Methods of using anti-amyloid beta protofibril antibodies and anti-tau antibodies

Abstract

The details of the mechanistic relationships between the pathogenesis of Alzheimer's disease, Aβ production, and tau-mediated neurotoxicity remain poorly understood. There remains the potential for improved therapies that target both Aβ production and tau-containing neurofibrillary tangles. Thus, there is a need for specific and effective therapeutic agents that target Aβ and tau. [Solution] Disclosed herein are antibodies for treating or preventing Alzheimer's disease, including anti-Aβ protofibril antibodies and anti-tau antibodies, pharmaceutical preparations, methods for treating or preventing Alzheimer's disease, and kits including pharmaceutical preparations for treating or preventing Alzheimer's disease.

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 291,315, filed December 17, 2021, and International Application No. PCT / IB2021 / 000937, filed December 17, 2021, the contents of which are incorporated by reference in their entireties into this specification.

[0002] This application contains a Sequence Listing that has been submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. Said ASCII copy, created on December 3, 2021, is named 08061_0053-00304_SL.txt and is 21,812 bytes in size.

[0003] This invention was made with Federal Government support under Grant Nos. U01AG042791, R01AG046179, R56AG053267, U01AG059798, R01AG053267 and R01AG068319 awarded by the National Institutes of Health. The Federal Government has certain rights in this invention. [Background technology]

[0004] Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in older adults. In 2006, there were 26.6 million cases of AD worldwide (range: 11.4-59.4 million cases) (Brookmeyer, R., et al., Forecasting the global burden of Alzheimer's Disease. Alzheimer Dement. 2007;3:186-91), while over 5 million people in the United States were reported to be living with AD (2010 Alzheimer's disease facts and figures. Alzheimer Dement. 2010;6:158-94). By 2050, the number of AD patients worldwide is projected to reach 106.8 million cases (range: 47.2-221.2 million cases), while in the United States alone, the number of patients is estimated to be 11-16 million cases. (Brookmeyer, supra and 2010 Alzheimer's disease facts and figures, supra).

[0005] The disease generally involves a generalized decline in cognitive function that progresses slowly, with end-stage subjects becoming bedridden. AD subjects typically survive only 3-10 years after the onset of symptoms, although extreme cases of 2 and 20 years have been known (Hebert, LE, et al., Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119-1122). Despite the fact that AD is rarely listed as the cause of death on death certificates, and therefore mortality attributable to AD is greatly underestimated, AD is the seventh most common cause of all deaths in the United States and the fifth most common cause of death among Americans over the age of 65 (2010 Alzheimer's disease facts and figures, supra).

[0006] Histologically, the disease is characterized by neuritic plaques found mainly in the association cortex, limbic system and basal ganglia. The main component of these neuritic plaques is the amyloid beta peptide (Aβ). Aβ exists in different conformational states - monomers, oligomers, protofibrils and insoluble fibrils.

[0007] In addition to Aβ plaques, Alzheimer's disease is also characterized by the presence of accumulations of neurofibrillary tangles containing tau. Human tau is encoded by the microtubule-associated protein tau gene MAPT, located on chromosome 17q21. There are six major tau isoforms in the adult human brain, which arise by alternative splicing of exons 2 (E2), E3, and E10. These isoforms differ according to the number of 29-residue repeat regions near the N-terminus. Tau isoforms with 0, 1, or 2 insertions are known as 0N, 1N, and 2N, respectively. Pre-processed tau isoforms also contain either three ("3R") or four ("4R") microtubule-associated repeat domains. The second of these repeat domains is encoded by E10 and is not included in the 3R tau isoforms.

[0008] Tau is normally highly soluble, but under pathological conditions can aggregate into paired helical filaments, neurofibrillary tangles and other structures that define a wide range of neurodegenerative diseases called tauopathies. Thus, tauopathies refer to a class of neurodegenerative diseases involving aggregation of the microtubule-associated protein tau, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD). Summary of the Invention [Problem to be solved by the invention]

[0009] The details of the mechanistic relationships between the pathogenesis of Alzheimer's disease, Aβ production, and tau-mediated neurotoxicity remain poorly understood. There remains the potential for improved therapies that target both Aβ production and tau-containing neurofibrillary tangles. Thus, there is a need for specific and effective therapeutic agents that target Aβ and tau. [Means for solving the problem]

[0010] Provided herein is a method for treating and / or preventing Alzheimer's disease, the method comprising administering to a subject in need thereof an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril and an anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau.

[0011] In some embodiments, the method of treating or preventing Alzheimer's disease in a subject in need thereof includes administering to the subject: (i) An isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril, (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13, and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14. An isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof comprising: (ii) an anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau, (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 15, and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 and an anti-tau antibody or an antigen-binding fragment thereof comprising wherein the anti-Aβ protofibril antibody or fragment thereof is administered in conjunction with (e.g., simultaneously or sequentially) the anti-tau antibody or fragment thereof. In some embodiments, the isolated anti-Aβ protofibril antibody or fragment thereof is administered once every two weeks. In some embodiments, the anti-tau antibody or fragment thereof is administered once every four weeks. In some embodiments, the anti-Aβ protofibril antibody or fragment thereof is administered prior to the initiation of treatment with the anti-tau antibody or fragment thereof, e.g., when the subject is symptomatic for Alzheimer's disease. In some embodiments, the anti-tau antibody or fragment thereof is administered prior to the initiation of treatment with the anti-Aβ protofibril antibody or fragment thereof, e.g., when the subject is asymptomatic for Alzheimer's disease. In some embodiments, the anti-Aβ protofibril antibody or fragment thereof is administered at a dose of 5 mg / kg to 20 mg / kg, e.g., the dose is 10 mg / kg. In some embodiments, the anti-tau antibody or fragment thereof is administered in an amount of 1000-45000 mg, e.g., the dose is 1500 mg. In some embodiments, the subject has a genetic mutation for dominantly inherited Alzheimer's disease, e.g., the subject has a genetic mutation in at least one of three genes - PSEN1, PSEN2, or APP.

[0012] In this specification, (i) An isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril, (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13, and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14. An isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof comprising: (ii) an anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau, (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 15, and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 and an anti-tau antibody or an antigen-binding fragment thereof comprising Also provided are kits and pharmaceutical combinations comprising the anti-Aβ protofibril antibody or fragment thereof, wherein the anti-tau antibody or fragment thereof is administered in conjunction (e.g., simultaneously or sequentially) with an anti-tau antibody or fragment thereof. [Brief description of the drawings]

[0013] [Figure 1] Illustrates the randomization scheme for treatment with E2814 in parallel with lecanemab. [Diagram 2] Illustrates the E2814 or placebo and open-label lecanemab treatment scheme. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition Below are definitions of terms used in this application.

[0015] As used herein, the singular terms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0016] The phrase "and / or," as used herein, refers to "either or both" of the elements so coordinated, i.e., elements that are coordinately present in some cases and disjunctively present in other cases. Thus, as a non-limiting example, "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in some embodiments to A only (optionally including elements other than B); in other embodiments to B only (optionally including elements other than A); in yet other embodiments to both A and B (optionally including other elements), etc.

[0017] As used herein, "at least one" means one or more of the elements in a list of elements, but does not necessarily include at least one of each and every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than those specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether or not related to the specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") may refer, in one embodiment, to at least one, optionally including more than one, A, with no B (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements), etc.

[0018] When a number is recited, whether alone or as part of a numerical range, it should be understood that the numerical value can vary upward and downward from the stated value by a variance of 10% of the stated value.

[0019] The term "antibody" as used herein is used in a broad sense to refer to an immunoglobulin or antibody molecule, including polyclonal antibodies, monoclonal antibodies, including murine, human, human-adapted, humanized and chimeric monoclonal antibodies, and antibody fragments. In general, an antibody is a protein or peptide chain that exhibits binding specificity to a specific antigen. An intact antibody is typically a heterotetrameric glycoprotein composed of two identical light chains and two identical heavy chains. Typically, each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide bonds varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (VH) at one end followed by a number of constant domains (CRC). Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain and the light chain variable domain is aligned with the variable domain of the heavy chain. The antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0020] Immunoglobulins can be assigned to five major classes or isotypes depending on the type of constant domain possessed by their heavy chains, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further classified as isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. The heavy chain constant domains corresponding to the different immunoglobulin classes are called α, δ, ε, γ and μ, respectively.

[0021] An immunoglobulin light or heavy chain variable region consists of a "framework" region separated by three complementarity determining regions (CDRs) that provide the main antigen binding determinants (Wu and Kabat, J. Exp. Med. 132:211-250, 1970). In general, an antigen binding site has six CDRs; three in VH (HCDR1, HCDR2, HCDR3) and three in VL (LCDR1, LCDR2, LCDR3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991). The CDRs can be determined according to the Kabat numbering scheme. SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (Kabat et al., 5th ed., USDepartment of Health and Human Services, NIH Publication No. 91-3242, 1991, hereafter referred to as the "Kabat report"). Instead, the "IMGT-CDRs" as proposed by Lefranc (Lefranc et al., Dev.Comparat.Immunol.27:55-77,2003) are based on a comparison of V domains from immunoglobulins and T cell receptors. The International Immunogenetics (IMGT) Database (http: / / www_imgt_org) provides standardized numbering and definitions of these regions. The correspondence between CDRs and IMGT designations is described in Lefranc et al., Dev.Comparat.Immunol.27:55-77,2003.

[0022] An antigen-binding fragment is composed of a portion of an intact antibody that retains the antigen-binding specificity of the parent antibody molecule. For example, an antigen-binding fragment may contain at least one variable region (either heavy or light chain variable region) or one or more CDRs of an antibody known to bind to a particular antigen. Examples of suitable antigen-binding fragments include, without limitation, diabodies and single chain molecules as well as Fab, F(ab')2, Fc, Fabc and Fv molecules, single chain (Sc) antibodies, individual antibody light chains, individual antibody heavy chains, chimeric fusions between antibody chains or CDRs and other proteins, protein scaffolds, heavy chain monomers or dimers, light chain monomers or dimers, dimers consisting of one heavy chain and one light chain, and the like. Any antibody isotype may be used to generate antigen-binding fragments. In addition, antigen-binding fragments may include non-antibody protein frameworks, such as protein scaffolds, that allow successful incorporation of polypeptide segments in an orientation that confers affinity for a given antigen of interest. Antigen-binding fragments may be produced recombinantly or by enzymatic or chemical cleavage of intact antibodies. The phrase "antibody or antigen-binding fragment thereof" may be used to indicate that one or more amino acid segments of the antibody referred to in the phrase are incorporated into a given antigen-binding fragment.

[0023] The term "subject" refers to humans and non-human animals, including all vertebrates, e.g., mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles. In many embodiments of the methods described, the subject is a human.

[0024] In some embodiments, the subject exhibits "high amyloid" or "intermediate amyloid". In some embodiments, the amyloid level is measured using amyloid PET. As one skilled in the art will recognize, amyloid levels from amyloid PET can be reported in "centiloid" units (CL) using the centiloid method (Klunk WE et al. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimer's Dement. 2015;11:1-15 e1-4). In the centiloid method, the tracer is measured on a scale of 0CL to 100CL, where 0 is considered the reference point and corresponds to the average value of young healthy controls, and 100CL corresponds to the average amyloid burden found in subjects with mild to moderate severity of dementia due to AD (Id.). As known to those skilled in the art, centiloid thresholds can vary and can be refined, for example, based on new or additional scientific information (see, for example, http: / / www.gaain.org / centiloid-project). Elevated amyloid levels can be set relative to a baseline threshold for healthy controls determined according to methods known in POSA. For example, a centiloid value of 32.5 can be used as a threshold for "high amyloid" and "intermediate amyloid" levels can refer to Aβ amyloid PET in the range of 20-32.5 CL. In another example, a centiloid value of 40 can be used as a threshold for "high amyloid" and "intermediate amyloid" levels can refer to Aβ amyloid PET in the range of 20-40 CL.Rowe et al.,Eur J Nucl Med Mol I 44,2053-2059(2017);Salvado et al.,Alzheimer's Res Ther 11.27(2019);Sabri et al.,Alzheimer's Dement 11:964-74(2015);Rowe et al.,Alzheimer's Dementia 14,P634(2018);Amadoru et al.,Alzheimer's Res Ther 12.22(2020);Roe-Vellve et al.,Alzheimer's Dementia 16,(2020);Bullich et al.,Alzheimer's Res Ther 13.67(2021);

[0025] A subject who is "asymptomatic for Alzheimer's disease", as described herein, is a cognitively normal subject with moderate or elevated amyloid levels in the brain, and may be identified by being in an asymptomatic stage with or without memory complaints (e.g., based on Aβ accumulation in the brain and / or by CSF or blood-based biomarkers) and emerging episodic memory and executive dysfunction. Cognitively normal may include subjects with a CDR of 0 or cognitive test scores within the normal range. Asymptomatic AD occurs prior to significant irreversible neurodegeneration and cognitive impairment, and is typically characterized by the appearance of in vivo molecular biomarkers of AD and the absence of clinical symptoms. Subclinical AD biomarkers that may be indicative of the onset of Alzheimer's disease include, but are not limited to, one or more of moderate or elevated brain amyloid and / or tau levels, e.g., as measured by amyloid or tau positron emission tomography (PET), cerebrospinal fluid Aβ1-42 levels, cerebrospinal fluid total tau levels, cerebrospinal fluid neurogranin levels, cerebrospinal fluid neurofilament light chain levels, and blood biomarkers measured in serum or plasma (e.g., Aβ1-42 levels, the ratio of the two forms of amyloid-β peptide (Aβ42 / Aβ40), plasma total tau (T-tau) levels, phosphorylated tau (P-tau) isoform levels (including tau phosphorylated at 181 (P-tau181), 217 (P-tau217), and 231 (P-tau231)), and neurofilament light chain (NfL)). For example, subjects treated with the beta-site amyloid precursor protein-cleaving enzyme (BACE) inhibitor elenbecestat (E2609) who had amyloid baseline positron emission tomography (PET) standardized uptake value (SUVr) ratio of 1.4 to 1.9 showed the greatest slowing of cognitive decline while on treatment.See Lynch, SY et al. “Elenbecestat, a BACE inhibitor: results from a Phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer's disease.” Poster P4-389, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA. Similarly, subjects with baseline florbetapir amyloid PET SUVr levels below 1.2 do not exhibit sufficient cognitive decline to be detectable, whereas subjects with SUVr levels above 1.6 have been found to have reached a saturation level of amyloid, which appears to correlate with a plateau effect in which treatment does not result in change in cognitive measures. Dhadda,S.et al.,“Baseline florbetapir amyloid PET standard update value ratio(SUVr)can predict clinical progression in prodromal Alzheimer's disease(pAD).”Poster P4-291,Alzheimer's Association International Conference,July 22-26,2018,Chicago,IL,USA;Sperling RA et al.,Alzheimer's Dement.2011;7:280-92;Jack CRet al.,Alzheimer's Dement.2018;14:535-62.

[0026] "Early-onset Alzheimer's disease," as used herein, refers to a continuum of AD severity ranging from mild cognitive impairment due to AD-moderately likely to mild Alzheimer's disease dementia. Subjects with early-onset AD include subjects with mild Alzheimer's disease dementia as defined herein and subjects with mild cognitive impairment (MCI) due to AD-moderately likely as defined herein. In some embodiments, subjects with early-onset AD have a Mini-Mental State Examination (MMSE) score of 22-30 and / or an overall CDR in the range of 0.5-1.0.

[0027] A subject with "mild Alzheimer's dementia" or "mild AD dementia", as used herein, is a subject who meets the National Institute of Aging-Alzheimer's Association (NIA-AA) core clinical criteria for probable Alzheimer's dementia in McKhann, GM et al., "The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer Dement. 2011; 7: 263-9. As used herein, subjects with a CDR score of 0.5 to 1.0 and / or a memory box score of 0.5 or more at screening and baseline are also included.

[0028] A subject with "moderately probable mild cognitive impairment due to AD" as used herein is a subject identified as conforming to the NIA-AA core clinical criteria for moderately probable mild cognitive impairment due to Alzheimer's disease (see McKhann supra). For example, the subject may be symptomatic but not demented, have low heterogeneity due to evidence of cerebral amyloid pathology, and are more similar to mild Alzheimer's dementia subjects in terms of cognitive and functional decline, and have a score of 0.5 and / or memory box score of 0.5 or more as measured by CDR at screening and baseline. Additionally, the present specification also includes subjects who report a history of slowly progressing subjective memory decline that began gradually in the past year before screening and is corroborated by informants.

[0029] A subject's amyloid levels can be detected by biomarkers such as, but not limited to: (a) amyloid detected by PET scan, either by visual reading or semi-quantitative threshold (SUVr or centiloid); (c) cerebrospinal fluid (CSF) Aβ1-42 and / or Aβ1-42 / 1-40 ratio; and / or (d) blood biomarkers (i.e., plasma Aβ1-42, Aβ1-42 / Aβ1-40, tau, total tau (T-tau), P-tau, and / or NfL). Secondary markers can confirm the primary amyloid determination, including, but not limited to, (a) tau detected by PET scan; (b) CSF tau, phosphorylated tau (p-tau), neurofilament light peptide (NfL), and / or neurogranin; (c) other blood biomarkers (i.e., tau, total tau (T-tau), P-tau, and / or NfL).

[0030] "Amyloid" refers to the unbranched, usually extracellular, fibrils found in vivo; in addition, the fibrils bind the dye Congo Red, which then exhibits green birefringence when viewed between crossed polarizers. Amyloidogenic proteins have been identified and linked to severe diseases, including amyloid-β peptide (Aβ) associated with Alzheimer's disease (AD), islet amyloid polypeptide (IAPP) associated with type 2 diabetes, and prion protein (PrP) associated with spongiform encephalopathies. As used herein, "amyloid," "brain amyloid," and "amyloid-β peptide (Aβ)" are used interchangeably.

[0031] As used herein, the term "ARIA" refers to amyloid-related imaging abnormalities as determined using MRI. In some embodiments, ARIA includes amyloid-related imaging abnormalities edema / exudation (ARIA-E). In some embodiments, ARIA includes amyloid-related imaging abnormalities hemorrhage (ARIA-H). In some embodiments, subjects with ARIA have headaches, confusion, and / or seizures, which may be used to identify subjects with ARIA or indicate further evaluation for ARIA. In some embodiments, ARIA is evaluated at specified intervals during treatment. In some embodiments, ARIA is evaluated when a subject has symptoms of ARIA.

[0032] As used herein, the term "treat" refers to achieving one or more beneficial or desired results, including, but not limited to, a therapeutic benefit, which means the eradication or amelioration of one or more of the underlying condition under treatment or the physiological symptoms associated therewith. The term encompasses, but does not require, complete treatment.

[0033] As used herein, the term "prevent" refers to achieving one or more beneficial or desired results, including, but not limited to, preventive benefits. Benefits may include delaying or reducing the severity of one or more symptoms of Alzheimer's disease, such as a symptom of the disease, e.g., progressive memory loss. For preventive benefits, a compound or formulation may be administered to a subject at risk of developing Alzheimer's disease, a subject with one or more presymptomatic symptoms of Alzheimer's disease but no clinical symptoms, or a subject complaining of one or more physiological symptoms of Alzheimer's disease, even if the subject has not been clinically diagnosed with Alzheimer's disease. As used herein, "prevention" may further include therapeutic benefits, which refer to the eradication or amelioration of one or more of the underlying pathology or physiological symptoms associated therewith under treatment.

[0034] As will be understood by those skilled in the art, digital, computerized and / or conventional (e.g., paper-based) cognitive tests can be used to detect early cognitive changes that may warn of the risk of developing mild cognitive impairment and / or dementia, and thus may be used to identify subjects in need of treatment as disclosed herein. Such tests may, for example, screen for cognitive impairment and possibly identify subjects with MCI. The tests may use artificial intelligence to analyze cognitive test results and determine whether a case of mild cognitive impairment will progress to Alzheimer's disease within one year. Early diagnosis of the condition before symptoms begin to appear may facilitate physicians to identify subjects in need of treatment as disclosed herein earlier, potentially delaying the onset of neurodegenerative diseases or reducing their severity.

[0035] As used herein, "MMSE" refers to the Mini-Mental State Examination, a cognitive function instrument often used for screening purposes but also often measured longitudinally in AD clinical trials. The MMSE is a 30-point scale, with higher scores indicating less impairment and lower scores indicating more impairment, ranging from 0 (most impaired) to 30 (no impairment). In some embodiments, as part of the MMSE score, seven items measuring orientation to time and place, memorization, recall, attention, language, and drawing may be assessed (Folstein, MF et al., "Mini-mental state. A practical method for grading the cognitive state of patients for the clinician." J. Psychiatr. Res. 1975; 12: 189-98).

[0036] As used herein, "ADAS-Cog" refers to the Alzheimer's Disease Assessment Scale-Cognitive Function. The ADAS-Cog is a cognitive function scale that is widely used in Alzheimer's disease testing, and has structured scales that assess memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational behavior (putting a notepaper into an envelope), and constructional behavior (copying a geometric pattern) (Rosen, WGet al., "A new rating scale for Alzheimer's disease." Am. J. Psychiatry 1984;141:1356-64). Ratings of oral language, language comprehension, word finding difficulties, memory for test instructions, maze and digit erasure may also be obtained. In some embodiments, the ADAS-Cog is a cognitive function subscale that assesses memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational behavior (putting a notepaper into an envelope), and constructional behavior (copying a geometric pattern) (Rosen, WGet al., "A new rating scale for Alzheimer's disease." Am. J. Psychiatry 1984;141:1356-64). Ratings of oral language, language comprehension, word finding difficulties, memory for test instructions, maze and digit erasure may also be obtained. 11 In some embodiments, the ADAS-Cog 11 is scored from 0 to 70, with a score of 0 indicating no impairment and a score of 70 indicating the greatest impairment. In some embodiments, the ADAS-Cog is 14 (ADAS-Cog14 The ADAS-Cog14 includes three additional items: maze, digit extinction, and delayed word recall, and is scored from 0 to 90, with a score of 0 indicating no impairment and a score of 90 indicating the greatest impairment. 14 Tasks include memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational tasks (placing letter paper in an envelope), constructional tasks (copying geometric patterns), oral language, language comprehension, word finding difficulties, memory for test instructions, mazes, and digit erasure (Rosen, WGet al., Am. J. Psychiatry 1984;141:1356-64).

[0037] As used herein, "CDR-SB" refers to the Clinical Dementia Scale-Item Total. The CDR is a clinical scale that describes a five-level degree of performance impairment in each of six functional categories, including memory, orientation, judgment and problem solving, community activities, household and hobbies, and self-care (Berg, L. et al., "Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment." Ann. Neurol. 1988;23:477-84). The impairment ratings obtained in each of the six functional categories are combined into one overall rating, the Dementia CDR score (range 0-3 points). The item total score provides an additional measure of change, with the maximum possible score for each category being 3 points, and the total score being the sum of the category scores, resulting in a possible total score of 0-18 points, with higher scores indicating greater impairment. This overall score can be used as a clinical measure of dementia severity.

[0038] In some embodiments, the efficacy of treatment for Alzheimer's disease can be measured by any one or combination of medical observation, cognitive function assessment, medical diagnosis, and medical imaging. In some embodiments, the efficacy of treatment is determined by measuring tau spread by tau PET when an isolated anti-tau antibody or fragment thereof is administered in parallel with an isolated anti-Aβ protofibril antibody or fragment thereof from week 24 to week 104 and week 208.

[0039] In some embodiments, therapeutic efficacy in symptomatic patients is determined by measuring the change from baseline in Clinical Dementia Rating Scale Total Items (CDR-SB) after a treatment period when an isolated anti-tau antibody or fragment thereof is administered in parallel with an isolated anti-Aβ protofibril antibody or fragment thereof, e.g., the change from week 24 to week 208. In some embodiments, therapeutic efficacy in asymptomatic patients is determined by measuring the change in cerebrospinal fluid (CSF) phosphorylated tau (p-tau217) / total tau after a treatment period when an isolated anti-tau antibody or fragment thereof is administered alone and then in parallel with an isolated anti-Aβ protofibril antibody or fragment thereof, e.g., the change from week 0 to week 104 and / or week 208.

[0040] In some embodiments, therapeutic efficacy is determined in symptomatic patients by measuring at least one of the following: 1) the change after a treatment period in a cognitive function composite score when an isolated anti-tau antibody or isolated fragment thereof is administered in combination with an isolated anti-Aβ protofibril antibody or fragment thereof, e.g., the change from week 24 to week 104 and / or week 208; 2) the change after a treatment period to assess the effect of an isolated anti-Aβ protofibril antibody or fragment thereof when administered alone, e.g., the change from week 0 to week 24. 3) change in amyloid PET from week 24 to week 104 and / or week 208 after a treatment period when an anti-tau antibody or fragment thereof is administered in combination with an anti-Aβ protofibril antibody or fragment thereof, e.g., change after 24 weeks; and 4) change in CSF neurofilament light chain (NFL) from week 24 to week 104 and / or week 208 after a treatment period when an anti-tau antibody or fragment thereof is administered in combination with an anti-Aβ protofibril antibody or fragment thereof, e.g., change from week 24 to week 104 and week 208.

[0041] In some embodiments, efficacy of treatment in asymptomatic patients is determined by measuring at least one of the following: 1) change after a treatment period when an anti-tau antibody or fragment thereof is administered alone, e.g., change in CSF p-tau217 / total tau from week 0 to week 52; 2) change after a treatment period when an anti-tau antibody or fragment thereof is administered in combination with an anti-Aβ protofibril antibody or fragment thereof, e.g., change in CSF p-tau217) / total tau from week 52 to week 104 and / or week 208; 3) production of anti-anti-tau antibodies after a treatment period, e.g., over 52 weeks, when an anti-tau antibody or fragment thereof is administered alone; 4) change after a treatment period in CSF neurofilament light chain (NFL), e.g., change from week 52 to week 104 and / or week 208, when an anti-tau antibody or fragment thereof is administered in combination with an anti-Aβ protofibril antibody or fragment thereof.

[0042] Anti-Aβ protofibril antibody or antigen-binding fragment thereof The methods, kits and combinations disclosed herein include anti-Aβ protofibril antibodies or antigen-binding fragments thereof capable of binding to human Aβ protofibrils.

[0043] In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2), SEQ ID NO:3 (HCDR3), SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3). See, for example, Table 11. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) from the heavy chain variable domain of SEQ ID NO:13 and the light chain variable domain of SEQ ID NO:14 (e.g., as defined by Kabat or IMGT). In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril comprises a heavy chain variable domain of SEQ ID NO: 13 and a light chain variable domain of SEQ ID NO: 14. See, e.g., Table 12.

[0044] In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril comprises a human constant region. In some embodiments, the human constant region of the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variants thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the heavy chain constant region comprises SEQ ID NO: 17.

[0045] In some embodiments, the human constant region of the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof comprises a light chain constant region selected from the kappa and lambda chain constant regions and any allelic variants thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the light chain constant region comprises SEQ ID NO: 18.

[0046] In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibrils is lecanemab, also known as BAN2401. Lecanemab is a humanized IgG1 monoclonal version of mAb158, a murine monoclonal antibody designed to target protofibrils, and is disclosed in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015). Lecanemab is an isolated anti-Aβ protofibril antibody that demonstrates low affinity for Aβ monomers while binding with high selectivity to soluble Aβ aggregate species. For example, lecanemab has been reported to demonstrate approximately 1000-fold and 5-fold to 10-fold higher selectivity for soluble Aβ protofibrils over Aβ monomers or Aβ insoluble fibrils, respectively. The full-length sequence of lecanemab is shown in WO 2007 / 108756 and in Journal of Alzheimer's Disease 43:575-588 (2015), the disclosures of both of which are incorporated herein by reference.

[0047] In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered twice a day. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered once a day. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered weekly. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered twice a week. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered three times a week. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered every two weeks. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered monthly.

[0048] In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose ranging from 3 mg / kg to 30 mg / kg. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 5 mg / kg to 30 mg / kg. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 10 mg / kg to 30 mg / kg. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 15 mg / kg to 30 mg / kg. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 20 mg / kg to 30 mg / kg. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 25 mg / kg to 30 mg / kg. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 5 mg / kg to 25 mg / kg. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 5 mg / kg to 20 mg / kg. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 5 mg / kg to 15 mg / kg. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 5 mg / kg to 10 mg / kg. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, or 30 mg / kg.In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at a dose of 10 mg / kg.

[0049] In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril (e.g., lecanemab) is administered at a dose of 10 mg / kg every two weeks.

[0050] In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered until a change in the level of the biomarker in the sample is observed compared to the ratio in a sample taken from the subject prior to administration (e.g., until an increase in the Aβ42 / 40 ratio is observed in the plasma or CSF sample). Methods for measuring the Aβ42 / 40 ratio are known in the art, such as assays using LC MS / MS. Methods can include the PrecivityAD™ assay (see, e.g., Kirmess et al., J. Clinica Chimica Acta 519:267-275 (2021)) and immunoassays using the HISCL™ platform (https: / / www.eisai.com / news / 2019 / news201990.html) for measuring Aβ42 and Aβ40 in the sample used to calculate the ratio.

[0051] In some embodiments, the biomarker is brain amyloid levels, for example, as measured by PET SUVr. Methods for calculating PET SUVr are known in the art and may include those described herein. In some embodiments, standard uptake value ratio quantitative analysis of amyloid levels is completed using PMOD Biomedical Image Quantification Software (PMOD Technologies, Zurich, Switzerland). In some embodiments, the PET images are first determined for subject motion in the X, Y, and Z planes, and motion is corrected as necessary, after which the individual images (e.g., 5-minute radiometric frames) are averaged (PET frames are averaged to increase signal-to-noise ratio), for example, using the PMOD averaging function. In some embodiments, a corresponding MRI from the subject is prepared (e.g., using a matrix size reduction process, cropping the MRI to include only the brain, segmentation to separate the image into binary maps of gray matter, white matter, and CSF, and stripping the image of the skull leaving only the brain mask). In some embodiments, the averaged PET images and the prepared MRI are matched using the PMOD matching function to place the images in the same orientation. In some embodiments, for example, the Brain Normalization function as provided by the PMOD software is used with the Brain Norm and Rigid Matching transformation matrix to generate an averaged PET. In some embodiments, this averaged PET, which is normalized to MNInst space (Senjem et al, 2005), is in the same orientation as the subject's segmented MRI for quantitative analysis. In some embodiments, the brain is masked using the PMOD Mask Function, and the images are zeroed outside the mask to create a normalized gray matter PET and a normalized white matter PET. Standard uptake values ​​(SUVs) for all gray matter mapping regions and three white matter regions (pons, cerebellar white matter, and subcortical white matter) may be calculated using the PMOD software, calculated using the normalized PET, subject's weight, and tracer injection dose to arrive at units of SUV.In some embodiments, SUVr is the ratio of the total cortical mean compared to the selected reference region.In some embodiments, the whole cerebellum mask is used as the reference region.In some embodiments, the reference region is a composite reference region consisting of subcortical white matter, whole cerebellum of origin, whole cerebellum adjusted by subcortical white matter, cerebellar gray matter, and cerebellar cortex, pontine subcortical white matter and cerebellar white matter.

[0052] In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprising the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered with one or more syringes and / or autoinjectors. In some embodiments, administration is by any suitable route, for example, intravenously.

[0053] Lecanemab and methods involving the use of lecanemab are disclosed in U.S. Provisional Patent Application No. 62 / 749,614 and PCT / US2019 / 043067, both of which are incorporated by reference in their entireties.

[0054] Methods involving the use of lecanemab in subjects with preclinical AD are disclosed in Clinical Trial Identification Number NCT04468659 (ClinicalTrials.gov), which is incorporated herein by reference in its entirety.

[0055] Anti-tau antibody or antigen-binding fragment thereof The methods, kits and combinations disclosed herein include anti-tau antibodies or antigen-binding fragments thereof capable of binding to human tau.

[0056] In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) comprising the amino acid sequences of SEQ ID NO:7 (HCDR1), SEQ ID NO:8 (HCDR2), SEQ ID NO:9 (HCDR3), SEQ ID NO:10 (LCDR1), SEQ ID NO:11 (LCDR2) and SEQ ID NO:12 (LCDR3) as defined by Kabat. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau comprises six CDRs (CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) comprising the amino acid sequences of SEQ ID NO:24 (HCDR1), SEQ ID NO:25 (HCDR2), SEQ ID NO:26 (HCDR3), SEQ ID NO:27 (LCDR1), SEQ ID NO:28 (LCDR2) and SEQ ID NO:29 (LCDR3) as defined by IMGT. See, for example, Table 11. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau comprises six CDRs (CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) comprising the amino acid sequences of SEQ ID NO:24 (HCDR1), SEQ ID NO:25 (HCDR2), SEQ ID NO:26 (HCDR3), SEQ ID NO:27 (LCDR1), SEQ ID NO:28 (LCDR2) and SEQ ID NO:29 (LCDR3) as defined by IMGT. The selected anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau comprises the six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3) from the heavy chain variable domain of SEQ ID NO: 15 and the light chain variable domain of SEQ ID NO: 16 (e.g., as defined by Kabat or IMGT). In some embodiments, the anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau comprises the heavy chain variable domain of SEQ ID NO: 15 and the light chain variable domain of SEQ ID NO: 16. See, for example, Table 12.

[0057] In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau comprises a human constant region. In some embodiments, the human constant region comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE and any allelic variants thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the heavy chain constant region comprises SEQ ID NO: 19.

[0058] In some embodiments, the human constant region of the isolated anti-tau antibody or antigen-binding fragment thereof comprises a light chain constant region selected from the kappa and lambda chain constant regions and any allelic variants thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the light chain constant region comprises SEQ ID NO:20.

[0059] In some embodiments, the anti-tau antibody or antigen-binding fragment comprises E2814 or an antigen-binding fragment thereof, which is disclosed in US Patent Application Publication No. 2019 / 0112364 A1 as clone 7G6-HCzu25 / LCzu18, the sequence of which is incorporated herein by reference.

[0060] In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is any of those disclosed in U.S. Patent Application Publication No. 2019 / 0112364 A1, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof comprises CDR and / or variable domain sequences from antibody clone 7G6-HCzu25 / LCzu18 as disclosed in U.S. Patent Application Publication No. 2019 / 0112364 A1, the sequences of which are incorporated herein by reference. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is produced by an antibody-producing cell deposited on October 11, 2017 at the American Type Culture Collection, 10801 University Blvd., Manassas, Va. 20110-2209, under accession number PTA-124524.

[0061] In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered twice daily. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered once daily. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered weekly. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered twice weekly. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered three times weekly. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered every two weeks. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered every four weeks or monthly.

[0062] In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered in a dose ranging from 200 mg to 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered in a dose of 500 mg to 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered in a dose of 1000 mg to 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered in a dose of 1500 mg to 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered in a dose of 3000 mg to 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered in a dose of 200 mg to 3000 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered in a dose of 200 mg to 1500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered in a dose of 200 mg to 1000 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 200 mg to 500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 200 mg, 500 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, or 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 1500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 3000 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 4500 mg. For further information regarding the dosing and dosage forms of anti-tau antibodies or antigen-binding fragments thereof that may be used in the methods disclosed herein, such as anti-tau antibody E2814, reference may be made to International Application PCT / IB2022 / 060604, the contents of which are incorporated herein by reference in their entirety.

[0063] In some embodiments, the anti-tau antibody is E2814 or an antigen-binding fragment thereof, administered at a dose of 3000 mg, for example, once every four weeks.

[0064] In some embodiments, an isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered in combination with an isolated anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau, where the isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered every two weeks at a dose of 10 mg / kg and the isolated anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau is administered every four weeks at a dose of 1500 mg or 3000 mg.

[0065] In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered until a change in the level of the biomarker in the sample is observed compared to the level in a sample taken from the subject prior to administration (e.g., until a decrease in phosphorylated tau 217 is observed in a plasma sample). In some embodiments, p-tau 217 can be measured in a sample taken from the subject at one time point, and a second sample can be taken from the subject at a later time point to measure the change in p-tau 217 in the subject. In some embodiments, the level of p-tau 217 in a sample taken from the subject after administration is decreased compared to the level of phosphorylated tau 217 in a sample taken from the subject prior to administration.

[0066] In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered in an increased dose due to an increase in the amount of p-tau 217 in the subject. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered in a decreased dose due to a decrease in the amount of p-tau 217 in the subject. Methods for measuring phosphorylated tau 217 in plasma are known in the art, such as immunoassays. Tatebe et al., Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology, 12 MOLECULAR NEURODEGENERATION 63 (Sept. 4, 2017).

[0067] In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered until a change in tau spread is detected as measured by PET. In some embodiments, tau PET can be used to confirm the presence and / or measure the amount of tau in the brain of an AD subject. In some embodiments, a tau PET scan can be taken at one time point and a second tau PET scan can be taken at a later time point to measure the subject's tau spread. In some embodiments, the administration of the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is increased because tau spread is observed in the patient as measured by PET. In some embodiments, the tau PET is MK-6240 tau PET.

[0068] Administration In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered at the same time as the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered from the same vial as the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered from a different vial than the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau.

[0069] In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered for a period of time prior to administration of the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered for a period of time prior to administration of the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered for 52 weeks prior to administration of the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril. In some embodiments, the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered for 24 weeks prior to administration of the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau.

[0070] In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril are administered during the same clinical visit. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril are administered during separate clinical visits. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril are administered intravenously to the subject. In some embodiments, the timing of administration of the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril depends on whether the person is symptomatic for Alzheimer's disease or asymptomatic for Alzheimer's disease.

[0071] In some embodiments, a patient symptomatic for Alzheimer's disease is administered an isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril prior to being administered an isolated anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau. In some embodiments, a patient symptomatic for Alzheimer's disease is administered an isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril for 24 weeks before the isolated anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau is administered in conjunction with the isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril. In some embodiments, a patient symptomatic for Alzheimer's disease is administered an isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril for 24 weeks, followed by administration of an isolated anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau in combination with an isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril from weeks 24 to 52 and / or from weeks 24 to 208.

[0072] In some embodiments, a patient asymptomatic for Alzheimer's disease is administered an isolated anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau prior to being administered an isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril. In some embodiments, a patient asymptomatic for Alzheimer's disease is administered an isolated anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau for 52 weeks prior to being administered an isolated anti-tau antibody or an antigen-binding fragment thereof capable of binding to human tau in combination with an isolated anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril. In some embodiments, a patient who is asymptomatic with respect to Alzheimer's disease is administered an isolated anti-tau antibody, or an antigen-binding fragment thereof, capable of binding to human tau, for 52 weeks, and then from week 52 to week 208, the isolated anti-tau antibody, or an antigen-binding fragment thereof, capable of binding to human tau is administered in combination with an isolated anti-Aβ protofibril antibody, or an antigen-binding fragment thereof, capable of binding to human Aβ protofibril.

[0073] Family History and Dominant Alzheimer's Disease In some embodiments, the subject has a family history of Alzheimer's disease, for example, a relative diagnosed with Alzheimer's disease before age 60.

[0074] In some embodiments, the subject has dominantly inherited Alzheimer's disease (DIAD). In some embodiments, the subject has a mutation in at least one of three genes: amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2). In some embodiments, the subject has a mutation in the APP gene. In some embodiments, the subject has a mutation in the PSEN1 gene. In some embodiments, the subject has a mutation in the PSEN2 gene. Specific mutations in the APP, PSEN1, or PSEN2 genes that contribute to DIAD are known in the art (e.g., Cruts & Van Broeckhoven, 1998; Cruts, Theuns, & Van Broeckhoven, 2012; Ryman et al., 2014; Sherva & Kowall, 2018).

[0075] Treatment outcomes In some embodiments, the subject's CDR-SB score is improved compared to the score before administration of the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and / or the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril according to the methods of treatment disclosed herein. In some embodiments, the subject's ADAS-cog score is improved compared to the score before administration of the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and / or the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril according to the methods of treatment disclosed herein. In some embodiments, the subject's MMSE is improved compared to the score before administration of the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and / or the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril according to the methods of treatment disclosed herein. In some embodiments, the subject's CDR score is improved compared to the score prior to administration of the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and / or the isolated anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril according to the methods of treatment disclosed herein.

[0076] Pharmaceutical Combinations and Kits In some embodiments, the isolated anti-tau antibodies or antigen-binding fragments thereof capable of binding to human tau and / or the isolated anti-Aβ protofibril antibodies or antigen-binding fragments thereof capable of binding to human Aβ protofibrils described herein are provided in the form of a pharmaceutical combination. In some embodiments, the isolated anti-tau antibodies or antigen-binding fragments thereof capable of binding to human tau and / or the isolated anti-Aβ protofibril antibodies or antigen-binding fragments thereof capable of binding to human Aβ protofibrils described herein are provided in the form of a kit, e.g., comprising one or more vials containing the antibodies or antigen-binding fragments and instructions for administration, e.g., co-administration. In some embodiments, the antibodies or antigen-binding fragments of the kit are formulated for administration, e.g., intravenous administration, e.g., formulated as disclosed above.

[0077] Subcutaneous In some embodiments, the subject is administered a dose of an anti-Aβ protofibril antibody or antigen-binding fragment thereof subcutaneously. For example, the subject may be administered 400 mg to 800 mg or 400 mg to 1500 mg, such as 720 mg, of an anti-Aβ protofibril antibody or antigen-binding fragment thereof. The antibody may be lecanemab. The antibody may be administered at a particular frequency, such as twice weekly, weekly (QW), biweekly (every 2 weeks or Q2W), or monthly, for a period of time, such as at least 52 weeks or 18 months, or until a particular criterion (e.g., a particular behavioral and / or biomarker criterion) is reached. In some embodiments, the subject is then administered a maintenance dose of an anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril, for example, at a particular frequency and for a period of time or until a particular criterion is reached. The dose, frequency, duration of administration, and criteria may or may not be the same as the previous treatment dose, frequency, duration of administration, and / or criteria.

[0078] In some embodiments, the therapeutic dose is administered in two simultaneous or sequential subcutaneous injections every week, for example at a total dose of 720 mg per week. In some embodiments, the treatment is for at least 52 weeks or at least 18 months. In some embodiments, the treatment is administered by subcutaneous injection. In some embodiments, the treatment is administered by a subcutaneous autoinjector.

[0079] In some embodiments, after a period of receiving a therapeutic dose (e.g., two simultaneous or sequential subcutaneous injections, e.g., at a total dose of 720 mg per week), e.g., after 18 months, a maintenance dose is administered, e.g., subcutaneously, e.g., twice weekly or weekly, e.g., at 720 mg per dose. In some embodiments, two or more therapeutic doses and two or more maintenance doses of an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril are administered, and the maintenance doses are administered lower and / or less frequently than the therapeutic doses. In some embodiments, criteria for switching to a maintenance dose or selecting a lower or less frequent maintenance dose can include changes in biomarkers, such as an increase in the Aβ42 / 40 ratio observed in a sample (e.g., a plasma sample) compared to the ratio in a sample taken from the subject before treatment, a decrease in p-tau217 or p-tau181 levels in a sample taken from the subject after treatment, and / or a decrease in amyloid PET SUVr after treatment.

[0080] In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered with one or more syringes and / or autoinjectors. In some embodiments, the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered in the abdominal region.

[0081] In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of at least 80 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of at least 100 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of at least 200 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of at least 250 mg / mL. In some embodiments, the antibody is present in the pharmaceutical composition at a concentration of 80 mg / mL to 300 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of 85 mg / mL to 275 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of 90 mg / mL to 250 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of 95 mg / mL to 225 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of 100 mg / mL to 200 mg / mL.In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibrils is present in the pharmaceutical composition at a concentration of 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, or 300 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibrils is present in the pharmaceutical composition at a concentration of 100 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of 200 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of 250 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is present in the pharmaceutical composition at a concentration of 300 mg / mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is lecanemab.

[0082] In some embodiments, the pharmaceutical composition comprising an anti-Aβ protofibril antibody or an antigen-binding fragment thereof further comprises at least one additional component. In some embodiments, the at least one additional component in the pharmaceutical composition is selected from a pharma- ceutically acceptable buffer. In some embodiments, the pharma- ceutically acceptable buffer is a citrate buffer. In some embodiments, the pharma- ceutically acceptable buffer is a histidine buffer. In some embodiments, the at least one additional component in the pharmaceutical composition is selected from an emulsifier. In some embodiments, the at least one additional component in the pharmaceutical composition is selected from citric acid (or citric acid monohydrate), sodium chloride, histidine (and / or histidine hydrochloride), arginine (and / or arginine hydrochloride), and polysorbate 80. In some embodiments, the at least one additional component in the pharmaceutical composition is selected from citric acid (and / or citric acid monohydrate), arginine (and / or arginine hydrochloride), and polysorbate 80. In some embodiments, the at least one additional ingredient in the pharmaceutical composition is selected from histidine (and / or histidine hydrochloride), arginine (and / or arginine hydrochloride), and polysorbate 80.

[0083] In some embodiments, the pharmaceutical composition comprising an anti-Aβ protofibril antibody or antigen-binding fragment thereof comprises arginine (and / or arginine hydrochloride). In some embodiments, the concentration of arginine (and / or arginine hydrochloride) in the pharmaceutical composition is in the range of 100 mM to 400 mM. In some embodiments, the concentration of arginine (and / or arginine hydrochloride) in the pharmaceutical composition is in the range of 110 mM to 380 mM, 120 mM to 360 mM, 125 mM to 350 mM, 140 mM to 340 mM, 160 mM to 325 mM, 175 mM to 300 mM, or 200 mM to 250 mM. In some embodiments, the concentration of arginine (and / or arginine hydrochloride) in the pharmaceutical composition is in the range of 110 mM to 150 mM, 150 mM to 200 mM, 200 mM to 250 mM, 250 mM to 300 mM, 300 mM to 350 mM, or 350 mM to 380 mM. In some embodiments, the concentration of arginine (and / or arginine hydrochloride) is 125 mM. In some embodiments, the concentration of arginine (and / or arginine hydrochloride) is 200 mM. In some embodiments, the concentration of arginine (and / or arginine hydrochloride) is 350 mM.

[0084] In some embodiments, the pharmaceutical composition comprising an anti-Aβ protofibril antibody or an antigen-binding fragment thereof comprises histidine. In some embodiments, the concentration of histidine in the pharmaceutical composition is in the range of 10 mM to 100 mM. In some embodiments, the concentration of histidine in the pharmaceutical composition is in the range of 10 mM to 100 mM, 12 mM to 80 mM, 14 mM to 60 mM, 15 mM to 55 mM, 15 mM to 35 mM, or 15 mM to 25 mM. In some embodiments, the concentration of histidine is 25 mM. In some embodiments, the concentration of histidine is 50 mM.

[0085] In some embodiments, the pharmaceutical composition comprising an anti-Aβ protofibril antibody or antigen-binding fragment thereof comprises polysorbate 80. In some embodiments, the concentration of polysorbate 80 in the pharmaceutical composition ranges from 0.01-0.1% w / v, 0.01-0.08% w / v, 0.02-0.08% w / v, 0.03-0.07% w / v, or 0.04-0.06% w / v. In some embodiments, polysorbate 80 is present in the pharmaceutical composition at a concentration of 0.01% w / v, 0.02% w / v, 0.03% w / v, 0.04% w / v, 0.05% w / v, 0.06% w / v, 0.07% w / v, or 0.08% w / v. In some embodiments, polysorbate 80 is present in the pharmaceutical composition at a concentration of 0.02% w / v. In some embodiments, polysorbate 80 is present in the pharmaceutical composition at a concentration of 0.05% w / v.

[0086] In some embodiments, the pharmaceutical composition comprising an anti-Aβ protofibril antibody or an antigen-binding fragment thereof comprises citric acid monohydrate. In some embodiments, the concentration of citric acid monohydrate in the pharmaceutical composition is in the range of 10 mM to 100 mM. In some embodiments, the concentration of citric acid monohydrate in the pharmaceutical composition is in the range of 10 mM to 100 mM, 10 mM to 90 mM, 15 mM to 85 mM, 20 mM to 80 mM, 25 mM to 75 mM, 30 mM to 70 mM, 30 mM to 60 mM, or 30 mM to 50 mM. In some embodiments, the concentration of citric acid monohydrate in the pharmaceutical composition is 50 mM.

[0087] In some embodiments, the pharmaceutical composition comprising an anti-Aβ protofibril antibody or antigen-binding fragment thereof has a pH in the range of 4.5 to 5.5. In some embodiments, the pH of the pharmaceutical composition is in the range of 4.0 to 6.0, 4.2 to 5.8, 4.3 to 5.7, 4.4 to 5.6, or 4.5 to 5.5. In some embodiments, the pH is 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. In some embodiments, the pH is 5.0.

[0088] In some embodiments, the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof may be in the form of a solution and / or any other suitable liquid formulation deemed appropriate by the skilled artisan. In some embodiments, the pharmaceutical composition is formulated as a sterile, nonpyrogenic liquid for subcutaneous administration. In some embodiments, the pharmaceutical composition is a saline solution.

[0089] In some embodiments, the pharmaceutical composition comprising an anti-Aβ protofibril antibody or antigen-binding fragment thereof is a liquid dosage form that comprises an anti-Aβ protofibril antibody that binds to Aβ protofibrils, such as lecanemab, or an antigen-binding fragment thereof capable of binding to human Aβ protofibrils, and further comprises, e.g., citric acid monohydrate, arginine, arginine hydrochloride, and polysorbate 80.

[0090] In some embodiments, the pharmaceutical composition comprises 100 mg / mL of an anti-Aβ protofibril antibody or antigen-binding fragment thereof, such as lecanemab, 50 mM citric acid monohydrate, 110 mM arginine, 240 mM arginine hydrochloride, and 0.05% (w / v) polysorbate 80, and has a pH of 5.0±0.4.

[0091] In some embodiments, the pharmaceutical composition comprising an anti-Aβ protofibril antibody or antigen-binding fragment thereof is a liquid dosage form that comprises an anti-Aβ protofibril antibody that binds to Aβ protofibrils, such as lecanemab, and further comprises, for example, histidine, histidine hydrochloride, arginine hydrochloride, and polysorbate 80. In some embodiments, the pharmaceutical composition comprises an anti-Aβ protofibril antibody that binds to Aβ protofibrils, such as lecanemab, at 100 mg / mL or 200 mg / mL, 25 mM histidine and histidine hydrochloride, 200 mM arginine hydrochloride, and 0.05% (w / v) polysorbate 80, and has a pH of 5.0±0.4. In some embodiments, the pharmaceutical composition comprises 200 mg / mL lecanemab, 200 mM arginine, 25 mM histidine and histidine hydrochloride, 0.05% (w / v) polysorbate 80 in a sterile aqueous solution.

[0092] In some embodiments, the pharmaceutical composition is a liquid dosage form comprising an anti-Aβ protofibril antibody that binds to Aβ protofibrils, such as lecanemab, and further comprising, for example, histidine, histidine hydrochloride, arginine hydrochloride, and polysorbate 80. In some embodiments, the pharmaceutical composition comprises an anti-Aβ protofibril antibody that binds to Aβ protofibrils, such as lecanemab at 200 mg / mL, 50 mM histidine and histidine hydrochloride, 125 mM arginine hydrochloride, and 0.02% (w / v) polysorbate 80, and has a pH of 5.0±0.4.

[0093] In some embodiments, the pharmaceutical composition is a liquid dosage form comprising an anti-Aβ protofibril antibody that binds to Aβ protofibrils, such as lecanemab, and further comprising, for example, histidine, histidine hydrochloride, arginine hydrochloride, and polysorbate 80. In some embodiments, the pharmaceutical composition comprises an anti-Aβ protofibril antibody that binds to Aβ protofibrils, such as lecanemab at 200 mg / mL, 50 mM citric acid (and / or citric acid monohydrate), 125 mM arginine (and / or arginine hydrochloride), and 0.02% (w / v) polysorbate 80, and has a pH of 5.0±0.4.

[0094] Exemplary formulations for subcutaneous administration are also disclosed in PCT / IB2021 / 000155, the contents of which are incorporated by reference in their entirety.

[0095] As used herein, the term "maintenance dose" refers to a dosage administered to a subject to maintain a desired therapeutic effect. In some embodiments, the maintenance dose for a subject is the same as the dose during the treatment period. In some embodiments, the maintenance dose is administered subcutaneously. In some embodiments, the maintenance dose is administered one or more times. In some embodiments, the maintenance dose is administered weekly, every 2 weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 10 weeks, every 12 weeks (every 3 months or quarter year), every 16 weeks, every 24 weeks (every 6 months or half year), every 48 weeks, every month, every 2 months, every 3 months, every 4 months, every 6 months, or every 12 months. In some embodiments, the maintenance dose comprises an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril. In some embodiments, the maintenance dose is 300mg to 800mg, 300mg to 400mg, 400mg to 500mg, 400mg to 450mg, 450mg to 500mg, 500mg to 600mg, 500mg to 550mg, 550mg to 600mg, 600mg to 700mg, 600mg to 650mg, 650mg to 700mg, 700mg to 800mg, 700mg to 750mg, or 750mg to 800mg. In some embodiments, the maintenance dose is 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, or 390mg. In some embodiments, the maintenance dose is 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, or 490mg. In some embodiments, the maintenance dose is 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, or 590mg. In some embodiments, the maintenance dose is 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, or 690mg. In some embodiments, the maintenance dose is 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, 760mg, 770mg, 780mg, or 790mg.In some embodiments, the maintenance dose is 800mg to 1600mg, 800mg to 1000mg, 800mg to 900mg, 900mg to 1000mg, 1000mg to 1200mg, 1000mg to 1100mg, 1100mg to 1200mg, 1200mg to 1400mg, 1200mg to 1300mg, 1300mg to 1400mg, 1400mg to 1600mg, 1400mg to 1500mg, or 1500mg to 16000mg. In some embodiments, the maintenance dose is 800mg, 820mg, 840mg, 860mg, 880mg, 900mg, 920mg, 940mg, 960mg, or 980mg. In some embodiments, the maintenance dose is 1000mg, 1020mg, 1040mg, 1060mg, 1080mg, 1100mg, 1120mg, 1140mg, 1160mg, or 1180mg. In some embodiments, the maintenance dose is 1200mg, 1220mg, 1240mg, 1260mg, 1280mg, 1300mg, 1320mg, 1340mg, 1360mg, or 1380mg. In some embodiments, the maintenance dose is 1400mg, 1420mg, 1440mg, 1460mg, 1480mg, 1500mg, 1520mg, 1540mg, 1560mg, or 1580mg. In some embodiments, the maintenance dose is provided in a single dose, e.g., administered as a single subcutaneous injection of 1440 mg, or in two or more doses, two doses of 720 mg for a total of 1440 mg, or four doses of 360 mg for a total of 1440 mg. In some embodiments, the maintenance dose is 3600 mg. In some embodiments, the maintenance dose is 440 mg. In some embodiments, the maintenance dose is 580 mg. In some embodiments, the maintenance dose is 720 mg. In some embodiments, the 720 mg maintenance dose is provided in a single dose, or in two doses of 360 mg. In some embodiments, the maintenance dose is 1440 mg. In some embodiments, the maintenance dose is provided in a single dose, e.g., administered as a single subcutaneous injection of 720 or 1440 mg, or in two or more doses, e.g., two parallel 360 mg doses for a total of 720 mg, or two 720 mg doses for a total of 1440 mg, or four 360 mg doses for a total of 1440 mg.In some embodiments, the maintenance dose is 120 mg. In some embodiments, the maintenance dose is 180 mg. In some embodiments, the maintenance dose is 240 mg. In some embodiments, the maintenance dose is 360 mg. In some embodiments, the maintenance dose is 440 mg. In some embodiments, the maintenance dose is 480 mg. In some embodiments, the maintenance dose is 540 mg. In some embodiments, the maintenance dose is 440 mg. In some embodiments, the maintenance dose is 580 mg. In some embodiments, the maintenance dose is 600 mg. In some embodiments, the maintenance dose is 720 mg. In some embodiments, the maintenance dose is 840 mg. In some embodiments, the maintenance dose is 900 mg. In some embodiments, the maintenance dose is 960 mg. In some embodiments, the maintenance dose is 1080 mg. In some embodiments, the maintenance dose is 1200 mg. In some embodiments, the maintenance dose is 1260 mg. In some embodiments, the maintenance dose is 1320 mg. In some embodiments, the maintenance dose is 1440 mg. In some embodiments, the maintenance dose is administered as a weekly 720 mg subcutaneous injection. In some embodiments, the maintenance dose is administered as a weekly 720 mg subcutaneous injection, including two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., sequential injections. In some embodiments, the maintenance dose is administered as a biweekly 720 mg subcutaneous injection. In some embodiments, the maintenance dose is administered as a biweekly 720 mg subcutaneous injection, including two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., sequential injections. In some embodiments, the maintenance dose is administered as a biweekly 1440 mg subcutaneous injection. In some embodiments, the maintenance dose is provided in a single biweekly administration of 1440 mg, including two parallel administrations of, e.g., two sequential administrations of 720 mg of a subcutaneous formulation totaling 1440 mg or four sequential administrations of 360 mg totaling 1440 mg.

[0096] In some embodiments, the maintenance dose is administered one or more times, hi some embodiments, the maintenance dose is administered at a lower dose and / or less frequently than during the initial course of treatment.

[0097] In some embodiments, the therapeutic dose is administered as a subcutaneous injection. In some embodiments, the therapeutic dose is administered as a weekly subcutaneous injection. In some embodiments, the therapeutic dose is administered as a biweekly subcutaneous injection. In some embodiments, the therapeutic dose is administered as a monthly subcutaneous injection. In some embodiments, the therapeutic dose is administered as a quarter-yearly subcutaneous injection.

[0098] In some embodiments, the maintenance dose is administered as a subcutaneous injection. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a biweekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a monthly subcutaneous injection. In some embodiments, the maintenance dose is administered as a quarter-yearly subcutaneous injection.

[0099] In some embodiments, the frequency of the maintenance dose is weekly. In some embodiments, the maintenance dose is every 2 weeks (biweekly). In some embodiments, the maintenance dose is every 4 weeks (monthly). In some embodiments, the subcutaneous maintenance dose is administered every 6 weeks. In some embodiments, the subcutaneous maintenance dose is administered every 8 weeks (2 months). In some embodiments, the maintenance dose is every 3 months (every 12 weeks or quarter yearly). In some embodiments, the maintenance dose is every 6 months (every 24 weeks or half yearly). In some embodiments, the maintenance dose of the subject is the same as the dose during the treatment period. In some embodiments, the maintenance dose is the same dose size as the dose before the maintenance dose is administered. In some embodiments, the maintenance dose size is a lower dose than the dose before the maintenance dose is administered. In some embodiments, the maintenance dose is the same dose frequency as the dose before the maintenance dose is administered. In some embodiments, the maintenance dose is a lower dose frequency than the dose before the maintenance dose is administered.

[0100] In some embodiments, the maintenance dose is administered as a subcutaneous injection of an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibrils. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection of a subcutaneous formulation of an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibrils. In some embodiments, the maintenance dose is administered as a weekly 720 mg subcutaneous injection with two parallel injections of a subcutaneous formulation of 360 mg (2×1.8 mL of 400 mg / 2 mL), e.g., sequential injections. In some embodiments, the maintenance dose is administered as a monthly 720 mg subcutaneous injection with two parallel injections of a subcutaneous formulation of 360 mg (2×1.8 mL of 400 mg / 2 mL), e.g., sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a 720 mg subcutaneous injection every quarter year, including sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a 720 mg subcutaneous injection every two weeks, including sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a 720 mg subcutaneous injection every month, including sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a 720 mg subcutaneous injection every quarter year, including sequential injections. In some embodiments, the subcutaneous maintenance dose is administered weekly. In some embodiments, the subcutaneous maintenance dose is administered every two weeks. In some embodiments, the subcutaneous maintenance dose is administered every four weeks (monthly). In some embodiments, the subcutaneous maintenance dose is administered every six weeks. In some embodiments, the subcutaneous maintenance dose is administered every eight weeks (two months). In some embodiments, the subcutaneous maintenance dose is administered every three months (every twelve weeks or quarter year).In some subcutaneous embodiments, the maintenance dose is administered every week, every 2 weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 10 weeks, every 12 weeks, every 16 weeks, every 24 weeks, every 48 weeks, every month, every 2 months, every 3 months, every 4 months, every 6 months, or every 12 months. In some embodiments, the subcutaneous maintenance dose comprises an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril at a dose of 300 mg to 800 mg, 300 mg to 400 mg, 400 mg to 500 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 600 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 700 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 800 mg, 700 mg to 750 mg, or 750 mg to 800 mg. In some embodiments, the maintenance dose is 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, or 390 mg. In some embodiments, the maintenance dose is 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, or 490mg. In some embodiments, the maintenance dose is 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, or 590mg. In some embodiments, the maintenance dose is 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, or 690mg. In some embodiments, the maintenance dose is 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, 760mg, 770mg, 780mg, or 790mg. In some embodiments, the maintenance dose is 800mg to 1600mg, 800mg to 1000mg, 800mg to 900mg, 900mg to 1000mg, 1000mg to 1200mg, 1000mg to 1100mg, 1100mg to 1200mg, 1200mg to 1400mg, 1200mg to 1300mg, 1300mg to 1400mg, 1400mg to 1600mg, 1400mg to 1500mg, or 1500mg to 16000mg.In some embodiments, the maintenance dose is 800mg, 820mg, 840mg, 860mg, 880mg, 900mg, 920mg, 940mg, 960mg, or 980mg. In some embodiments, the maintenance dose is 1000mg, 1020mg, 1040mg, 1060mg, 1080mg, 1100mg, 1120mg, 1140mg, 1160mg, or 1180mg. In some embodiments, the maintenance dose is 1200mg, 1220mg, 1240mg, 1260mg, 1280mg, 1300mg, 1320mg, 1340mg, 1360mg, or 1380mg. In some embodiments, the maintenance dose is 1400 mg, 1420 mg, 1440 mg, 1460 mg, 1480 mg, 1500 mg, 1520 mg, 1540 mg, 1560 mg, or 1580 mg. In some embodiments, the maintenance dose is provided in a single dose, e.g., administered as a single subcutaneous injection of 720 or 1440 mg, or administered in two or more doses, e.g., two parallel 360 mg doses totaling 720 mg, or two 720 mg doses totaling 1440 mg, or four 360 mg doses totaling 1440 mg. In some embodiments, the maintenance dose is 440 mg. In some embodiments, the maintenance dose is 580 mg. In some embodiments, the maintenance dose is administered as a single 720 mg dose or two 360 mg doses. In some embodiments, the maintenance dose is 1440 mg. In some embodiments, the maintenance dose is administered as a weekly 720 mg subcutaneous injection. In some embodiments, the maintenance dose is administered as a weekly 360 mg subcutaneous injection. In some embodiments, the maintenance dose is administered as a biweekly 720 mg subcutaneous injection. In some embodiments, the maintenance dose is administered as a biweekly 1440 mg subcutaneous injection. In some embodiments, the maintenance dose is provided in a single biweekly administration of 1440 mg, comprising two parallel, e.g. sequential, administrations of 720 mg subcutaneous formulations totaling 1440 mg.

[0101] In some embodiments, the treatment comprises subcutaneous administration of an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril, followed by switching to an intravenous maintenance dose. In some embodiments, the treatment comprises subcutaneous administration of lecanemab weekly, e.g., until the patient is amyloid negative or for a period of time, e.g., at least 18 months, e.g., two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL), e.g., 720 mg subcutaneous injections with sequential injections. In some embodiments, the treatment comprises subcutaneous administration of lecanemab weekly, e.g., at a dose of 720 mg, e.g., for at least 18 months or for at least 18 months, e.g., until the patient is amyloid negative, followed by switching to a maintenance dose. In some embodiments, the treatment comprises subcutaneous administration of lecanemab weekly, e.g., at a dose of 720 mg, e.g., for at least 18 months or for at least 18 months, e.g., until the patient is amyloid negative, followed by switching to an intravenous maintenance dose of 10 mg / kg weekly. In some embodiments, the treatment comprises administering lecanemab subcutaneously every week, e.g., at a dose of 720 mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by switching to an intravenous maintenance dose of 10 mg / kg every other week. In some embodiments, the treatment comprises administering lecanemab subcutaneously every week, e.g., at a dose of 720 mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by switching to an intravenous maintenance dose of 10 mg / kg every month. In some embodiments, the treatment comprises administering lecanemab subcutaneously every week, e.g., at a dose of 720 mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by switching to an intravenous maintenance dose of 10 mg / kg every 6 weeks. In some embodiments, the treatment comprises administering lecanemab subcutaneously every week, e.g., at a dose of 720 mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by switching to an intravenous maintenance dose of 10 mg / kg every 8 weeks.In some embodiments, the treatment includes administering lecanemab subcutaneously weekly, for example at a dose of 720 mg, for example for at least 18 months, or for example until the patient is amyloid negative, followed by switching to an intravenous maintenance dose of 10 mg / kg every quarter year. In some embodiments, the subject's maintenance dose is administered in the same amount and / or frequency as the dose during the treatment period. In some embodiments, the subject's maintenance dose is 50% of the dose during the treatment period.

[0102] In some embodiments, the maintenance dose is administered intravenously after an intravenous treatment period, for example as disclosed above. In some embodiments, the intravenous maintenance dose, for example a dose of 10 mg / kg lecanemab, is administered weekly, biweekly, monthly, bimonthly or trimonthly (quarter yearly). In some embodiments, the intravenous maintenance dose is administered every two weeks. In some embodiments, the intravenous maintenance dose is administered every four weeks. In some embodiments, the intravenous maintenance dose is administered every six weeks. In some embodiments, the intravenous maintenance dose is administered every eight weeks (two months). In some embodiments, the intravenous maintenance dose is administered every three months (quarter yearly). In some embodiments, the intravenous maintenance dose is administered every 24 weeks (six months or six months). In some embodiments, the intravenous maintenance dose is between 2.5 mg / kg and 10 mg / kg. In some embodiments, the maintenance dose is administered as a biweekly intravenous dose of 10 mg / kg lecanemab. In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 4 weeks (monthly). In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 6 weeks. In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 8 weeks (2 months). In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 12 weeks (every 3 months or every 4th year). In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 24 weeks (every 6 months or every 6 months). In some embodiments, the treatment comprises intravenously administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril at 10 mg / kg every other week, e.g., for at least 18 months or until, e.g., the patient becomes amyloid negative, followed by switching to a weekly intravenous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a biweekly intravenous maintenance dose.In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously at 10 mg / kg every other week, for example for at least 18 months or until, for example, the patient is amyloid negative, followed by switching to a monthly intravenous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously at 10 mg / kg every other week, for example for at least 18 months or until, for example, the patient is amyloid negative, followed by switching to a monthly intravenous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously at 10 mg / kg every other week, for example for at least 18 months or until, for example, the patient is amyloid negative, followed by switching to a monthly intravenous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg, for at least 18 months or, e.g., until the patient becomes amyloid negative, followed by switching to an intravenous maintenance dose every quarter year.

[0103] In some embodiments, the patient is started on an intravenous maintenance dose, e.g., a titration of 10 mg / kg lecanemab as disclosed above, followed by a subcutaneous maintenance dose, e.g., a subcutaneous injection of 720 mg, including two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., sequential injections. In some embodiments, the patient is started on a subcutaneous maintenance dose, e.g., a subcutaneous injection of 720 mg, including two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., sequential injections, followed by an intravenous maintenance dose, e.g., a titration of 10 mg / kg lecanemab as disclosed above.

[0104] In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously (SC). In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered in an injection having a volume of 1.1 mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered in an injection having a volume of 1.4 mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered in an injection having a volume of 1.45 mL. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered in an injection having a volume of 1.8 mL.

[0105] In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered once a day. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered twice a day. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered once or multiple times; for example, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered as a single dose of 720 mg or two doses of 720 mg for a total of 1440 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered once or multiple times; for example, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered as a single dose of 720 mg or two doses of 360 mg for a total of 720 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered weekly. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered twice weekly. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered three times weekly. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered every two weeks. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered monthly. In some embodiments, the dose size and / or dose frequency can be reduced after the desired therapeutic effect is achieved. The reduced frequency can be every two weeks or every four weeks, every six weeks, every eight weeks, every ten weeks, every twelve weeks, every sixteen weeks, every month, every two months, every three months, every four months, every six months, or every twelve months.In some embodiments, the desired therapeutic effect associated with a reduction in dose size or dose frequency may be one or more selected from reduction in brain amyloid achieving a sufficient or predetermined level, reduction in amyloid PET SUVr, increase in plasma Aβ42 / 40 ratio, reduction in plasma p-tau 181, and changes in other biomarkers correlated with reduction in brain amyloid. In some embodiments, when the desired therapeutic effect is maintained after a reduction in dose size or dose frequency, administration of the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibrils is discontinued. In some embodiments, administration of the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is interrupted if the desired therapeutic effect, which may be assessed by one or more selected from reduction in brain amyloid, reduction in amyloid PET SUVr, increase in plasma Aβ42 / 40 ratio, reduction in plasma p-tau181, and changes in other biomarkers correlated with reduction in brain amyloid, is not realized in the subject or is not expected to be at a sufficient or predetermined level.

[0106] In some embodiments, the treatment comprises administering lecanemab subcutaneously weekly, e.g., at a dose of 720 mg, e.g., for at least 18 months. In some embodiments, the treatment comprises administering lecanemab subcutaneously twice weekly, e.g., at 720 mg per dose, e.g., for at least 18 months. In some embodiments, the treatment continues until a desired improvement in one or more biomarkers or other treatment outcome measures is achieved, e.g., when an increase in the Aβ42 / 40 ratio is observed in a sample (e.g., a plasma sample) compared to the ratio in a sample taken from the subject before treatment, e.g., before 18 months of treatment. In some embodiments, the subject has been diagnosed with early AD. In some embodiments, the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease-moderately likely and / or has been diagnosed with mild Alzheimer's disease dementia.

[0107] In some embodiments, the treatment method includes determining a first ratio of Aβ42 to Aβ40 (Aβ42 / 40 ratio) by measuring the concentration of Aβ42 and the concentration of Aβ1-40 (Aβ40) in a first blood sample obtained from the subject. In some embodiments, the subject is then administered a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody. In some embodiments, a second blood sample is obtained after the first sample and a second Aβ42 / 40 ratio is determined. In some embodiments, the second blood sample is obtained from the subject after treatment has been discontinued or reduced. In some embodiments, the change in the Aβ42 / 40 ratio is used to determine a second therapeutically effective dose. In some embodiments, a subject having a second ratio that is elevated compared to the first ratio is administered a second therapeutically effective dose comprising an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril that is equal to or lower than the first dose for the subject. In some embodiments, a subject having a second ratio that is lower compared to the first ratio is administered a second therapeutically effective dose comprising an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril that is higher than the first dose. In some embodiments, a subject having a second ratio that is lower compared to the first ratio is administered a different AD treatment. After the first therapeutically effective dose has been administered multiple times (e.g., biweekly or monthly for 6-18 months), the subject may be changed to a second therapeutically effective dose or dose administration regimen after measuring a second Aβ42 / 40 ratio. In some embodiments, the first therapeutically effective dose may be administered for at least 18 months before being switched to a maintenance dose. In some embodiments, a first therapeutically effective dose may be administered until the patient is amyloid negative and then switched to a maintenance dose.In some embodiments, the patient is amyloid negative (e.g., amyloid or tau positron emission tomography (PET), cerebrospinal fluid Aβ1-42 levels and / or Aβ1-42 / 1-40 ratio, cerebrospinal fluid total tau levels, cerebrospinal fluid neurogranin levels, cerebrospinal fluid neurofilament light peptide (NfL) levels, and blood biomarkers when measured in serum or plasma (e.g., Aβ1-42 levels, the ratio of two forms of amyloid-β peptide (Aβ1-42 / 1-40 ratio), plasma levels of plasma total tau (T-tau), levels of phosphorylated tau (P-tau) isoforms (e.g., P-tau 181 (P ... A first therapeutically effective dose may be administered until the patient is amyloid negative, e.g., as measured by Aβ42 / 40 ratio of 0.092-0.094 or greater (e.g., 0.092 or greater), or has a florbetapir amyloid PET of 1.17 or less (e.g., 0.092 or greater), after which the patient may be switched to a maintenance dose. In some embodiments, the patient may be amyloid negative, e.g., as measured by Aβ42 / 40 ratio of 0.092-0.094 or greater (e.g., 0.092 or greater), or has a florbetapir amyloid PET of 1.17 or less (e.g., 0.092 or greater). A first therapeutically effective dose may be administered until SUVr negative, followed by switching to a maintenance dose. In some embodiments, a first therapeutically effective dose may be administered until the patient is amyloid negative, e.g., as measured by an Aβ42 / 40 ratio greater than 0.092, or a florbetapir amyloid PET SUVr negative at or below 1.17, followed by switching to a maintenance dose. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously, e.g., at 10 mg / kg every other week for at least 18 months, or until the patient is amyloid negative, followed by switching to a maintenance dose.

[0108] In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to an intravenous maintenance dose (e.g., every other week or every 4, 6, 8, 10 or 12 weeks at 10 mg / kg). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to an intravenous maintenance dose every other week. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until the patient is amyloid negative (e.g., after administering lecanemab at 10 mg / kg), followed by switching to a monthly intravenous maintenance dose. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until the patient is amyloid negative, followed by switching to a monthly intravenous maintenance dose. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative (e.g., after administering lecanemab at 10 mg / kg), followed by switching to an intravenous maintenance dose every 8 weeks. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to an intravenous maintenance dose every 2 months.In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or, e.g., until the patient is amyloid negative (e.g., after administering lecanemab at 10 mg / kg), followed by switching to an intravenous maintenance dose every quarter year.

[0109] In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody subcutaneously weekly, e.g., at 720 mg for at least 18 months or, e.g., until the patient is amyloid negative, followed by switching to a subcutaneous maintenance dose (e.g., at 720 mg, e.g., weekly, biweekly, or every 4, 6, 8, 10, or 12 weeks). In some embodiments, the maintenance dose is 360 mg weekly.

[0110] In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a weekly subcutaneous maintenance dose (e.g., a dose of 720 mg). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a weekly subcutaneous maintenance dose (e.g., a dose of 360 mg). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a biweekly subcutaneous maintenance dose (e.g., a 720 mg dose or a 360 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a monthly subcutaneous maintenance dose (e.g., a 720 mg dose or a 360 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative (e.g., after administering lecanemab at 10 mg / kg), followed by switching to a subcutaneous maintenance dose every 6 weeks (e.g., a 720 mg dose or a 360 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a subcutaneous maintenance dose every 8 weeks (e.g., a 720 mg dose or a 360 mg dose).In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a subcutaneous maintenance dose every two months (e.g., a 720 mg dose or a 360 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a subcutaneous maintenance dose every quarter year (e.g., a 720 mg dose or a 360 mg dose).

[0111] In some embodiments, the first therapeutically effective dose comprises administering the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril subcutaneously weekly, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, e.g., two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation in a given week, e.g., a subcutaneous injection of 720 mg including sequential injections, followed by switching to a weekly subcutaneous maintenance dose (e.g., a 720 mg dose or a 360 mg dose). In some embodiments, the first therapeutically effective dose comprises weekly subcutaneous administration of an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, e.g., two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation in a given week, e.g., a subcutaneous injection of 720 mg with sequential injections, followed by a biweekly subcutaneous maintenance dose (e.g., a dose of 720 mg). In some embodiments, the first therapeutically effective dose comprises administering the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril subcutaneously weekly, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, e.g., two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation in a given week, e.g., 720 mg subcutaneous injections including sequential injections, followed by switching to a weekly subcutaneous maintenance dose (e.g., a single dose of 360 mg). In some embodiments, the first therapeutically effective dose comprises administering the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril subcutaneously weekly, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, e.g., two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation in a given week, e.g., 720 mg subcutaneous injections including sequential injections, followed by switching to a monthly subcutaneous maintenance dose (e.g., a 720 mg dose).In some embodiments, the first therapeutically effective dose comprises administering the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril subcutaneously every week, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, e.g., two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation in a given week, e.g., a subcutaneous injection of 720 mg including sequential injections, followed by switching to a subcutaneous maintenance dose (e.g., a dose of 720 mg) every 6 weeks. In some embodiments, the first therapeutically effective dose comprises administering the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril subcutaneously weekly, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, e.g., two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation in a given week, e.g., a subcutaneous injection of 720 mg including sequential injections, followed by a switching to a subcutaneous maintenance dose (e.g., a dose of 720 mg) every 8 weeks. In some embodiments, the first therapeutically effective dose comprises administering the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril subcutaneously weekly, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, e.g., two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation in a given week, e.g., a subcutaneous injection of 720 mg including sequential injections, followed by switching to a subcutaneous maintenance dose (e.g., a dose of 720 mg) every two months. In some embodiments, the first therapeutically effective dose comprises administering the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril subcutaneously weekly, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, e.g., two parallel injections of 360 mg (2×1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation in a given week, e.g., 720 mg subcutaneous injections including sequential injections, followed by switching to a quarter-yearly subcutaneous maintenance dose (e.g., a 720 mg dose).

[0112] In some embodiments, the treatment comprises intravenously administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril every other week, e.g., at 10 mg / kg for at least 18 months. In some embodiments, the treatment comprises intravenously administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril, followed by switching to a maintenance dose. In some embodiments, the treatment comprises intravenously administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril, every other week, e.g., at 10 mg / kg for at least 18 months, followed by switching to a maintenance dose. In some embodiments, the subject is switched to the maintenance dose without an initial titration step to reach the maintenance dose. In some embodiments, the subject is switched to the maintenance dose through at least one step of titration until the maintenance dose, for example, the subject's dosage or administration frequency can be reduced in multiple steps until the final maintenance dose regimen is achieved (e.g., from a subcutaneous therapeutic dose regimen of 720mg per week to a maintenance dose regimen of 360mg per week or 720mg every other week, with intermediate doses or durations such as 540mg per week or 720mg every 10 days). In some embodiments, the maintenance dose of the subject is the same as the dose during the treatment period. In some embodiments, the maintenance dose of the subject is 50% of the dose during the treatment period.

[0113] In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a weekly intravenous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a weekly intravenous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a monthly intravenous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg, for at least 18 months or, e.g., until the patient becomes amyloid negative, followed by switching to an intravenous maintenance dose every quarter year.

[0114] In some embodiments, the maintenance dose is administered subcutaneously (e.g., as a subcutaneous injection). In other embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril subcutaneously followed by switching to an intravenous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously followed by switching to a subcutaneous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient becomes amyloid negative, followed by switching to a subcutaneous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a weekly subcutaneous maintenance dose. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a weekly subcutaneous maintenance dose of 360 mg. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or until, e.g., the patient is amyloid negative, followed by switching to a weekly subcutaneous maintenance dose of 720 mg. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously every other week, e.g., at 10 mg / kg for at least 18 months or, e.g., until the patient is amyloid negative, followed by switching to a subcutaneous maintenance dose of 720 mg every other week.In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously at 10 mg / kg every other week, e.g. for at least 18 months or until the patient is amyloid negative, followed by switching to a monthly subcutaneous maintenance dose of 720 mg. In some embodiments, the treatment comprises administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously at 10 mg / kg every other week, e.g. for at least 18 months or until the patient is amyloid negative, followed by switching to a quarter-yearly subcutaneous maintenance dose of 720 mg.

[0115] In some embodiments, the patient will begin treatment comprising intravenously administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril at a dose of 10 mg / kg, and then switch to treatment comprising subcutaneous administration of an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril, for example at a dose of 720 mg. In some embodiments, the patient will begin treatment comprising intravenously administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril at 10 mg / kg every other week, and then switch to treatment comprising subcutaneous administration of lecanemab weekly, for example at a dose of 720 mg, for example for a total treatment period of at least 18 months or until the patient is amyloid negative. In some embodiments, the patient will be initiated on a treatment comprising administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously at 10 mg / kg every other week, followed by switching to a treatment comprising administering lecanemab subcutaneously weekly, e.g., at a dose of 720 mg, followed by switching to a weekly subcutaneous maintenance dose of 360 mg. In some embodiments, the patient will be initiated on a treatment comprising administering an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibril intravenously at 10 mg / kg every other week, followed by switching to a treatment comprising administering lecanemab subcutaneously weekly, e.g., at a dose of 720 mg, followed by switching to a monthly subcutaneous maintenance dose of 720 mg.

[0116] In some embodiments, the maintenance dose is administered as a subcutaneous injection of an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibrils (e.g., lecanemab). In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection of a subcutaneous formulation of an anti-Aβ protofibril antibody or an antigen-binding fragment thereof capable of binding to human Aβ protofibrils. In some embodiments, the maintenance dose is administered as a weekly 720 mg subcutaneous injection with two parallel injections of a subcutaneous formulation of 360 mg (2×1.8 mL of 400 mg / 2 mL), e.g., sequential injections. In some embodiments, the maintenance dose is administered as a monthly 720 mg subcutaneous injection with two parallel injections of a subcutaneous formulation of 360 mg (2×1.8 mL of 400 mg / 2 mL), e.g., sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a 720 mg subcutaneous injection every quarter year, including sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a 720 mg subcutaneous injection every two weeks, including sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a 720 mg subcutaneous injection every month, including sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a 720 mg subcutaneous injection every quarter year, including sequential injections.

[0117] In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose ranging from 300 mg to 800 mg or 400 to 1500 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 300 mg to 400 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 400 mg to 500 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 400 mg to 450 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 450 mg to 500 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 500 mg to 600 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 500 mg to 550 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 550 mg to 600 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 600 mg to 700 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 600 mg to 650 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 650 mg to 700 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 700 mg to 800 mg.In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 700 mg to 750 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 750 mg to 800 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, or 390 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibrils is administered subcutaneously at a dose of 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, or 490 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibrils is administered subcutaneously at a dose of 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, or 590 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, or 690 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, or 790 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 440 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 580 mg.In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 720 mg.

[0118] In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose ranging from 800 mg to 1600 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose ranging from 800 mg to 1000 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose ranging from 800 mg to 900 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose ranging from 900 mg to 1000 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose ranging from 1000 mg to 1200 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1000 mg to 1100 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1100 mg to 1200 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1200 mg to 1400 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1200 mg to 1300 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1300 mg to 1400 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1400 mg to 1600 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1400 mg to 1500 mg.In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1500 mg to 1600 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg, 920 mg, 940 mg, 960 mg, or 960 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1000 mg, 1020 mg, 1040 mg, 1060 mg, 1080 mg, 1100 mg, 1120 mg, 1140 mg, 1160 mg, or 1180 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1200 mg, 1220 mg, 1240 mg, 1260 mg, 1280 mg, 1300 mg, 1320 mg, 1340 mg, 1360 mg, or 1380 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1400 mg, 1400 mg, 1440 mg, 1460 mg, 1480 mg, 1500 mg, 1520 mg, 1540 mg, 1560 mg, or 1580 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 880 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1160 mg. In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human Aβ protofibril is administered subcutaneously at a dose of 1440 mg.

[0119] Further exemplary subcutaneous doses, dosing frequencies, maintenance doses and formulations for subcutaneous administration that may be used in the methods discussed herein are described in International Application No. PCT / US2022 / 041926, the contents of which are incorporated herein by reference in their entirety.

[0120] In some embodiments, the anti-Aβ protofibril antibody or antigen-binding fragment thereof used in the methods disclosed herein is delivered by an autoinjector. In some embodiments, the autoinjector delivers the anti-Aβ protofibril antibody or antigen-binding fragment thereof subcutaneously. In some embodiments, the autoinjector delivers an injection volume of 1.1 mL. In some embodiments, the autoinjector delivers an injection volume of 1.4 mL. In some embodiments, the autoinjector delivers an injection volume of 1.8 mL. In some embodiments, the autoinjector delivers about 400-800 mg, e.g., 360 mg, of the anti-Aβ protofibril antibody or antigen-binding fragment thereof subcutaneously. EXAMPLES

[0121] The present disclosure is further illustrated by the following examples, which should not be construed as limiting. The contents and figures of all references, patents and published patent applications cited throughout this application are hereby incorporated by reference in their entirety for all purposes.

[0122] Example 1: Treatment of Alzheimer's Disease by Administering Lecanemab in Combination with E2814 1.1 Dose selection during the double-blind period 1.1.1 E2814 1500 mg of the anti-tau antibody E2814 or its antigen-binding fragment will be administered intravenously (IV) every 4 weeks. Future protocol amendments may consider studying higher doses (3000 mg or 4500 mg) based on safety, PK, and TE data at these higher doses.

[0123] 1.1.2 Lecanemab Lecanemab treatment will be administered Q2W by intravenous infusion at a dose of 10 mg / kg.

[0124] 1.2 Drug-specific study designs This is a placebo-controlled, double-blind Phase II / III study evaluating the treatment effects of E2814, when administered alone or in parallel with lecanemab, on safety, tolerability, biomarkers, cognitive function and clinical efficacy.

[0125] Inclusion criteria included: · People aged 18-80 years; · Individuals known to have an Alzheimer's disease-causing mutation; · The predicted or actual age of onset of cognitive symptoms is within the range of -10 to +10 years; · cognitively normal or with mild cognitive impairment or mild dementia, with a Clinical Dementia Scale (CDR) score between 0 and 1; · Evidence of trial-recognized language fluency and appropriate premorbid intellectual functioning; ·Ability to undergo Magnetic Resonance Imaging (MRI), Lumbar Puncture (LP), Positron Emission Tomography (PET) and complete all study-related testing and evaluations. ·For women of childbearing potential, if their partner is not sterilized, participants must agree to use effective contraception (hormonal contraception, intrauterine device, abstinence, or spermicidal barrier method); ·Sufficient visual and hearing abilities to perform all aspects of cognitive and functional assessments; ·Has a research partner who, in the investigator's judgment, can provide accurate information regarding the subjects' cognitive and functional abilities and who agrees to provide information at study visits where informant input is required for completion of scale assessments.

[0126] Exclusion criteria included the following: ·Significant neurological (other than AD) or psychiatric illness that may affect cognition or the participant's ability to complete the study, currently or over the course of the study; · High risk of suicide, e.g., significant suicidal ideation or suicide attempt within the past 12 months – does not exclude currently stable minor depression or current use of antidepressant medication; · History or current brain MRI scan indicating any other significant abnormality; ·Current or within the past year, substance or alcohol use disorder; · have a pacemaker, aneurysm clip, artificial heart valve, in-ear implant or any metallic foreign body in the eye, skin or body that may interfere with an MRI scan; · History or current illness of clinically significant cardiovascular disease, hepatic / renal disorders, infectious or immune disorders or metabolic / endocrine disorders; ·Taking low-dose (less than 325 mg) anticoagulants other than aspirin; · History of exposure to monoclonal antibodies targeting beta-amyloid peptides within the past 6 months; · History of cancer within the past 5 years, except for basal cell carcinoma, nonsquamous cell skin cancer, prostate cancer, or carcinoma in situ without significant progression within the past 2 years; -A positive urine or serum pregnancy test or plans or desires to become pregnant during the course of the study; Subjects unable to complete all study-related testing, including metallic implants that cannot be removed at the time of MRI scanning, the need for anticoagulation, and pregnancy.

[0127] Approximately 168 participants will be enrolled in the E2814 blinded study drug arm with 84 participants in each of two cohorts. All 168 participants with estimated years since onset (EYO) between -10 and +10 years will be assigned to two cohorts based on their baseline (week 0) CDR scores as follows:

[0128] Symptomatic population (Cohort 1): A minimum of 84 participants with CDR=0.5-1 (symptomatic mild cognitive impairment)

[0129] Asymptomatic population (Cohort 2): A minimum of 84 participants with CDR=0 (cognitively normal)

[0130] At the time of randomization, participants will be randomized 1:1 to active E2814 vs. placebo using a minimization algorithm that includes the following factors (Figure 1): 1.Clinical Dementia Scale-Item Total (CDR-SB; 0 points, 0.5~1 points, 1.5~3 points, >3 points) 2. Estimated years from onset (EYO) (-10 to -5 years, -4 to -1 years, 0 to 4 years, 5 to 10 years) 3. Genotype (APP, PSEN1, PSEN2) 4. Years of education (less than 12 years, 12 years, 13-16 years, more than 16 years) 5. Age (18-40, 41-55, 56-80) 6. Presence or absence of APOE4 allele (APOE4 positive, APOE4 negative) 7. Region (US / Australia / Canada, Europe, Rest of the World) 8. Research facilities, and 9. Gender (male, female).

[0131] A minimization randomization algorithm will be used to achieve two goals: 1) balancing prognostic or non-prognostic factors that may affect clinical and cognitive progression (these factors include baseline CDR-SB, EYO, age at randomization, years of education, and region), and 2) balancing factors that may affect adverse events or interfere with drug effect (these factors include genotype, APOE4 allele, and gender).

[0132] E2814 or placebo will be administered in parallel with open-label lecanemab as part of the E2814 blinded study drug arm. E2814 or placebo will be administered intravenously at a dose of 1500 mg every 4 weeks (Q4W) and lecanemab will be administered intravenously at 10 mg / kg every 2 weeks (Q2W), with each cohort initiating treatment at different times as specified in Figure 2. Participants will continue treatment until all co-enrolled participants have received a minimum of 4 years of treatment (210 weeks) or until withdrawal (common censoring). Each cohort will begin treatment with E2814 or placebo and lecanemab for parallel administration as follows:

[0133] Symptomatic population (cohort 1) At week 0, participants will receive open-label lecanemab 10 mg / kg intravenously every 2 weeks (Q2W) for the entire treatment period.

[0134] At week 24, participants will be randomized in a 1:1 ratio to receive 1500 mg E2814 or placebo intravenously Q4W in a blinded manner for the remainder of the treatment period.

[0135] Asymptomatic population (Cohort 2) Beginning at week 0, participants will be randomized in a 1:1 ratio to receive 1500 mg E2814 or placebo intravenously Q4W in a blinded fashion for the entire treatment period.

[0136] At week 52, all participants will begin open-label lecanemab 10 mg / kg intravenously Q2W for the remainder of their treatment period.

[0137] This staggering of the administration of each drug allows the effects of lecanemab and E2814 alone to be evaluated prior to evaluation of the drugs together.

[0138] 1.3 Biomarker Rationale Objectives and Endpoints Based on the evolution of tau pathophysiology through distinct stages in DIAD, the primary study endpoint in the symptomatic population (cohort 1) is tau PET, and the key secondary study endpoint in the asymptomatic population (cohort 2) is cerebrospinal fluid (CSF) phosphorylated tau (p-tau217) / total tau ratio (p-tau217 / total tau ratio).

[0139] There was a dose-dependent decrease in free MTBR tau after a single E2814 infusion of 3, 10, and 30 mg / kg, demonstrating that E2814 can reduce MTBR tau levels in the CSF. Target engagement (TE) was estimated using E2814-bound and free MTBR tau as the percentage of bound MTBR tau relative to total MTBR tau (free + bound). These preliminary data suggest a dose-dependent increase in TE of approximately 26%, 45%, and 60% (3, 10, and 30 mg / kg, respectively), with TE sustained up to 29 days.

[0140] 1.4 Primary Study Objectives and Endpoints The primary study endpoint is to determine in the symptomatic population (cohort 1) whether E2814 is superior to placebo when administered in parallel with lecanemab in terms of change in tau spread as measured by tau PET from week 24 to week 104 (interim analysis) and week 208 (final analysis), respectively.

[0141] 1.5 Secondary Study Endpoints 1.5.1 Key Secondary Endpoints Key secondary endpoints were:

[0142] Symptomatic population (Cohort 1): To determine whether E2814 is superior to placebo when administered in parallel with lecanemab, respectively, in terms of change from Week 24 to Week 208 in the Clinical Dementia Rating Scale-Summary Score (CDR-SB)

[0143] Asymptomatic population (Cohort 2): To determine whether E2814, administered alone and then in parallel with lecanemab, is superior to placebo in terms of change in cerebrospinal fluid (CSF) phosphorylated tau (p-tau217) / total tau from week 0 to week 104 (interim analysis) and week 208 (final analysis), respectively.

[0144] 1.5.2 Additional Secondary Endpoints Additional secondary endpoints for the population cohorts, individually and combined, are:

[0145] Symptomatic population (Cohort 1): 1) to determine if E2814 is superior to placebo when administered in parallel with lecanemab in terms of change in cognitive composite score from week 24 to week 104 and week 208, respectively; 2) to determine the effect of lecanemab when administered alone in terms of change in amyloid PET from week 0 to week 24; 3) to determine if lecanemab is superior to external control when administered alone or with placebo in terms of change in CDR-SB from week 0 to week 208; 4) to determine the safety and tolerability of lecanemab when administered alone for 24 weeks, including assessment of immunogenicity (production of anti-lecanemab antibodies); and 5) to determine if E2814 is superior to placebo when administered in parallel with lecanemab in terms of change in CSF neurofilament light chain (NFL) from week 24 to week 104 and week 208, respectively.

[0146] Asymptomatic population (Cohort 2): 1) To evaluate whether E2814 is superior to placebo when administered alone in terms of change in CSF p-tau217 / total tau from week 0 to week 52, respectively; 2) To determine whether E2814 is superior to placebo when administered in parallel with lecanemab in terms of change in CSF p-tau217) / total tau from week 52 to week 104 (interim analysis) and week 208 (final analysis), respectively; 3) To determine the safety and tolerability of E2814 when administered alone for 52 weeks, including assessment of immunogenicity (production of anti-E2814 antibodies); 4) To determine whether E2814 is superior to placebo when administered in parallel with lecanemab in terms of change in CSF neurofilament light chain (NFL) from week 52 to week 104 and week 208, respectively.

[0147] 1.6 Exploratory Endpoints The following are exploratory endpoints for each population cohort in the E2814 arm of this study:

[0148] Symptomatic population (Cohort 1): To evaluate the efficacy of E2814 compared to placebo when administered in parallel with lecanemab in terms of change from week 24 to week 104 and week 208 in reducing CSF p-tau217 / total tau, respectively To evaluate the effect of lecanemab when administered alone in terms of changes from week 0 to week 24 in tau PET, CSF and blood biomarkers (amyloid beta [Aβ]42, Aβ40, p-tau, total tau, NFL)

[0149] Asymptomatic population (Cohort 2): To evaluate whether E2814 is superior to placebo when administered in parallel with lecanemab in terms of change in CSF p-tau217 / total tau from week 52 to week 104 and week 208, respectively To evaluate the efficacy of E2814 compared to placebo when administered in parallel with lecanemab in terms of change in cognitive composite score from week 52 to week 104 and week 208, respectively To evaluate the effect of E2814 compared to placebo when administered in parallel with lecanemab in terms of change from week 52 to weeks 104 and 208, respectively, in reducing brain tau spread as measured by tau PET To evaluate whether E2814, when administered alone, is superior to placebo in terms of changes from week 0 to week 52 in tau PET, CSF biomarkers (NFL and MTBR tau), and blood biomarkers (p-tau217 / total tau and NFL)

[0150] Symptomatic (Cohort 1) and Asymptomatic (Cohort 2) populations: To evaluate the efficacy of E2814 compared to placebo when administered in parallel with lecanemab in terms of change in CDR-SB from week 24 to week 104 (cohort 1) and from week 52 to weeks 104 and 208 (cohort 2), respectively To evaluate the efficacy of E2814 compared to placebo when administered in parallel with lecanemab in terms of change in CSF microtubule binding region (MTBR) tau from week 24 to weeks 104 and 208 (cohort 1) and from week 52 to weeks 104 and 208 (cohort 2), respectively To evaluate whether E2814 is superior to placebo when administered in parallel with lecanemab in terms of change in plasma NFL from week 24 to weeks 104 and 208 (cohort 1) and from week 52 to weeks 104 and 208 (cohort 2), respectively To evaluate whether E2814 is superior to placebo when administered in parallel with lecanemab in terms of change from 24 to 104 and 208 weeks (cohort 1) and from 52 to 104 and 208 weeks (cohort 2) in CSF and blood biomarkers of neurodegeneration, neuroinflammation, amyloid and tau (other than those already listed above), respectively. To evaluate the effect of E2814 compared to placebo when administered in parallel with lecanemab, in terms of change from weeks 24 to 208 (cohort 1) and from weeks 52 to 208 (cohort 2), respectively, in cognitive and functional endpoints, including: Geriatric Depression Scale (GDS) Neuropsychiatric Inventory Questionnaire (NPI-Q) Functional Assessment Scale (FAS) Mini-Mental State Examination (MMSE) -DIAN Memory Complaints Questionnaire (MAC-Q) · Buschke and Grober Free and Cued Selective Recall Test-Immediate Recall (FCSRT-IR) Wechsler Memory Scale-Revised (WMS-R) Logical Memory / Paragraph Memory (immediate and delayed recall), Alternating Paragraphs of Logical Memory I & II - Version A (immediate and delayed), and Alternating Paragraphs of Logical Memory I & II - Version B (immediate and delayed) Category Fluency (Animals) Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol Substitution Task Trail Making Tasks Parts A and B Wechsler Memory Scale-Revised (WMS-R) Digit Spatial Span Forward and Backward Span Ambulatory Research in Dementia (ARC) Smartphone-based cognitive function assessment (grids, prices, symbols) To evaluate the effect of E2814 compared to placebo when administered in parallel with lecanemab in terms of change from Week 24 to Week 104 and Week 208 (Cohort 1) and from Week 52 to Week 104 and Week 208 (Cohort 2), respectively, in imaging measures including: Amyloid burden based on (11)C-labeled Pittsburgh compound B ([11C]PiB) PET Fluorodeoxyglucose (FDG)-PET metabolism in specific regions of interest (e.g., precuneus) Rate of brain atrophy as measured by cortical thickness in regions of interest, including total brain volume and ventricular volume (volumetric magnetic resonance imaging [vMRI]) ·Functional connectivity MRI (fc-MRI) Diffusion Tensor Imaging (DTI) MRI parameters, including Diffusion-Based Spectral Imaging (DBSI) - Arterial spin labeling (ASL) MRI for blood flow measurement Identification of MRI clinical features such as microhemorrhages (MCH), white matter hyperintensities (WMH), cerebral infarction and amyloid-related imaging abnormalities (ARIA) using conventional MRI sequences To evaluate the population pharmacokinetics (PK) of E2814 in plasma and serum To evaluate the population PK of serum lecanemab - To explore the PK (E2814 / lecanemab exposure)-pharmacodynamics (PD) (CSF, blood and imaging biomarkers) relationship Collect pharmacogenomic (PG) samples for future analysis

[0151] 1.7 Safety Objectives and Endpoints The study will determine the safety and tolerability of E2814 and lecanemab treatment in patients with DIAD. Safety endpoints will include AEs, clinical laboratory results, vital signs, ECG, CSSRS, and physical and neurological examinations.

[0152] To assess the immunogenicity (production of anti-E2814 and anti-lecanemab antibodies) of concurrent administration of E2814 and lecanemab.

[0153] Safety measurements of plasma fibrinogen binding include monitoring of functional fibrinogen using the Clauss assay.

[0154] Safety MRI to monitor ARIA will also be evaluated.

[0155] 1.8 Drug-specific testing 1.8.1 Pharmacokinetic assessment 1.8.1.1 Blood PK of E2814 and lecanemab Blood samples for E2814 PK assessment (plasma and serum) and lecanemab (serum) will be collected pre-dose at that visit, immediately prior to the start of any drug administration, and 30 minutes after completing all drug administrations post-dose at that visit. Blood will be collected based on cohort assignment as outlined below in Year 1, approximately every 26 weeks (approximately every 6 months) through Year 4, then annually and at safety follow-up visits. Samples must also be collected if a participant discontinues early.

[0156] [Table 1]

[0157] Serum and plasma concentrations of E2814 will be measured by a validated electrochemiluminescence (ECL) assay.

[0158] 1.8.1.2 E2814 and Lecanemab Cerebrospinal Fluid (CSF) PK - Cohort Specific Collection Schedules At the visits specified below, CSF samples for E2814 and lecanemab PK characterization will be collected pre-dose via lumbar puncture (LP) based on assigned cohort.

[0159] [Table 2]

[0160] CSF concentrations of E2814 will be measured by a validated electrochemiluminescence (ECL) assay. CSF concentrations of lecanemab will be measured by a validated immunoprecipitation-liquid chromatography-tandem mass spectrometry (IP / LC-MS / MS) method.

[0161] 1.8.2 Immunogenicity determination Blood samples for immunogenicity will be collected immediately prior to LP at the annual visit where LP is required and prior to drug administration at all other visits. Immunogenicity will be determined by measuring sera for the presence of anti-E2814 and anti-lecanemab antibodies based on cohort allocation as outlined below in Year 1, approximately every 26 weeks (approximately every 6 months) through Year 4 and in the event of early discontinuation (ET).

[0162] [Table 3]

[0163] Participants with significant immunogenicity at the last collected assessment (Week 208 or ET visit) will continue to have anti-E2814 or anti-lecanemab antibody assessments every 24 weeks until resolution when / if possible. In addition, clinical measurements such as CRP may be performed to monitor inflammation that may be associated with immunogenicity.

[0164] Serum anti-E2814 antibodies will be measured by a suitable validated ECL assay. Serum anti-lecanemab antibodies will be measured using a validated Meso Scale Discovery® bridging assay.

[0165] 1.8.3 Pharmacodynamic and Biomarker Characterization Blood samples for plasma pharmacodynamic (PD) biomarkers will be collected immediately prior to the LP at the annual visit where LP is required and prior to drug administration at all other visits. Samples will be collected on the same schedule for both cohorts, approximately every 12 weeks in Year 1, approximately every 26 weeks (approximately every 6 months) through Year 4, and annually thereafter, including safety follow-up visits, as outlined below. ·1st year: 0th week (V2), 12th week (V5), 24th week (V8), 36th week (V11), 52nd week (V15) Year 2: Week 76 (V21) and Week 104 (V28) Year 3: Week 128 (V34) and Week 156 (V41) Year 4: Week 180 (V47) and Week 208 (V54) Year 5: Week 260 (V67), if applicable Year 6: Week 312 (V80), if applicable Year 7: Week 364 (V93), if applicable Safety follow-up - Early discontinuation, if applicable

[0166] At the following visits, CSF samples for PD biomarkers will be collected by lumbar puncture pre-dose: Week 0 (V2), baseline Week 24 (V8) - Cohort 1 only Week 52 (V15) Week 104 (V28) Week 208 (V54) or ET ·260th week (V67) If discontinued before Week 260 (V67), early discontinuation

[0167] CSF and blood concentrations of AD-related biomarkers (including but not limited to Aβ[1-42], neurogranin, neurofilament light chain [NFL], MTBR tau [bound, free and total], total tau [t-tau] and phosphorylated tau [p-tau]) will be measured.

[0168] 1.8.4 Genomic DNA Blood Samples for Banking Pharmacogenomic and biomarker samples obtained from participants in this study may be analyzed by global proteomics, metabolomics, or lipidomics and single or multiplexed assays in an attempt to identify predictive biomarkers of PK and PD. In addition, biomarkers identified in other clinical trials may be assessed in samples collected from participants enrolled in this study.

[0169] Example 2: Treatment of Alzheimer's Disease with Subcutaneous Lecanemab in Combination with E2814 Dose selection during the double-blind period E2814: 3000 mg of the anti-tau antibody E2814 or its antigen-binding fragment will be administered intravenously (IV) every 4 weeks. A higher dose (4500 mg) may be considered for study in a future protocol amendment based on safety, PK and TE data at this higher dose.

[0170] Lecanemab: Lecanemab treatment will be administered subcutaneously using two autoinjectors delivering 360 mg of lecanemab each for a total dose of 720 mg. Patients will receive two 360 mg doses weekly or every other week.

[0171] Symptomatic population (Cohort 1): At week 0, participants will receive 720 mg open-label lecanemab subcutaneously using two consecutive 360 ​​mg doses via an autoinjector throughout the entire treatment period.

[0172] At week 24, participants will be randomized in a 1:1 ratio to receive 3000 mg E2814 or placebo intravenously Q4W in a blinded manner for the remainder of the treatment period.

[0173] Asymptomatic population (Cohort 2): At week 0, participants will be randomized in a 1:1 ratio to receive 3000 mg E2814 or placebo intravenously Q4W in a blinded manner for the entire treatment period.

[0174] At week 52, all participants will begin receiving 720 mg open-label lecanemab subcutaneously in two consecutive 360 ​​mg doses delivered using an autoinjector throughout the remainder of their treatment period.

[0175] Embodiment Embodiment 1: Lecanemab background anti-amyloid therapy in the next generation clinical trial evaluating investigational therapies targeting tau for dominantly inherited Alzheimer's disease (Tau NexGen trial)

[0176] Carriers of this DIAD gene mutation are known to develop AD and will likely develop symptoms at approximately the same age as their affected parent, often in their 50s, 40s, or even 30s. The purpose of the Tau NexGen study is to determine the safety, tolerability, biomarkers, and efficacy of the investigational therapy on cognitive function in carriers of the Alzheimer's disease-causing gene mutation. The study will evaluate whether treatment with the investigational drug slows the progression of cognitive impairment and improves disease-related biomarkers.

[0177] In the revised Tau NexGen protocol, symptomatic participants will be randomized to receive lecanemab for six months, followed by E2814 or a placebo. Because amyloid plaques build up in AD before tau tangles form, this study design will allow researchers to determine whether clearing amyloid paves the way for anti-tau drugs to work most effectively. Presymptomatic participants will be randomized to receive the anti-tau drug E2814 or a placebo for one year before starting lecanemab. This staggering of the drugs will allow for evaluation of the effect of the anti-tau drug alone before determining the combined effect of the two drugs. Lecanemab will be administered every other week at a dose of 10 mg / kg, which does not require dose adjustment, and the incidence of amyloid-related imaging abnormalities is 9.9%, of which less than 2% are symptomatic. The primary endpoint will be slowing of brain tau accumulation (as an effect of adding E2814) in symptomatic participants as seen on PET brain scans. A secondary endpoint will be the effect (of E2814 alone or in combination with lecanemab) on levels of a specific type of tau - phosphorylated tau 217 - in the cerebrospinal fluid (CSF) of pre-symptomatic participants. If these primary and secondary endpoints are met at the two-year analysis, the study will be extended for an additional two years to determine whether the drug slows cognitive decline and has an additional effect on tau pathology.

[0178] [Table 4]

[0179] [Table 5]

[0180] [Table 6]

[0181]

Table 7

Claims

1. 1. A pharmaceutical composition for treating or preventing Alzheimer's disease in a subject, comprising: comprising an anti-Aβ protofibril antibody or an antigen-binding fragment thereof, the pharmaceutical composition is used to be administered in combination with a pharmaceutical composition comprising an anti-tau antibody or an antigen-binding fragment thereof; The anti-Aβ protofibril antibody or antigen-binding fragment thereof is a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13, and A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14 Including, The anti-tau antibody or antigen-binding fragment thereof is a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 15; and A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 A pharmaceutical composition comprising:

2. 1. A pharmaceutical composition for treating or preventing Alzheimer's disease in a subject, comprising: comprising an anti-tau antibody or an antigen-binding fragment thereof, the pharmaceutical composition is used to be administered in combination with a pharmaceutical composition comprising an anti-Aβ protofibril antibody or an antigen-binding fragment thereof; The anti-Aβ protofibril antibody or antigen-binding fragment thereof is a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13, and A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14 Including, The anti-tau antibody or antigen-binding fragment thereof is a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 15; and A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 A pharmaceutical composition comprising:

3. The anti-Aβ protofibril antibody or antigen-binding fragment thereof is a heavy chain comprising the amino acid sequence of SEQ ID NO: 17; and A light chain comprising the amino acid sequence of SEQ ID NO: 18 3. The pharmaceutical composition of claim 1 or 2, comprising:

4. The anti-tau antibody or antigen-binding fragment thereof is a heavy chain comprising the amino acid sequence of SEQ ID NO: 19, and A light chain comprising the amino acid sequence of SEQ ID NO: 20 3. The pharmaceutical composition of claim 1 or 2, comprising:

5. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered once a week or once every two weeks.

6. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered intravenously.

7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered intravenously once every two weeks at a dose of 10 mg / kg of the anti-Aβ protofibril antibody or antigen-binding fragment thereof.

8. 3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered subcutaneously as a weekly dose containing either 500 mg or 720 mg.

9. 3. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered for at least 52 weeks or 18 months, followed by administration of a maintenance dose.

10. 10. The pharmaceutical composition of claim 9, wherein the maintenance dose comprises weekly or biweekly subcutaneous administration of 120 mg, 180 mg, 240 mg, 360 mg, or 720 mg of the anti-Aβ protofibril antibody or antigen-binding fragment thereof.

11. 10. The pharmaceutical composition of claim 9, wherein the maintenance dose comprises intravenous administration of 10 mg / kg of the anti-Aβ protofibril antibody or antigen-binding fragment thereof once every two weeks, once every four weeks, or once every 12 weeks.

12. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof is administered once every four weeks.

13. The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof is administered once every four weeks in an amount of 1000 to 4500 mg of the anti-tau antibody or antigen-binding fragment thereof.

14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof is administered once every four weeks in an amount of 1500 mg of the anti-tau antibody or antigen-binding fragment thereof.

15. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof is administered once every four weeks in an amount of 3000 mg of the anti-tau antibody or antigen-binding fragment thereof.

16. The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof is administered once every four weeks at a dose of 3, 10, or 30 mg / kg of the anti-tau antibody or antigen-binding fragment thereof.

17. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof is administered intravenously.

18. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered alone before the start of treatment in combination with the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof.

19. 19. The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered for at least 24 weeks prior to the initiation of treatment with the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof.

20. 19. The pharmaceutical composition of claim 18, wherein the subject is symptomatic for Alzheimer's disease.

21. 21. The pharmaceutical composition of claim 20, wherein the subject has early-onset Alzheimer's disease.

22. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof is administered alone before the start of treatment in combination with the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof.

23. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof is administered alone for at least 25 weeks prior to the initiation of treatment in combination with the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof.

24. 24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof is administered alone for 52 weeks prior to initiation of treatment with the pharmaceutical composition comprising the anti-Aβ protofibril antibody or antigen-binding fragment thereof.

25. 23. The pharmaceutical composition of claim 22, wherein the subject is asymptomatic with respect to Alzheimer's disease.

26. 3. The pharmaceutical composition of claim 1 or 2, wherein the subject has a genetic mutation for dominantly inherited Alzheimer's disease, the subject having a genetic mutation in at least one of three genes - PSEN1, PSEN2 or APP.

27. 27. The pharmaceutical composition of claim 26, wherein the subject has a mutation in APP.

28. 3. The pharmaceutical composition of claim 1 or 2, wherein the subject has a family history of Alzheimer's disease.

29. 3. The pharmaceutical composition of claim 1 or 2, wherein tau spreading is reduced after administration compared to untreated control subjects.

30. The pharmaceutical composition of claim 1 or 2, wherein the level of phosphorylated tau 217 in a sample taken from the subject after administration is reduced compared to the level of phosphorylated tau 217 in a sample taken from the subject before administration.

31. 3. The pharmaceutical composition of claim 1, wherein the clinical dementia scale item total score after administration improves in the subject compared to the subject's score before administration.

32. 3. The pharmaceutical composition according to claim 1 or 2, wherein the ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale), MMSE (Mini-Mental State Evaluation) and / or Clinical Dementia Scale (CDR) score after administration improves in the subject compared to the score before administration.

33. 3. The pharmaceutical composition of claim 1, wherein the Aβ42 / 40 ratio in a sample taken from the subject after administration is increased compared to the ratio in a sample taken from the subject before administration.

34. 3. The pharmaceutical composition of claim 1, wherein the level of Aβ protofibrils in the subject after administration is reduced compared to the level of Aβ protofibrils in the subject before administration and / or compared to an untreated control or subject.

35. A kit comprising: a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13, and A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14 an anti-Aβ protofibril antibody or an antigen-binding fragment thereof, comprising: a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 15; and A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 an anti-tau antibody or an antigen-binding fragment thereof, Includes a kit.

36. 36. The kit of claim 35, wherein the anti-Aβ protofibril antibody or antigen-binding fragment thereof is present in an amount suitable for intravenous administration at a dose of 10 mg / kg or subcutaneous administration at a dose of 500 mg or 720 mg, and the anti-tau antibody or antigen-binding fragment thereof is present in an amount suitable for administration at a dose of 1500 or 3000 mg.

37. 36. The kit of claim 35, wherein the anti-Aβ protofibril antibody or antigen-binding fragment thereof is present in an amount suitable for subcutaneous administration at a dose of 500 mg or 720 mg, and the anti-tau antibody or antigen-binding fragment thereof is present in an amount suitable for administration at a dose of 3000 mg.

38. 36. The kit of claim 35, wherein the anti-Aβ protofibril antibody or antigen-binding fragment thereof and the anti-tau antibody or antigen-binding fragment thereof are formulated in separate containers within the kit.

39. The anti-Aβ protofibril antibody or antigen-binding fragment thereof is a heavy chain comprising the amino acid sequence of SEQ ID NO: 17; and A light chain comprising the amino acid sequence of SEQ ID NO: 18 36. The kit of claim 35, comprising:

40. The anti-tau antibody or antigen-binding fragment thereof is a heavy chain comprising the amino acid sequence of SEQ ID NO: 19, and A light chain comprising the amino acid sequence of SEQ ID NO: 20 36. The kit of claim 35, comprising:

41. A pharmaceutical combination for treating or preventing Alzheimer's disease, comprising: a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13, and A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14 an anti-Aβ protofibril antibody or an antigen-binding fragment thereof, comprising: a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 15; and A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 an anti-tau antibody or an antigen-binding fragment thereof, 10. A pharmaceutical combination comprising:

42. 42. The pharmaceutical combination of claim 41, wherein the anti-Aβ protofibril antibody or antigen-binding fragment thereof is present in an amount suitable for intravenous administration at a dose of 10 mg / kg or subcutaneous administration at a dose of 500 mg or 720 mg, and the anti-tau antibody or antigen-binding fragment thereof is present in an amount suitable for administration at a dose of 1500 or 3000 mg.

43. 1. Use of an anti-Aβ protofibril antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating or preventing Alzheimer's disease in a subject, the medicament being used in combination with an anti-tau antibody or an antigen-binding fragment thereof, comprising: the anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered in combination with the anti-tau antibody or antigen-binding fragment thereof; The anti-Aβ protofibril antibody or antigen-binding fragment thereof is a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 13, and A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 14 Including, The anti-tau antibody or antigen-binding fragment thereof is a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 15; and A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 16 Including, use.

44. The use according to claim 43, wherein the anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered alone prior to the initiation of treatment in combination with the anti-tau antibody or antigen-binding fragment thereof.

45. 45. The use of claim 44, wherein the anti-Aβ protofibril antibody or antigen-binding fragment thereof is administered for at least 24 weeks prior to initiation of treatment with the anti-tau antibody or antigen-binding fragment thereof.

46. 45. The use of claim 44, wherein the subject is symptomatic for Alzheimer's disease.

47. 47. The use of claim 46, wherein the subject has early-onset Alzheimer's disease.

48. The use according to claim 43, wherein the anti-tau antibody or antigen-binding fragment thereof is administered alone prior to the initiation of treatment in combination with the anti-Aβ protofibril antibody or antigen-binding fragment thereof.

49. 49. The use of claim 48, wherein the anti-tau antibody or antigen-binding fragment thereof is administered alone for at least 25 weeks prior to initiation of treatment with the anti-Aβ protofibril antibody or antigen-binding fragment thereof.

50. 50. The use of claim 49, wherein the anti-tau antibody or antigen-binding fragment thereof is administered alone for 52 weeks prior to initiation of treatment in combination with the anti-Aβ protofibril antibody or antigen-binding fragment thereof.

51. 49. The use of claim 48, wherein the subject is asymptomatic with respect to Alzheimer's disease.

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