visit where the variable was not scheduled to be collected. This data was used in all other analyses.

[0264] Population and Baseline Characteristics: Baseline population demographics for the placebo and donanemab monotherapy groups, respectively, were mean age 75.4 and 75.0 years, 51.6% and 51.9% female, 96.0% and 93.1% white, and 74.2% and 72.5% APOE4 carriers (Table B). [Table 2-1] [Table 2-2]

[0265] At the start of the study, the study consisted of three arms, including a combination arm of donanemab and a BACE1 inhibitor. This arm was discontinued early in the study, and 15 participants were randomly assigned to it. In the modified intention-to-treat population, of the 1955 participants screened, 126 were randomized to placebo and 131 to donanemab. Mean baseline iADRS scores were 105.9 for placebo and 106.2 for donanemab, MMSE scores were 23.7 and 23.6, respectively, CDR-SB scores were 3.4 and 3.6, F18-flortaucipir PET overall tau loads were 0.46 and 0.47, and amyloid PET scores were 101.1 and 107.6 (Table B).

[0266] Primary Outcome: Donanemab demonstrated a greater slowing of decline in a composite measure of cognition and daily functioning in patients with early symptomatic Alzheimer's disease compared to placebo. Donanemab met the primary endpoint of change from baseline to week 76 in the Integrated Alzheimer's Disease Rating Scale (iADRS), slowing the decline by 32% versus placebo (Figure 2A-C), which was statistically significant. The iADRS is a composite of two commonly used measures of Alzheimer's disease: the cognitive scale ADAS-Cognitive Assessment and Response Assessment (ADAS-Cognitive Assessment). 13 and functional scale ADCS-iADL. At 76 weeks, the change from baseline in iADRS 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-C and Table D). Figure 2A-C shows clinical outcomes for primary iADRS, secondary CDR-SB, ADAS-Cog13, ADCS-iADL, and MMSE. Figure 2A shows the results of the primary outcome, LS mean change from baseline to week 76 in 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 across the entire 18-month study. 95% confidence intervals are shown. Figure 2C shows the secondary outcomes analyzed in MMRM: (i) CDR-SB, (ii) ADAS-Cog 13 2A-C show the results of the LS mean change from baseline to week 76 in (iii) ADCS-iADL, and (iv) MMSE scores. In Figure 2A-C, Δ = difference, W = weeks, iADRS = integrated Alzheimer's Disease Rating Scale, ADAS-Cog 13 = Alzheimer's Disease Rating 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, DPM=disease progression model, LS=least squares, CI=confidence interval, n=number of participants, SE=standard error.

[0267] Figure 2D shows clinical results of primary iADRS and secondary CDR-SB outcomes using a Bayesian model of disease progression from TRAILBLZER-ALZ (AACG Study, Example 2). In Figure 2D, iADRS = Unified Alzheimer's Disease Rating Scale, CDR-SB = Clinical Dementia Rating-Sum of Boxes, ++ indicates at least 0% posterior probability of >99% slowing.

[0268] FIG. 2E shows a frequentist analysis of the clinical results of Example 2 for the iADRS primary efficacy outcome and the CDR-SB secondary outcome using a natural cubic spline with 2 degrees of freedom (NCS2), a natural cubic spline with 3 degrees of freedom (NCS3), and a quadratic mixed model (QMM) from TRAILBLZER-ALZ (*=p<0.05 vs. placebo, **=p<0.01 vs. placebo) (AACG study, Example 2). The natural cubic spline (NCS) model provides a kind of smoothing function for the data, allowing for appropriate estimation of longitudinal trajectories under various shapes (linear, quadratic, etc.) for each treatment group. The degrees of freedom of the model may be specified in advance to establish the level of smoothing of the data. The quadratic mixed model has many similar characteristics to the MMRM, but additional assumptions are made on the estimation of longitudinal mean values ​​so that the longitudinal trajectories of each treatment group are smoothed over the planned or observed visit times, allowing for linear or quadratic shapes. In Figure 2E, iADRS = integrated Alzheimer's Disease Rating Scale, CDR-SB = Clinical Dementia Rating-Sum of Boxes, ++ indicates at least 0% posterior probability of >99% slowing, NCS2 = natural cubic spline with 2 degrees of freedom, NCS3 = natural cubic spline with 3 degrees of freedom, QMM = quadratic mixed model. [Table 3] [Table 4-1] [Table 4-2]

[0269] Percentage slowing of disease progression estimates versus placebo from the MMRM model at the 18-month endpoint and from the Bayesian DPM over the entire 18-month period showed a slowing of decline in the iADRS with both methods (Figure 2B). The posterior probability of at least a 25% slowing of disease progression versus placebo in the iADRS was calculated to be 0.78 from the Bayesian DPM.

[0270] 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 difference from baseline in CDR-SB at week 76 vs placebo was -0.36 (95% CI: -0.83 to 0.12) for CDR-SB and -0.49 (95% CI: -0.49 to 0.52) for ADAS-Cog. 13 for ADCS-iADL, the mean score was -1.86 (95% CI: -3.63 to -0.09), for ADCS-iADL, 1.21 (95% CI: -0.77 to 3.20), and for MMSE, the mean score was 0.64 (95% CI: -0.40 to 1.67) (Figure 2C and Table E). [Table 5-1] [Table 5-2]

[0271] Biomarker: N3pGlu By targeting 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 showed a reduction in 85CL amyloid plaques at 76 weeks compared to placebo (placebo=0.93, donanemab=-84.13) (Figure 3A). A distinct reduction of 68CL was evident by week 24 in the donanemab group compared to placebo (placebo=-1.82, donanemab=-69.64, 65% reduction from baseline in the donanemab group). The percentage of participants in the donanemab group who were "amyloid negative" (defined as CL amyloid plaques <24.1) was 40.0%, 59.8%, and 67.8% at weeks 24, 52, and 76, respectively (Figure 3A). Approximately 27% and 55% of donanemab participants administered at weeks 28 and 56, respectively, achieved sufficient amyloid slowing to reduce versus placebo infusions. In this study, patients stopped receiving donanemab and switched to placebo if amyloid plaque levels were <25 centiloids for two consecutive measurements or <11 centiloids for any one measurement.

[0272] Assessment of overall tau load as assessed by F18-florbetapir PET revealed no differences between groups from baseline to week 76 (Figure 3B). Hippocampal volume change assessed by vMRI did not differ between groups (Figure 3C(iii)). A greater decrease in total brain volume and a greater increase in ventricular volume were seen in participants treated with donanemab at 52 compared to placebo (Figure 3C(i) and (ii)). Figures 3A-C show secondary biomarker outcomes. Figure 3A shows results from baseline to week 76 in cerebral amyloid plaque deposition measured by F18-florbetapir PET scans in the secondary outcome, centiloid (CL). Figure 3B shows overall tau load as measured by F18-florbetapir PET scans. "Amyloid negative" / <24.1CL = mean CL level in similar aged, otherwise healthy individuals. Figure 3C shows vMRI of (i) the whole brain, (ii) the ventricles, and (iii) the hippocampus. In Figure 3, Δ = difference, W = weeks, LS = least squares, CI = confidence interval, CL = centiloid, n = number of participants, SE = standard error.

[0273] Adverse events: There was no difference in the incidence of deaths or serious adverse events (SAEs) between the donanemab and placebo groups. A total of 113 of 125 participants (90.4%) in the placebo group and 119 of 131 participants (90.8%) 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 in 6.1% of participants overall in the donanemab group (22% of participants with ARIA-E) compared with 0.8% in the placebo group. Most ARIA-E cases occurred within the first 12 weeks of dosing. Severe symptomatic ARIA-E requiring hospitalization occurred in 2 participants (1.5%) treated with donanemab. Both participants had symptoms of confusion and one reported difficulty expressing himself, all of which resolved completely. ARIA-E resolved completely in both cases, with the mean time to resolution of ARIA-E being 18 weeks. The incidence of superficial siderosis of the central nervous system (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. Two participants (1.5%) discontinued the study due to ARIA-E. No massive cerebral hemorrhages were observed in either group. IRRs were reported in 7.6% of participants in the donanemab group and 0% in the placebo group. Severe IRRs or hypersensitivity occurred in three participants (2.3%) treated with donanemab. The incidence of treatment-emergent anti-drug antibodies (TE-ADA) in participants treated with donanemab was approximately 90%.

[0274] These results indicate that amyloid clearance in the donanemab group was accompanied by slowing of disease progression compared with placebo in an amyloid plaque-specific intervention for patients with early symptomatic Alzheimer's disease.The treatment difference of 3.20 at 76 weeks on the iADRS scale should be interpreted taking into account not only the range of scores across the 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).

[0275] The results provided here are unexpected and surprising in several aspects: the donanemab dosing regimen cleared a large amount of amyloid early in the trial, with almost 60% of participants having "amyloid-negative" scans by week 52. This is the first study to screen all participants with F18-flotaucipir PET scans, likely narrowing the extent of underlying pathology and thereby reducing the variance of clinical decline.

[0276] Tau PET screening of patients excluded subjects with high tau, who may have disease that is less responsive or more resistant to anti-amyloid treatment.

[0277] Using a relatively new disease progression model as proposed by the European Alzheimer's Disease Prevention Project, we compared the iADRS, ADAS-Cog 13Analyses of treatment differences in ADCS-iADL, CDR-SB, and MMSE scores were performed. Given the greater 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), the model allows for a significant 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), and the study revealed estimates of disease slowing similar to single-point estimates of the MMRM model.

[0278] The observed lack of treatment effect on overall tau load may be due to the fact that PET tau changes lag significantly behind amyloid changes, and that 18 months is too short a time to detect imaging changes. Modeling in autosomal dominant subjects suggests a 10-20 year lag from the first detectable PET amyloid changes and the first detectable tau PET changes (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 are incorporated herein by reference in their entirety). The lack of effect on overall tau may raise questions about whether targeting amyloid-β reduction will impact biological disease progression. However, additional pre-specified analyses of brain regions suggested reduced tau accumulation in various regions of the brain (e.g., frontal, parietal, occipital, and temporal regions) in the donanemab group compared to placebo (Figure 4).

[0279] A robust reduction in tau accumulation or prevention of further increases is seen, for example, in the frontal lobe of the brain. The occipital lobe has some of the highest baseline signals and therefore may have a ceiling effect on the ability to show a reduction in increasing tau load. Figure 4 shows a regional SUVr analysis of tau accumulation in the cerebellar gray reference. Using the cerebellar reference region, frontal lobe tau load measured by F18 flortaucipir correlates with changes in iADRS and CDR-SB over the following 76 weeks in symptomatic early AD subjects. Figure 5 shows that low frontal tau load is associated with less decline in patients. Higher frontal tau load is associated with more rapid decline in patients. In other words, patients with low frontal tau load decline more slowly (measured by iADRS or CDR-SB) compared to patients with high frontal tau load.

[0280] This measurement reflects global changes in tau load and further investigation may indicate subregions that are more susceptible to change. Optimal methods for region selection and analysis to quantify tau changes and therapy response are still in their infancy.

[0281] 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 77:199-209 (2020), which is incorporated herein by reference in its entirety). The observation that donanemab treatment resulted in greater reductions in total brain volume and greater increases in ventricular volume compared to placebo may be interpreted in the context of protein clearance rather than atrophy. In natural history studies of AD, global volumetric MRI changes are typically attributed to atrophy, but 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 therapy 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 by reference in its entirety.)

[0282] 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 7:367-85(2011); Sevigny et al., “The Antibody Aducanumab Reduces Aβ Plaques in Alzheimer's Disease,” Nature 537:50-6(2016); Ostrowitzki et al., “Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab,” Archives of Neurology 69:198-207(2012); Salloway et al., “Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease,” New England Journal of Medicine 370:322-33 (2014); Salloway et al., "A Phase 2 Multiple Ascending Dose Trial of Bapineuzumab in Mild to Moderate Alzheimer Disease," Neurology 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. 11:241-9 (2012), each of which is incorporated by reference in its entirety.

[0283] In the phase 1b study, the incidence of ARIA-E in participants treated with donanemab was 26.1%, with two participants reporting symptomatic ARIA-E (4.3%). In this study, a similar incidence of ARIA-E (27%) was seen in the donanemab group, with 6.1% reporting symptomatic ARIA-E. As seen in other trials of plaque-targeting antibodies, the incidence of ARIA-E was more common in APOE4 carriers (Sevigny et al., “The Antibody Aducanumab Reduces Aβ Plaques in Alzheimer's Disease,” Nature 2016;537:50-6; Ostrowitzki et al., “Mechanism of Amyloid Removal in Patients With Alzheimer's Disease Treated With Gantenerumab,” Archives of Neurology 69:198-207; Salloway et al., “Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease,” NEJM 2014;370:322-33(2014); and Sperling et al., “Amyloid-related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Bapineuzumab: A Retrospective Study”). (2012), which are incorporated by reference in their entireties. The incidence of treatment-emergent anti-drug antibodies (TE-ADAs) in participants treated with donanemab (approximately 90%) was similar to findings in phase 1 (>85%).

[0284] These results show that in participants with early symptomatic AD, treatment with donanemab led to the clearance of amyloid plaques and slowed cognitive and functional decline as measured by the iADRS scale.

[0285] Example 4: Efficacy associated with baseline Tau PET patient stratification Anti-N3pGlu Aβ antibody, Donanemab, has been found to be most effective in subjects with the lowest baseline flortaucipir levels. This antibody 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, particularly anti-N3pGlu antibody-based therapy, including Donanemab.

[0286] Tau levels (e.g., for stratification purposes in human subjects suffering from Alzheimer's disease) are determined based on an initial visual assessment of the flortaucipir scan, followed by quantitative analysis. The visual assessment relies on a three-level 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 the counts within a specific target region of interest in the brain when compared to a reference region (Parametric Estimation of Reference Signal Intensity or PERSI) (Multiblock Centroid Discriminant Analysis or MUBADA). Lower SUVr values ​​indicate less tau burden, whereas higher SUVr values ​​indicate greater tau burden.

[0287] As shown in Table F, scans in the low to moderate tau group (e.g., having an SUVr of 1.10 or greater and 1.46 or less) are eligible for administration of anti-N3pGlu Aβ antibodies in the AACG study.

[0288] Visual assessment: The method for visual assessment of human subjects was described by Fleisher et al., “Positron Emission Tomography Imaging with 18[F]flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes,” JAMA Neurol. 77(7):829-839 (2020), which is incorporated 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 the activity is isolated to regions of the temporal lobe that do not include the frontal or posterolateral temporal (PLT) regions. Positive scans are classified into two categories based on the region of increased neocortical tracer activity. Flortaucipir scans in which neocortical tracer activity is limited to the posterolateral temporal (PLT) or occipital regions are classified as tAD+.

[0289] Finally, if the flortaucipir scan showed increased parietal or precuneus region tracer activity, or if activity in the frontal regions was present along with activity in the PLT or occipital regions, it was classified as tAD++. Quantitative analysis was performed on all tAD+ and tAD++ scans.

[0290] Quantitative Analysis: Quantitative analysis is performed via an automated image processing pipeline. A previously developed neocortical target volume of interest (VOI) (MUBADA, see 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) is applied to each scan and derived counts are normalized to a patient-specific reference region (PERSI). Other target and reference regions are also extracted via the pipeline. PERSI reference regions are a subject-specific, data-driven technique that identifies voxels with non-specific 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 by reference in its entirety). MUBADA target regions were developed using statistical methods that maximize separation of diagnostic groups based on image features (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 by reference in its entirety). When applied to F18 flortaucipir images from a large dataset of 202 subjects (55 Aβ- aged cognitive normal, 43 Aβ-MCI, 54 Aβ+MCI, 16 Aβ-AD, and 34 Aβ+AD), the analysis yielded two dimensions (aka components).The first dimension (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 MUBADAVOI (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).

[0291] The MUBADA VOI relative to the PERSI reference region was 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 and low were 1.10, low and moderate were 1.23, and moderate and high were 1.46. These values ​​were used to screen subjects according to the algorithm described above.

[0292] Based on the hypothesis that cognitive decline in patients with high tau is primarily caused by tauopathy and therefore does not respond to anti-amyloid therapy, subjects with tAD+ and tAD++ scans with SUVr > 1.46 did not receive anti-N3pGlu Aβ antibodies. [Table 6]

[0293] As shown below in Figure 6A-C, donanemab, an anti-N3pGlu Aβ antibody, was found to be most effective in the treatment subgroup with the lowest baseline flortaucipir signal. Based on Figure 6, it is hypothesized that patients with high tau (>1.46 SUVr) are less likely to respond to treatment.

[0294] The data demonstrate that the anti-N3pGlu Aβ antibody, donanemab, was most effective in human subjects with tau levels of about 1.14 SUVr or less or about 1.27 SUVr or less (Figures 6A and 6B). Changes in scale scores were not statistically significant in the donanemab treatment group compared to placebo in the right-most graph, defined by baseline tau PET SUVr values ​​above 1.274 SUVr (Figure 6C). Figures 6A-C show baseline tau subgroup analysis based on iADRS (FTP=F18-flortaucipir).

[0295] Example 5: Efficacy and Safety Associated with Carriers of the Apolipoprotein E4 (APOE4) Allele The Phase 2 clinical trial (NCT03367403, clinitritrials.gov) (disclosed in Examples 2, 3, and 4 above) 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 APOE4.

[0296] This phase 2 clinical trial was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study evaluating the safety, tolerability, and efficacy of donanemab in patients with early symptomatic AD. Clinical changes from baseline to week 76 were assessed for all enrolled patients with intermediate tau pathology levels using the Integrated AD Rating Scale (iADRS, primary endpoint) and the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB, secondary endpoint), a composite tool measuring cognition and daily function. Baseline characteristics showed 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 subpopulation.

[0297] RESULTS: Compared to placebo, donanemab treatment resulted in a 49% slower of cognitive decline as measured by iADRS (p=0.004) (Figure 7A) and a 36% slower of cognitive decline as measured by CDR-SB (p=0.038) in APOE4 carriers at 76 weeks (Figure 7B).

[0298] The difference in donanemab treatment between carriers and non-carriers was significantly greater in carriers (iADRS: p=0.001, CDR-SB: p=0.046). Additional key secondary endpoints demonstrated consistent and robust efficacy of donanemab compared to placebo in APOE4 carriers. See Tables G and H below. [Table 7] [Table 8]

[0299] The safety profile in APOE4 carriers was consistent with the overall donanemab-treated population. The slowing of tau PET increases after treatment with donanemab was numerically greater in APOE4 carriers receiving donanemab than in non-carriers.

[0300] Amyloid-related imaging abnormalities (ARIA) with edema or exudate, most of which were asymptomatic, were more common in APOE4 carriers (33.7%) than noncarriers (8.3%). ARIA with hemosiderin deposits such as microhemorrhages occurred in 34.5% of APOE4 carriers who received donanemab. Cancelling out 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).

[0301] Analysis of the study population demonstrated greater efficacy of donanemab in APOE4 carriers than non-carriers, demonstrating a significant slowing of disease progression on both the iADRS and CDR-SB.

[0302] Figures 7A-B show that donanemab showed higher efficacy in APOE4 carriers than non-carriers. Figure 7A shows that donanemab showed higher efficacy in APOE4 carriers than non-carriers on the iADRS scale. Figure 7B shows that donanemab showed higher efficacy in APOE4 carriers than non-carriers on the CDR-SB scale. Figure 7C shows amyloid change (centiloid) by patient APOE4 status in the treatment and placebo groups. Figure 7D shows tau PET SUVR change by patient APOE4 status. The graph on the left shows frontal lobe data for APOE4 carriers (referred to as E4 carriers in the figure) and non-carriers (referred to as E4 non-carriers in the figure). The graph on the right shows lateral temporal lobe data for APOE4 carriers (referred to as E4 carriers in the figure) and non-carriers (referred to as E4 non-carriers in the figure). 7E-G show baseline tau subgroup analysis based on iADRS for APOE4 carriers in both the donanemab treated and placebo groups. The bottom third shows patients with baseline F18-flortaucipir (FTP) SUVR≦1.144 for both the placebo and donanemab groups. The middle third shows patients with baseline FTP SUVR between 1.144 and 1.268 for both the placebo and donanemab groups. The top third shows patients with baseline FTP SUVR>1.268 for both the placebo and donanemab groups.

[0303] Example 6. Kinetics of amyloid reduction following donanemab treatment Donanemab treatment led to rapid 24-week amyloid reduction, with the rate of reduction directly proportional to baseline amyloid burden. After 6 months of donanemab treatment, participants with greater plaque clearance showed less tau progression in frontal, parietal, and temporal brain regions, and greater changes in amyloid plaques associated with less cognitive decline.

[0304] Figure 8A shows that donanemab induced rapid amyloid reduction in patients. This figure shows individual 24-week amyloid reduction trajectories for patients treated with donanemab.

[0305] The individual amyloid trajectories shown in FIG. 8A are based on baseline and 24-week amyloid measurements (in centiloid units, CL) observed in the clinical study TRAILBLAZER-ALZ (AACG, Clinicaltrials.gov identifier NCT03367403). Participants (N=115) were treated with donanemab and completed both baseline and 24-week F18-florbetapir PET scans. Complete amyloid clearance (also referred to herein as amyloid negativity, shown by the dashed line in FIG. 8A) is defined as an amyloid plaque level of <24.1 CL (Mintun et al., “Donanemab in Early Alzheimer's Disease,” New England Journal of Medicine 384(18)(2021):1691-1704, 2021, incorporated herein by reference in its entirety). Donanemab induced rapid and significant amyloid plaque reduction. All participants showed amyloid reduction ranging from -1.8 CL to -174.8 CL. The mean amyloid reduction rate across all participants was -2.9 CL / week. The group mean approached the complete amyloid clearance threshold of 24.1 CL over the first 24 weeks. As indicated by the upper points on the plot, the individual trajectories also imply that individuals with higher baseline amyloid plaque levels were far from complete amyloid clearance over the first 24 weeks of treatment. Conversely, participants with lower baseline amyloid plaque levels approached complete amyloid clearance over the first 24 weeks of treatment, as indicated by the lower points on the plot.

[0306] Figure 8B shows the association between baseline amyloid levels (X-axis) and change in amyloid levels over 24 weeks (Y-axis) for participants treated with donanemab in TRAILBLAZER-ALZ. Amyloid plaque reduction is associated with baseline amyloid plaque levels.

[0307] The relationship between baseline amyloid levels and change in amyloid levels over 24 weeks of treatment with donanemab, shown in Figure 8B, is based on baseline and 24-week amyloid measurements observed in the clinical study TRAILBLAZER-ALZ (AACG, Clinicaltrials.gov identifier NCT03367403). In this analysis, participants (N=115) were treated with donanemab and underwent both baseline and 24-week F18-florbetapir PET scans. A robust correlation (Pearson correlation coefficient r=-0.57, p<0.001) between total amyloid plaque levels at baseline and the total amount of plaque removed during the first 24 weeks was observed. Higher baseline amyloid plaque levels resulted in more amyloid plaque removal. Conversely, lower baseline amyloid plaque levels resulted in less plaque removal.

[0308] The lower the amyloid plaque level at baseline, the sooner amyloid clearance is completed, on average. Figure 8C shows the association between baseline amyloid levels (Y-axis) and the amount of amyloid clearance achieved at 24 weeks (X-axis) for participants treated with donanemab in TRAILBLAZER-ALZ. Participants who completely cleared amyloid at 24 weeks had lower amyloid plaque levels at baseline. In Figure 8C, the bars indicate the mean + / - standard deviation, CL = centroid, PET = positron emission tomography, Q = quartile.

[0309] The relationship between baseline amyloid levels and amyloid clearance levels (partial or complete) obtained at 24 weeks, shown in Figure 8C, is based on baseline and 24-week amyloid measurements observed in the clinical study TRAILBLAZER-ALZ. In this analysis, participants (N=115) were treated with donanemab and underwent both baseline and 24-week florbetapir PET scans and were included in this analysis. Patients were divided into two groups according to their amyloid plaque levels at 24 weeks. Complete amyloid clearance (also referred to herein as amyloid negative) is defined as an amyloid plaque level below 24.1 CL, and partial amyloid clearance is defined as an amyloid plaque level above 24.1 CL. Two-sample t-tests are used to compare the two groups. Participants who achieved complete amyloid clearance at 24 weeks had, on average, significantly (p<0.0001) lower baseline amyloid plaque levels than participants who had partial amyloid clearance at 24 weeks.

[0310] Participants with lower baseline levels of amyloid plaque were observed to achieve complete amyloid clearance faster (Figure 8D). Figure 8D shows the modeled relationship to achieving plaque clearance as a function of baseline amyloid plaque level. Figure 8D represents the time to achieve complete amyloid plaque clearance (defined as a PET measurement of less than 24.1 CL) in patients with various levels of amyloid deposition at baseline. The simulations shown in Figure 8D were performed using an exposure-response model developed using data from clinical studies TRAILBLAZER-ALZ (AACG, Clinicaltrials.gov identifier NCT03367403) and AACD (Clinicaltrials.gov identifier NCT02624778). The model is an indirect response model, in which donanemab activity is modeled as increasing the clearance rate constant associated with amyloid plaque level. To conduct the simulation, 10,000 hypothetical patients were simulated receiving three doses of 700 mg donanemab IV spaced 4 weeks apart, followed by 17 doses of 1400 mg donanemab Q4W, similar to the dosing regimen used in TRAILBLAZER-ALZ. Patients were divided into quartiles (Q1-Q4) by baseline amyloid-β plaque load (CL) values, with Q1 being 38.7-81.6 ccl, Q2 being 81.6-100.3 ccl, Q3 being 100.3-126.3 ccl, and Q4 being 126.4-251.4 ccl. At the end of 76 weeks of treatment, the model-estimated percentages of patients who achieved amyloid clearance (by quartile) were 92.1% (Q1), 86.8% (Q2), 83.1% (Q3), and 76.0% (Q4).

[0311] Analysis of FIG. 8D shows that patients with lower baseline amyloid levels were more likely to achieve amyloid clearance within 76 weeks of treatment than patients who began therapy with higher baseline amyloid levels. For example, 92.1% of patients achieved complete amyloid clearance in Q1, whereas 76.0% of patients achieved amyloid clearance in Q4. As the time required for 50% of patients in each quartile to achieve amyloid clearance, corresponding to the relative amount of amyloid at baseline in each quartile, patients with lower baseline amyloid appear to achieve plaque clearance sooner than patients with higher baseline amyloid.

[0312] The association between baseline amyloid levels and donanemab dosing regimens is shown in Figure 8E. The figure shows the association between baseline amyloid levels (Y-axis) and the dose of donanemab used. Participants with lower baseline levels of amyloid plaques were eligible for earlier dose reduction. In Figure 8E, bars indicate mean + / - standard deviation, CL = centiloid, Max = maximum value, PET = positron emission tomography, ***p<0.001.

[0313] In participants treated with donanemab, the dose was reduced to 700 mg if amyloid plaque levels (assessed by F18-florbetapir PET performed at weeks 24 and 52) were less than 11 CL–25 CL, indicating clearance of amyloid plaques. Donanemab-treated participants were switched to placebo if amyloid plaque levels were less than 11 CL on an individual scan or less than 11 CL–25 CL on two consecutive scans. Figure 8E includes two subgroups: participants who continued on the maximum dose until the end of the study and participants eligible for a dose reduction at week 24. Two-sample t-tests were used to compare the two groups. Participants who met the dose modification criteria had significantly lower baseline amyloid plaque levels than participants who continued on maximal treatment until the end of the study.

[0314] Response rates to treatment with donanemab depend on baseline amyloid plaque levels, and discontinuation of drug treatment does not result in significant amyloid reaccumulation over a year. Figure 8F shows the model-predicted change in amyloid plaque levels after cessation of treatment in patients who achieved amyloid clearance within 6 months.

[0315] Using the model described above in FIG. 8F, the change in amyloid plaque levels was simulated in 2000 patients using the dosing regimen utilized in TRAILBLAZER-ALZ. The subset of these 2000 patients who reached amyloid plaque levels below 11 CL was examined graphically to assess the predicted time course of amyloid plaque levels over the remainder of the study. A value of 11 CL was used as the cutoff for this simulation since this was the criterion used in TRAILBLAZER-ALZ for discontinuing donanemab treatment. Median values ​​(solid line) and 90% prediction intervals (shaded regions) are plotted for the on-treatment and off-treatment periods.

[0316] The effect on plaque reaccumulation of stopping treatment after patients reach <11 CL was investigated by simulation using a treatment-exposure-response model (Figure 8F). In the patient group simulated to achieve a PET signal <11 CL by week 24, cessation of donanemab treatment did not result in a significant increase in PET signal until the end of the simulation (week 76) due to the amount of plaque accumulation estimated by the model (approximately 6.7 CL / year). The assumption of the model is that the rate of plaque formation / accumulation after donanemab treatment is similar to the baseline rate. The implication of the model is that there is limited further benefit from continuing donanemab treatment after complete amyloid clearance is achieved, as the relatively low amyloid accumulation rate (6.7 CL / year) suggests that patients who achieve 11 CL while on donanemab will require more than 13 years to return to the model-estimated baseline of 101 CL.

[0317] Donanemab treatment reduced tau accumulation over 76 weeks, and in participants who achieved complete clearance of amyloid plaques at 24 weeks. Figure 8G shows the effect on tau PET in participants who achieved complete clearance of amyloid plaques at 24 weeks compared with participants who had partial amyloid clearance or placebo. At baseline and week 76, [ 18 F]TRAILBLAZER-ALZ study participants who underwent flortaucipir PET scans are included in the analysis. Participants who received donanemab (green bars in Figure 8G) are designated as having partial or complete amyloid clearance based on amyloid plaque levels at 24 weeks. Complete amyloid clearance was defined as an amyloid plaque level <24.1 CL, and the partial amyloid clearance cohort included donanemab-treated participants who did not reach that threshold by week 24. Tau PET accumulation is measured by F18 flortaucipir regional SUVR in temporal, parietal, and frontal brain regions, using the cerebellar crus as the reference region. P values ​​indicate statistical significance versus placebo regional tau PET change over 76 weeks (grey). In FIG. 8G, bars indicate the mean + / - standard error, LS=least squares, PET=positron emission tomography, SUVR=standardized uptake value ratio, *p<0.05, **p<0.01 vs. placebo.

[0318] In TRAILBLAZER-ALZ participants treated with donanemab, less accumulation of aggregated tau was observed across the temporal, parietal, and frontal brain regions at week 76, as measured by F18-flortaucipir PET. Numerically greater effects on tau change (even less accumulation) were seen in participants who achieved complete amyloid clearance at week 24 of the study. These data highlight the value of rapid clearance of amyloid plaques and support the relevance of these biomarkers to models of amyloid-induced tauopathy and the development and / or progression of Alzheimer's disease.

[0319] Figure 8H shows percent change in amyloid plaque levels vs. iADRS change from baseline at week 24. Greater amyloid clearance at week 24 was associated with less clinical decline.

[0320] The percentage change from baseline in CL values ​​for each patient was calculated at week 24 and plotted against the change from baseline in iADRS for TRAILBLAZER-ALZ at weeks 52, 64, and 76 (indicating a reduction in clinical disease progression) (Figure 8H). Both donanemab- and placebo-treated patients were included in the plot. A simple linear regression line was fitted to show the relationship between plaque reduction at week 24 and iADRS clinical outcome, and Pearson correlation coefficients were calculated. A negative correlation coefficient indicates a linear relationship between increasing amounts of amyloid plaque removed and less clinical decline. At weeks 52, 64, and 76, the correlation coefficients were -0.15, -0.13, and -0.09, respectively. This analysis shows a moderate correlation suggesting that removing more amyloid plaque is associated with less clinical decline.

[0321] Figure 8I shows the relationship between amyloid plaque reduction and slowing of the rate of disease progression using a model integrating PK, PET, and clinical endpoint (iADRS) data, where iADRS = integrated Alzheimer's Disease Rating Scale, mean and 90% CI, CI = confidence interval, PET = positron emission tomography, and PK = pharmacokinetics.

[0322] A model was developed to describe the relationship between changes in amyloid plaque levels and changes in the rate of disease progression as measured by the iADRS scale. The model is based on the disease progression model described by Conrado et al., “An Updated Alzheimer's Disease Progression Model: Incorporating Non-linearity, Beta Regression, and a Third-level Random Effect in NONMEM,” Journal of Pharmacokinetics and Pharmacodynamics 41(6)581-598, 2014 (incorporated herein by reference in its entirety). In this study, the Conrado model was modified to include a drug effect modeled as moderating the slope of disease progression correlated with the percent change in amyloid plaque levels from baseline as predicted by the exposure-response model of donanemab and amyloid plaques. Figure 8I was generated using the model-estimated slope of disease progression in the TRAILBLAZER-ALZ population along with the model-estimated effect of amyloid plaque reduction on the disease slope. The 90% confidence intervals of the relationships were estimated using the standard errors of each of the model parameters. The predicted relationships of the model are plotted as solid lines, and the 90% confidence intervals are represented by the shaded regions in Figure 8I.

[0323] FIG. 8I shows the modeled relationship between the change in amyloid with donanemab treatment and the change in disease progression rate relative to placebo patients. This relationship is based on an exposure-response model that relates serum donanemab concentration to the change in amyloid levels and the subsequent change in disease progression as a result of the change in amyloid levels. The model suggests that complete removal of amyloid plaques may reduce the rate of disease progression by >40%. The model suggests that there is a continuous relationship between the reduction in amyloid plaque levels and the change in disease progression rate. The continuous nature of this relationship suggests that non-complete plaque removal will slow the rate of disease progression in patients and lengthen the period during which they can maintain sufficient cognitive and functional activity to allow them to maintain an independent lifestyle.

[0324] Example 7: Amyloid clearance results in a rapid and sustained reduction in plasma levels of human tau phosphorylated at threonine 217 (P-tau217) Clearance of amyloid in subjects results in rapid and sustained reduction of plasma P-tau217 levels. Plasma P-tau217 correlated with baseline amyloid plaque levels measured by F18-florbetapir PET and baseline neurofibrillary tangles measured by F18-flortaucipir PET. Treatment with donanemab drives rapid reduction of plasma P-tau217 detected within 12 weeks. As shown by the Conrado model, changes in plasma P-tau217 positively correlated with reduction of amyloid plaques by PET, slower growth of tau neurofibrillary tangles by PET, and slower clinical progression. Furthermore, early and complete clearance of amyloid plaques suggests a significant reduction in plasma P-tau217, similar to the trend observed in the reduction of local tau-PET.

[0325] An immunoassay for human tau phosphorylated at threonine residue 217 (P-tau217) was used to measure tau loading in human K2EDTA plasma of patients on TRAILBLAZER-ALZ (see, e.g., International Patent Application Publication No. WO2020 / 242963, which is incorporated by reference in its entirety). The anti-tau antibodies disclosed in WO2020 / 242963 are directed against isoforms of human tau expressed in the CNS (e.g., recognize isoforms expressed in the CNS, but not isoforms of human tau expressed only outside the CNS).

[0326] A Quanterix Simoa® HD-X Analyzer™ was used for the p-tau 217 immunoassay. The analyzer uses P-tau 217 immunoassay reagents (capture antibody: Fab clone against P-tau 217, detection antibody: antibody clone against tau protein, calibrator and control: two synthetic peptides linked with a PEG linker, representing the epitopes recognized by the capture and detection antibodies. See, for example, International Patent Application Publication No. WO 2020 / 242963 (incorporated herein by reference in its entirety) which uses single molecule array (Simoa®) technology. This assay can detect low levels of P-tau 217 in human plasma and is a fully automated immunoassay.

[0327] In the first step, capture beads coated with target antibodies were combined with a human plasma sample. Target molecules present in the sample were captured by the antibody-coated capture beads. After washing, a biotinylated detection antibody was mixed with the capture beads. The detection antibody binds to the captured targets. After a second wash, a conjugate of streptavidin-β-galactosidase (SBG) was mixed with the capture beads. SBG binds to the biotinylated detection antibody, resulting in enzymatic labeling of the captured targets. After a third wash, the capture beads were resuspended in a resorufin β-D-galactopyranoside (RGP) substrate solution and transferred to a Simoa® disk. Individual capture beads were then sealed into the microwells of the array. Once the targets were captured and labeled, the β-galactosidase hydrolyzes the RGP substrate to produce a fluorescent product that provides a signal for measurement. A single-labeled target molecule provides sufficient fluorescent signal to be detected and counted by the Simoa® optical system within 30 seconds. At low target concentrations, the percentage of bead-containing wells in the array with a positive signal is proportional to the amount of target present in the sample. At higher target concentrations, when most of the wells containing beads have one or more labeled target molecules, the total fluorescent signal is proportional to the amount of target present in the sample. The concentration of target in an unknown sample is interpolated from the standard curve using unweighted log-log power regression.

[0328] Figures 9A-B show that baseline plasma P-tau 217 correlates with baseline amyloid plaque levels and neurofibrillary tangles. Figure 9A shows a scatter plot of baseline amyloid PET centroid and baseline plasma P-tau 217. Open circles indicate TRAILBLAZER-ALZ patients who received placebo, and solid green lines indicate TRAILBLAZER-ALZ patients who received donanemab. P-tau 217 values ​​were normalized by log10 transformation. Correlation between the two variables was assessed using Spearman's rank correlation. At baseline, β-amyloid measured by F18-florbetapir PET was positively correlated with plasma P-tau 217 levels (R=0.147, p=0.026). Figure 9B shows a scatter plot of baseline tau PET MUBADASUVR and baseline plasma P-tau 217. Open circles indicate TRAILBLAZER-ALZ patients who received placebo, and solid green lines indicate TRAILBLAZER-ALZ patients who received donanemab. P-tau217 values ​​were normalized by log10 transformation. Correlation between the two variables was assessed using Spearman's rank correlation. At baseline, brain tau measured by F18-florbetapir PET was positively correlated with plasma P-tau217 levels (R=0.383, p<0.0001). In Figures 9A-9B, CL=centiloid, SUVR=standardized uptake value ratio, PET=positron emission tomography, p=p-value, R=correlation coefficient, SUVR=standardized uptake value ratio.

[0329] Immunoassay data show that plasma P-tau 217 was significantly reduced with donanemab treatment in human subjects. Figure 9C shows a mixed model with repeated measures (MMRM) to compare the change in P-tau 217 from baseline between treatment groups. This figure shows that donanemab reduces plasma P-tau 217 early. Figure 3A (provided above) shows that amyloid plaques are significantly reduced with donanemab treatment. P-tau 217 showed rapid clearance after treatment, starting from the 12-week measurement. At week 76, the donanemab-treated group showed a 24% reduction compared to baseline (P<0.0001), while the placebo-treated group showed a 6% increase (p=0.03). Compared to the placebo-treated group, the donanemab-treated group showed a 29% reduction in P-tau 217 accumulation. In Figure 9C, LS = least squares, p = p-value, **p<0.01, ****p<0.0001 vs placebo.

[0330] Changes in plasma P-tau217 were associated with amyloid plaque clearance status after 24 weeks. Figure 9D shows a mixed model with repeated measures (MMRM) to compare changes in P-tau217 from baseline across placebo, donanemab treated with partial amyloid clearance, and donanemab treated with complete amyloid clearance. Complete amyloid clearance was defined as a florbetapir PET centiloid level <24.1 (also referred to herein as amyloid negative). Amyloid clearance status was measured using F18-florbetapir PET scan at 24 weeks. In Figure 9D, bars indicate mean + / - standard error, LS = least squares, p = p value, ****p<0.0001 vs. placebo.

[0331] Consistent with findings from brain tau PET, amyloid clearance was associated with a reduction in P-tau 217. Complete amyloid clearance at 24 weeks showed a numerically greater reduction in P-tau 217 than partial amyloid clearance, although this was not statistically significant at 76 weeks (p=0.34). Both treatment groups showed a statistically significant reduction in P-tau 217 accumulation compared to the placebo group (p<0.0001).

[0332] Figures 9E and 9F show that the reduction in plasma P-tau217 is associated with the clearance of amyloid. Figures 9E and 9F show scatter plots of amyloid PET centiloid change from baseline with the change in P-tau217 from baseline values ​​at 24 and 76 weeks, respectively. P-tau217 values ​​were normalized by log10 transformation. Correlation between the two sets of variables was assessed using Spearman's rank correlation. In the figures, open circles represent TRAILBLAZER-ALZ patients who received placebo and solid green lines represent TRAILBLAZER-ALZ patients who received donanemab, CL=centiloid, PET=positron emission tomography, p=p-value, r=correlation coefficient.

[0333] At both time points (24 and 76 weeks), change from baseline in β-amyloid as measured by F18-florbetapir PET correlated positively with P-tau217 levels (r=0.349 and 0.482, respectively, for both correlation coefficients; p<0.001).

[0334] Reductions in plasma P-tau217 were associated with reductions in neurofibrillary tangles at 76 weeks. Figures 9G and 9H show scatter plots of tau PET regional SUVR (frontal and parietal) change from baseline with change in P-tau217 from baseline values ​​at 76 weeks. P-tau217 values ​​were normalized by log10 transformation. Correlation between the two sets of variables was assessed using Spearman's rank correlation. In the figures, open circles indicate TRAILBLAZER-ALZ patients who received placebo and closed circles indicate TRAILBLAZER-ALZ patients who received donanemab, PET = positron emission tomography, p = p-value, r = correlation coefficient.

[0335] Changes from baseline in frontal and parietal SUVR were positively correlated with changes from baseline in P-tau217 (r=0.171, p=0.031 and r=0.257, p=0.0011, respectively).

[0336] The PK / PD model shows the relationship between plasma P-tau217 and slowing of clinical decline. The model was developed to describe the relationship between changes in plasma P-tau217 levels and changes in the rate of disease progression as measured by the iADRS scale. The model is based on the disease progression model described by Conrado et al. (Conrado et al., "An Updated Alzheimer's Disease Progression Model: Incorporating Non-linearity, Beta Regression, and a Third-level Random Effect in NONMEM," Journal of Pharmacokinetics and Pharmacodynamics 41(6)581-598, 2014, which is incorporated herein by reference in its entirety).

[0337] The model shows that reduction in P-tau217 is statistically significant as a predictor of delayed clinical decline (p<0.001). In Figure 9I, iADRS = integrated Alzheimer's Disease Rating Scale, mean and 90% CI, CI = confidence interval, PK = pharmacokinetics, p = p-value.

[0338] Example 8: Design and Rationale of the TRAILBLAZER-ALZ3 Study OBJECTIVE: TRAILBLAZER-ALZ3 (herein referred to as TB3, NCT05026866) is a multicenter, randomized, double-blind, placebo-controlled, event-driven, phase 3 study with a centrally assessed decentralized design designed to evaluate the impact of donanemab versus placebo in cognitively unimpaired participants with evidence of AD pathology (preclinical AD). Figure 10 shows the study design of the clinical protocol. SP stands for study duration. Participants randomized to placebo and who completed SPIII may have access to donanemab in SPIV, an open-label extension, if donanemab meets defined success factors.

[0339] Overview and Primary Endpoint: Approximately 3,300 participants who meet the inclusion criteria will be randomized in a 1:1 ratio to either donanemab (700 mg intravenously (IV) once every four weeks (Q4W) for the first three doses, followed by 1,400 mg IV Q4W for the next six doses) or placebo (IV Q4W for nine doses). Participants will be followed until approximately 434 participants experience the primary outcome event of clinical progression (an increase in Clinical Dementia Rating-Global Score (CDR-GS or gCDR) from CDR-GS=0 at baseline at two consecutive visits), with total duration of participation in the study varying by participant, with continuous follow-up for 3-5 years. Treatment with donanemab will be stratified by APOE4 allele dose from 0 to 2. For example, individuals may have 0, 1, or 2 copies of the E4 allele. Zero copies of the APOE4 allele is APOE4 negative, one copy of the APOE4 allele is heterozygous, and two copies of the APOE4 allele are homozygous. Rather than categorizing individuals by APOE4 carrier status, this stratification by APOE4 dose allows for equal amounts of homozygous and heterozygous E4 carriers in each treatment group.

[0340] The study will use a decentralized clinical trial (DCT) model in which all or part of the visits will be conducted remotely with the goal of increasing the number of eligible participants, including those from underrepresented groups. All clinical and cognitive assessments will be conducted remotely by a centralized assessor. The DCT model includes the use of technology, flexible locations, and centralized staffing to optimize the potential for strong participant retention and enhanced standardization with a centralized assessor for clinical assessments. Participants and partners will be assigned a Central Study Coordinator (CSC) who will serve as a central point of contact throughout the study.

[0341] Inclusion / Exclusion Criteria: Selection criteria included: ●Men and women aged 55 to 80 years old Telephone Interview for Cognitive Status - Complete Cognitive Function Modification (TICS-m) score, and • Qualified plasma P-tau217 result (SIMOA assay).

[0342] Exclusion criteria included: Mild cognitive impairment (MCI) / dementia or other neurodegenerative diseases that affect cognition, current or previous use of prescription medications for the treatment of MCI or dementia; Currently seriously ill or unstable - a history of cancer with a high risk of recurrence that would prevent completion of the study; • Clinically significant multiple or severe drug allergies or a history of severe hypersensitivity reactions following a procedure; - previous treatment with anti-amyloid immunotherapy, Any clinically significant abnormality on screening MRI or clinical examination, Any contraindications to MRI, and • Central-read MRI showing the presence of ARIA-E (amyloid-related imaging abnormality with exudate or edema), >4 cerebral microbleeds, >1 superficial siderosis, macroscopic hemorrhage, or severe white matter disease at screening.

[0343] Other Efficacy Assessments: Secondary endpoints to assess clinical progress include the International Shopping List Test, Serial Paired Associate Learning, International Everyday Symbol Substitution Test-Medicine, Category Fluency, Face-Name Association Test, Behavioral Pattern Separation-Object Test, Cogstate Brief Battery, CDR-Sum of Boxes, Cognitive Function Index, Montreal Cognitive Assessment, and Cognitive Composite Score (including a combination of individual assessments). Optional additions may include florbetapir-18F PET scan (N=200), flortaucipir-18F PET scan (N=500), and APOE disclosure.

[0344] Safety Assessments: To evaluate the safety and tolerability of donanemab, the study will monitor spontaneously reported adverse events (AEs), MRIs (for ARIAs and urgent radiological findings), infusion-related reactions, and the Columbia Suicide Severity Rating Scale. MRIs to assess / monitor ARIAs may be performed at baseline, after the first dose, prior to dose escalation to 700mg-1400mg, during the dosing period (e.g., double-blind treatment period), at weeks 4, 12, 20, and every 1-2 weeks, or as determined by the investigator. MRI scheduling may resume during the open-label extension period to assess / monitor ARIAs.

[0345] Biomarkers: Serum, plasma, and whole blood RNA samples for biomarker studies will be collected at screening and throughout the study. Biomarker analysis will be performed to address questions of relevance to drug disposition, target engagement, pharmacodynamics, mechanism of action, and variability of participant response (including safety). Plasma P-tau217 and other blood-based biomarkers will be used to further inform clinical outcomes and response to therapy. A subset of participants will undergo PET imaging of florbetapir and / or flortaucipir to evaluate the effect of donanemab on brain amyloid plaque burden and brain neurofibrillary tangle burden versus placebo in a preclinical Alzheimer's disease population.

[0346] Potential Impact / Conclusions: TB3 represents an innovative decentralized study design with central assessors. It includes a time-to-clinical-event model, blood-based AD biomarker inclusion criteria, and potentially supportive AD biomarker endpoints. Results from this study may help address the question of whether donanemab treatment with rapid reduction in brain amyloid plaques can delay or even prevent the progression of AD to the clinical stage.

[0347] Example 9: Biomarkers of TRAILBLAZER-ALZ Additional biomarker data was generated using the Simoa® Neurology4-Plex E Advantage Kit (additional information regarding the assay / kit is provided at quanterix.com / wp-content / uploads / 2020 / 12 / Neurology-4-Plex-E-Data-Sheet-HD-X.pdf, which is incorporated herein by reference in its entirety). Briefly, the Simoa® Neuro4-plexE assay measures amyloid beta 40 (Aβ) levels in human plasma. 40 ), amyloid beta 42 (Aβ 42Neuro4-plexE is a digital immunoassay for quantitative measurement of NF-kappaB, ... After a final wash, the beads were resuspended in resorufin β-D-galactopyranoside (RGP) substrate solution and transferred to a Simoa® disk. Individual beads are then sealed into the microwells of the array. If a target is captured and labeled on the bead, β-galactosidase hydrolyzes the RGP substrate in the microwell to produce a fluorescent product that provides a signal for measurement. A single labeled target molecule results in a fluorescent signal sufficient to be detected and counted by the Simoa® optical system within 30 seconds. At low target concentrations, the percentage of bead-containing wells in the array with a positive signal is proportional to the amount of target present in the sample. At higher target concentrations, when most of the wells containing beads have one or more labeled target molecules, the total fluorescent signal is proportional to the amount of target present in the sample. The concentration of target in an unknown sample is expressed as 1 / y 2 The linear regression line is interpolated from the standard curve using a 4 / 5 parameter logistic regression with weighting:

[0348] Neurofilament light chain (NfL) Neurofilament light chain (NfL) is an important biomarker (plasma or CSF) that can indicate neuronal damage due to many disease mechanisms, but is also elevated in Alzheimer's disease in particular. Therapies that can reduce NfL are predicted to reduce neuronal damage and portend improved outcomes for the disease. Data from the Simoa® Neuro4-plexE assay demonstrate that NfL in the entire population treated with donanemab can be reduced by at least 4% compared to placebo over the course of the treatment / dosing regimen (Figure 11A shows reduction in plasma NFL). This reduction effect may be enhanced in APOE4 carriers, as shown in Figure 11B, with a marked reduction at later time points in the study. The plasma data in the figure are the first to demonstrate reduction of NfL with anti-Aβ antibodies in Alzheimer's disease in an APOE4 carrier population. Figure 11B shows the change from baseline in NfL in APOE4 carriers (LS mean estimates from the MMRM model.

[0349] Amyloid beta (Aβ) Aβ 42 / 40 The ratio is known to decrease slowly over time in plasma and CSF when amyloid plaques are deposited in the brain parenchyma. Treatments that remove amyloid plaques may normalize this ratio, which translates to an increase toward higher levels. Data from TRAILBLAZER-ALZ show that donanemab treatment increases this ratio, showing significant improvement at least at one time point (Figure 12). Figure 12 shows an increase in the Aβ42 / 40 ratio.

[0350] It is noteworthy that unlike other antibodies, donanemab does not interact with any soluble species, therefore, the increase in this ratio provides a conclusive result regarding its ability to clear amyloid plaques to normalize this biomarker without the confounding effects of binding to other soluble blood species previously demonstrated with other antibodies.

[0351] Glial fibrillary acidic protein (GFAP) Normalization and reduction of the GFAP biomarker is an important first step for a plaque-lowering antibody. GFAP is an intermediate cytoskeletal protein that is upregulated in reactive astrocytes and is recognized as a pathological hallmark of many diseases, but is also well described in AD. GFAP is associated with amyloidosis, and recent studies have linked GFAP in the blood with amyloid deposits. The data shown in Figure 13A show for the first time the ability of a therapeutic agent (donanemab) to reduce the pathological response of astrocytes to amyloid through the reduction of GFAP measured in the blood. Figure 13A shows that GFAP is significantly reduced by donanemab treatment. In addition, P-tau217 and GFAP show a similar relationship to the clearance of amyloid plaques in TRAILBLAZER-ALZ. Figure 13B shows the correlation between plaque clearance and GFAP at 76 weeks.

[0352] Other ways of recording this reduction in pathology exist in theory, but may include PET tracers such as C11 deprenyl. Astrocytes play an important role in maintaining the blood-brain barrier through capillary interactions via astrocyte endplate junctions. In addition, astrocytes play an important role in glutamate toxicity by regulating and supporting glutamate removal or uptake in the synaptic cleft. Improvement in this biomarker portends clinical benefit and improvemen...

Claims

1. 1. A medicament for treating Alzheimer's disease (AD) in a subject in need thereof, comprising: (i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, wherein each 700 mg first dose is administered once every four weeks; (ii) performing a magnetic resonance imaging (MRI) scan of the subject's brain after administration of the three first doses to assess for amyloid-related imaging abnormalities (ARIA); (iii) if the evaluating step does not indicate ARIA, four weeks after administration of the three first doses, administering one or more 1400 mg second doses of the anti-N3pGlu Aβ antibody once every four weeks; The anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the LCVR consisting of the amino acid sequence of SEQ ID NO: 1, and the HCVR consisting of the amino acid sequence of SEQ ID NO:

2.

2. 1. A medicament for treating Alzheimer's disease (AD) in a subject in need thereof, comprising: (i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, wherein each 700 mg first dose is administered once every four weeks; (ii) performing a magnetic resonance imaging (MRI) scan of the subject's brain after administration of the three first doses to assess for ARIA; (iii) if the evaluating step indicates ARIA, temporarily withholding treatment with the anti-N3pGlu Aβ antibody until resolution of the ARIA or MRI radiographic stabilization; (iv) upon resolution of ARIA or MRI radiographic stabilization, administering one or more second doses of 1400 mg of the anti-N3pGlu Aβ antibody once every four weeks; The anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the LCVR consisting of the amino acid sequence of SEQ ID NO: 1, and the HCVR consisting of the amino acid sequence of SEQ ID NO:

2.

3. The second dose comprises: i) the Aβ plaques are removed; ii) the Aβ plaques in the subject are less than or equal to 25 centiloids as measured by two consecutive amyloid PET imaging scans, and the two consecutive amyloid PET imaging scans are separated by at least six months; iii) the Aβ plaques in the subject are less than or equal to 11 centiloids as measured by a single amyloid PET imaging scan; iv) the subject is amyloid negative; or v) The agent of claim 1 or 2, administered until an Aβ plaque level of <24.1 CL is reached as measured by amyloid PET imaging scan.

4. The method of any one of claims 1 to 3, wherein the doses of the anti-N3pGlu Aβ antibody are administered for a period of up to 72 weeks.

5. The method of any one of claims 1 to 4, further comprising obtaining a baseline MRI scan prior to administering to the subject the three first doses.

6. The method of any one of claims 1 to 5, wherein the second dose is administered for a period of up to 60 weeks.

7. a) slowing disease progression by at least 15% compared to untreated as predicted by a disease progression model (DPM) as measured by iADRS or CDR-SB; b) slowing disease progression by at least 15% compared to untreated as measured by iADRS or CDR-SB as estimated by mixed model repeated measures analysis (MMRM); c) slowing the progression of disease by at least 15% as measured by the integrated Alzheimer's Disease Rating Scale (iADRS) compared to untreated; d) slowing the progression of disease by at least 3 points as measured by the integrated Alzheimer's Disease Rating Scale (iADRS) compared to untreated; e) slowing the progression of the disease by at least 20% compared to untreated, as measured by the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB); f) reducing the level of Aβ plaques in the subject's brain by at least 40% as measured by amyloid PET imaging; g) slowing tau accumulation in the frontal lobe by at least 50% compared to untreated; h) limiting the increase in frontal lobe tau in said subject to less than 0.04 SUVr (standardized uptake value ratio) over a 72 week period as measured by tau PET imaging; i) reducing plasma P-tau217 by at least 5% from baseline; or j) A method according to any one of claims 1 to 6, which reduces glial fibrillary acidic protein (GFAP) by at least 5% from baseline.

8. 3. The method of claim 1, wherein administering the anti-N3pGlu Aβ antibody reduces Aβ plaques by about an average of about 50 to about 100 centiloids compared to Aβ plaques before administering the one or more first doses, and the Aβ plaques are measured by an amyloid PET imaging scan.

9. The method of claim 1 or 2, wherein administration of the anti-N3pGlu Aβ antibody for 24 weeks reduces the Aβ plaques by at least 60%.

10. The method of any one of claims 1 to 9, wherein each of the first and second doses is administered intravenously over at least 30 minutes at a concentration of between 4 mg / mL and 10 mg / mL.

11. The method of claim 1 or 2, wherein the subject's hippocampal volume is not reduced.

12. 3. The method of claim 1 or 2, wherein the level of Aβ plaques in the subject's brain is maintained at a normal level for at least 52 weeks after administering the one or more second doses.

13. 3. The method of claim 1, wherein if Aβ plaque levels in the subject's brain reach normal levels or stop decreasing 24 weeks after administration of the anti-N3pGlu Aβ antibody, the step of administering the one or more second doses is discontinued.

14. 3. The method of claim 1 or 2, wherein the level of Aβ plaques in the subject's brain is maintained at normal levels for at least 52 weeks after the step of administering the one or more second doses is discontinued.

15. The method of claim 1 or 2, wherein the level of Aβ plaques in the subject's brain is reduced to normal levels by 24 weeks.

16. 16. The method of claim 15, wherein the level of Aβ plaques in the subject's brain is maintained at normal levels for at least 52 weeks after administering the one or more second doses is discontinued.

17. 17. The agent of any one of claims 12-16, wherein the subject has an increase in tau levels in the parietal lobe of less than 0.06 SUVr 76 weeks after administering the one or more second doses, wherein the brain tau levels are measured by a tau PET imaging scan.

18. 18. The agent of any one of claims 12-17, wherein the subject has brain tau levels of less than 0.4 SUVr in the frontal lobe region 76 weeks after administering the one or more second doses, wherein the brain tau levels are measured by a tau PET imaging scan.

19. 1. A medicament for treating Alzheimer's disease in a subject in need thereof, comprising: (i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, wherein each 700 mg first dose is administered once every four weeks; (ii) performing a magnetic resonance imaging (MRI) scan of the subject's brain after administration of the three first doses to assess for ARIA; (iii) discontinuing treatment with the anti-N3pGlu Aβ antibody if the evaluating step indicates ARIA; The anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the LCVR consisting of the amino acid sequence of SEQ ID NO: 1, and the HCVR consisting of the amino acid sequence of SEQ ID NO:

2.

20. The drug of any one of claims 1 to 19, wherein the ARIA is ARIA-E.

21. The method of claim 20, wherein ARIA-E is moderate or severe.

22. The drug of any one of claims 1 to 19, wherein the ARIA is ARIA-H.

23. The method of claim 22, wherein the ARIA-H is moderate or severe.

24. Prior to administering the three first doses to the subject, the subject: (i) having a brain tau level of less than 1.46 standardized uptake value ratio (SUVr); (ii) have a brain tau level greater than 1.10 SUVr and less than 1.46 SUVr; or (iii) have negative brain tau imaging levels in the frontal lobe brain region; The method of any one of claims 1 to 23, wherein the brain tau levels are measured by a tau PET imaging scan.

25. Brain tau levels １８ The method of claim 24, wherein F-flortaucipir PET imaging is used.

26. Prior to administering the three first doses to the subject, the subject: (i) identified as having early symptomatic Alzheimer's disease; (ii) identified as having at least one APOE4 allele, or (iii) having a baseline MMSE (Mini-Mental State Examination) score of 20-28.

27. 1. A medicament for treating Alzheimer's disease in a subject in need thereof, comprising: i) administering to the subject up to three first doses, each first dose comprising 700 mg of an anti-N3pGlu Aβ antibody, administered at a frequency of one first dose every four weeks, the subject being evaluated for ARIA after each dose, and if ARIA is observed, administration of the anti-N3pGlu Aβ antibody is temporarily discontinued until resolution of ARIA symptoms or MRI radiographic stabilization; ii) upon resolution of ARIA or MRI radiographic stabilization, administering the remaining first dose or one or more 1400 mg second doses of the anti-N3pGlu Aβ antibody once every four weeks; The anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the LCVR consisting of the amino acid sequence of SEQ ID NO: 1, and the HCVR consisting of the amino acid sequence of SEQ ID NO:

2.

28. 1. A medicament for treating Alzheimer's disease in a subject in need thereof, comprising: i) administering to the subject up to three first doses, each first dose comprising 700 mg of an anti-N3pGlu Aβ antibody, administered at a frequency of one first dose every four weeks, and wherein the subject is evaluated for ARIA after each first dose; ii) if the evaluating step does not indicate ARIA, administering one or more second doses of 1400 mg of the anti-N3pGlu Aβ antibody once every four weeks; The anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the LCVR consisting of the amino acid sequence of SEQ ID NO: 1, and the HCVR consisting of the amino acid sequence of SEQ ID NO:

2.

29. The agent according to any one of claims 1 to 28, wherein the anti-N3pGlu Aβ antibody comprises a light chain (LC) and a heavy chain (HC), the LC comprising the amino acid sequence of SEQ ID NO: 3, and the HC comprising the amino acid sequence of SEQ ID NO:

4.

30. The drug described in any one of claims 1 to 28, wherein the drug is for suppressing the progression of mild cognitive impairment and mild dementia due to Alzheimer's disease.

31. A drug for inhibiting disease progression of mild cognitive impairment and mild dementia due to Alzheimer's disease in a subject in need thereof, comprising: i) administering to the subject three 700 mg first doses of an anti-N3pGlu Aβ antibody, wherein each 700 mg first dose is administered once every four weeks; ii) performing a magnetic resonance imaging (MRI) scan of the subject's brain after administration of the three first doses to assess for ARIA; iii) if the evaluating step does not indicate ARIA, four weeks after administration of the three first doses, administering one or more 1400 mg second doses of the anti-N3pGlu Aβ antibody once every four weeks; The anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the LCVR consisting of the amino acid sequence of SEQ ID NO: 1, and the HCVR consisting of the amino acid sequence of SEQ ID NO:

2.

32. A drug for inhibiting disease progression of mild cognitive impairment and mild dementia due to Alzheimer's disease in a subject in need thereof, comprising: i) administering to the subject up to three first doses, each first dose comprising 700 mg of an anti-N3pGlu Aβ antibody, administered at a frequency of one first dose every four weeks, the subject being evaluated for ARIA after each dose, and if ARIA is observed, administration of the anti-N3pGlu Aβ antibody is temporarily discontinued until resolution of ARIA symptoms or MRI radiographic stabilization; ii) upon resolution of ARIA or MRI radiographic stabilization, administering the remaining first dose or one or more 1400 mg second doses of the anti-N3pGlu Aβ antibody once every four weeks; The anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the LCVR consisting of the amino acid sequence of SEQ ID NO: 1, and the HCVR consisting of the amino acid sequence of SEQ ID NO:

2.

33. A drug for inhibiting disease progression of mild cognitive impairment and mild dementia due to Alzheimer's disease in a subject in need thereof, comprising: i) administering to the subject up to three first doses, each first dose comprising 700 mg of an anti-N3pGlu Aβ antibody, administered at a frequency of one first dose every four weeks, and wherein the subject is evaluated for ARIA after each first dose; ii) if the evaluating step does not indicate ARIA, administering one or more second doses of 1400 mg of the anti-N3pGlu Aβ antibody once every four weeks; The anti-N3pGlu Aβ antibody comprises a light chain variable region (LCVR) and a heavy chain variable region (HCVR), the LCVR consisting of the amino acid sequence of SEQ ID NO: 1, and the HCVR consisting of the amino acid sequence of SEQ ID NO:

2.

34. The agent of any one of claims 1, 2, 19, 27, and 28, further comprising performing a magnetic resonance imaging (MRI) scan of the subject's brain to assess for amyloid-related imaging abnormalities (ARIA) after i) administering a first dose of the anti-N3pGlu Aβ antibody or ii) after three doses of the anti-N3pGlu Aβ antibody.

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