Methods for treating alzheimer's disease

Abstract

Provided herein arc methods of administering BIIB080 for treating Alzheimer's disease, reducing Tau RNA, Tau protein and / or reducing Tau neurofibrillary tangles (NFTs) in a human subject in need thereof that has been treated with an anti-beta amyloid antibody prior to initiation of treatment with BIIB080. The Alzheimer's disease can be, for example, early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease, and / or Alzheimer's disease dementia (e.g., mild Alzheimer's disease dementia).

Description

[0001] METHODS FOR TREATING ALZHEIMER’S DISEASE

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Patent Application number 63 / 675, 586 filed on July 25, 2024, which is hereby incorporated by reference in its entirety.

[0004] FIELD

[0005] This disclosure relates generally to methods for treating Alzheimer’s disease.

[0006] BACKGROUND

[0007] Alzheimer’ s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and functional decline resulting in significant disability (Lane, et al., 2018, Eur. J. Neurol. 25: 59-70). Symptom onset typically occurs in patients aged 65 and older, while symptom onset before age 65 comprises < 5% of all patients with AD (Alzheimer’s Association, 2021, 2021 Alzheimer's disease facts and figures, Alzheimer’s Dement. 17: 327-406). Current management for AD is limited to multidisciplinary management of symptoms including pharmacological therapies. Accumulating evidence suggests that aggregated, hyperphosphorylated Tau protein may be a key driver of neurodegeneration in AD. Tau protein is encoded by the MAPT gene and is a microtubule-associated protein primarily expressed in neurons (Dixit, et al., 2008, Science 319: 1086-1089). Under pathogenic conditions, hyperphosphorylated Tau accumulates intracellularly and extracellularly, and aggregates into oligomers and fibrils resulting in Tau neuronal neurofibrillary tangles (NFTs), which spread through specific neural networks via a trans-synaptic route (Braak and Del Tredici, 2016, Cold Spring Harb. Perspect. Biol. 8: a023630; Ossenkoppele, et al., 2019, Neuroimage Clin. 23: 101848) and cause neurodegeneration, synaptic dysfunction and synaptic loss (DeVos, et al., 2018, Front. Neurosci. 12: 267; Guo, et al., 2018, Acta Neuropathologica 133: 665- 704; Wilcock, et al., 1982, J Neurol. Sci. 56: 343-56; Hanseeuw, et al. 2019, JAMA Neurol. 76: 915-924; Gordon, et al., 2019, Brain 142: 1063-1076). SUMMARY OF THE INVENTION

[0008] The present disclosure provides a recognition that one or more therapeutic agents can be useful for the treatment of Alzheimer’s disease. The present disclosure further provides the insight that using two or more therapeutic agents, particularly two or more therapeutic agents that, e.g., are different modalities and / or have different administration routes, dosing, targets, and / or mechanisms of action can result in improved clinical benefits. In some embodiments, the present disclosure provides methods of treating Alzheimer’ s disease by administering a therapeutically effective amount of an anti-beta amyloid antibody to a subject (e.g., a human subject). In some embodiments, the present disclosure provides methods of treating Alzheimer’s disease by administering a therapeutically effective amount of an oligonucleotide (e.g., an antisense oligonucleotide, e.g., a gapmer) to a subject (e.g., a human subject). In some embodiments, a method of treating Alzheimer’s disease comprises administering a therapeutically effective amount of an anti-beta amyloid antibody and a therapeutically effective amount of an oligonucleotide (e.g., an antisense oligonucleotide, e.g., a gapmer) to a subject (e.g., a human subject).

[0009] In some embodiments, the present disclosure provides a method comprising administering a therapeutically effective amount of an oligonucleotide to a human subject (e.g., a human subject suffering from Alzheimer’s disease) after the human subject (e.g., the human subject suffering from Alzheimer’s disease) has received one or more administrations of an anti-beta amyloid antibody. In some embodiments, the present disclosure provides a method comprising administering a therapeutically effective amount of an oligonucleotide to a human subject (e.g., a human subject suffering from Alzheimer’s disease) prior to the human subject (e.g., the human subject suffering from Alzheimer’s disease) receiving one or more administrations of an anti-beta amyloid antibody.

[0010] In some embodiments, the present disclosure provides a method comprising administering an anti-beta amyloid antibody to a human subject (e.g., a human subject suffering from Alzheimer’s disease) after the human subject (e.g., the human subject suffering from Alzheimer’ s disease) has received one or more administrations of a therapeutically effective amount of an oligonucleotide or salt thereof. In some embodiments, the present disclosure provides a method comprising administering an antibeta amyloid antibody to a human subject (e.g., a human subject suffering from Alzheimer’s disease) prior to the human subject (e.g., the human subject suffering from Alzheimer’ s disease) receiving one or more administrations of an oligonucleotide or salt thereof.

[0011] In some embodiments, the present disclosure provides a method comprising administering a therapeutically effective amount of an oligonucleotide concurrently with an anti-beta amyloid antibody to a human subject in need thereof (e.g., a human subject suffering from Alzheimer’s disease).

[0012] In some embodiments, an anti-beta amyloid antibody is or comprises aducanumab. In some embodiments, an anti-beta amyloid antibody is or comprises lecanemab. In some embodiments, an anti-beta amyloid antibody is or comprises donanemab. In some embodiments, an anti-beta amyloid antibody is or comprises bapineuzumab. In some embodiments, an anti-beta amyloid antibody is or comprises gantenerumab. In some embodiments, an anti-beta amyloid antibody is or comprises solanezumab. In some embodiments, an anti-beta amyloid antibody is or comprises crenezumab. In some embodiments, an anti-beta amyloid antibody is or comprises aducanumab, lecanemab, donanemab, bapineuzumab, gantenerumab, solanezumab, crenezumab, or any combination thereof.

[0013] In some embodiments, the present disclosure provides an oligonucleotide or salt thereof. In some embodiments, an oligonucleotide binds to a target RNA. In some embodiments, an oligonucleotide binds to Tau RNA (e.g., Tau mRNA). In some embodiments, an oligonucleotide is or comprises BIIB080 (MAPTRx).

[0014] Among other things, the present disclosure provides a method of treating Alzheimer’s disease in a human subject in need thereof. In some embodiments, a method described herein comprises administering to a human subject suffering from Alzheimer’s disease a therapeutically effective amount of an oligonucleotide or salt thereof.

[0015] In some embodiments, a method described herein comprises administering to a human subject a therapeutically effective amount of an oligonucleotide according to the following chemical structure:

[0016]

[0017] (nucleobase sequence of SEQ ID NO:4), or a salt thereof.

[0018] In some embodiments, a method described herein comprises administering to a human subject a therapeutically effective amount of an oligonucleotide, wherein the oligonucleotide has the following chemical notation (5’ to 3’): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Acs mCeo mCes mCes Tc (nucleobase sequence of SEQ ID NO:4); wherein,

[0019] A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,

[0020] G = a guanine nucleobase,

[0021] T = a thymine nucleobase, e = a 2’ -MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar moiety, s = a phosphorothioate intemucleoside linkage, and o = a phosphodicstcr intemucleoside linkage.

[0022] In some embodiments, a human subject has received one or more administrations of an anti-beta amyloid antibody. In some embodiments, a human subject has received one or more administrations of an anti-beta amyloid antibody prior to initiation of treatment with an oligonucleotide or salt thereof.

[0023] In some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a human subject in need thereof by administering to the human subject a therapeutically effective amount of an oligonucleotide according to the

[0024] (nucleobase sequence of SEQ ID NO:4), or a salt thereof, wherein the human subject has received one or more administrations of an anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof.

[0025] In some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a human subject in need thereof by administering to the human subject a therapeutically effective amount of an oligonucleotide, wherein the oligonucleotide has the following chemical notation (5’ to 3’): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (nucleobase sequence of SEQ ID NO:4); wherein,

[0026] A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,

[0027] G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’ -MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar' moiety, s = a phosphoro thioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage, wherein the human subject has received one or more administrations of an anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide.

[0028] In some embodiments, at least three months have elapsed between a first administration of an anti-beta amyloid antibody and a last administration of an anti-beta amyloid antibody prior to initiation of treatment with an oligonucleotide or salt thereof. In some embodiments, at least six months have elapsed between a first administration of an anti-beta amyloid antibody and a last administration of an anti-beta amyloid antibody prior to initiation of treatment with an oligonucleotide or salt thereof. In some embodiments, at least nine months have elapsed between a first administration of an antibeta amyloid antibody and a last administration of an anti-beta amyloid antibody prior to initiation of treatment with an oligonucleotide or salt thereof. In some embodiments, at least 12 months have elapsed between a first administration of an anti-beta amyloid antibody and a last administration of an anti-beta amyloid antibody prior to initiation of treatment with an oligonucleotide or salt thereof. In some embodiments, at least 18 months have elapsed between a first administration of an anti-beta amyloid antibody and a last administration of the anti-beta amyloid antibody prior to initiation of treatment with an oligonucleotide or salt thereof.

[0029] In some embodiments, a method described herein comprises measuring a beta amyloid plaque level in a human subject. In some embodiments, a method described herein comprises measuring a beta amyloid plaque level in the brain of a human subject at a first point in time and a second point in time. In some embodiments, a method described herein comprises measuring a reduction in beta amyloid plaque levels in the brain of a human subject between a first point in time and a second point in time. In some embodiments, a first point in time is prior to a first administration of an anti-beta amyloid antibody. In some embodiments, a reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time, wherein a first point in time is prior to a first administration of an anti-beta amyloid antibody. In some embodiments, a second point in time is after a last administration of the anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof. In some embodiments, a second point in time is prior to initiation of treatment with an oligonucleotide or salt thereof.

[0030] In some embodiments, at least a 50% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 60% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 70% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least an 80% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 90% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 95% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0031] In some embodiments, beta amyloid plaque levels in the brain of a human subject are measured by positron emission tomography (PET) imaging. In some embodiments, beta amyloid plaque levels in the brain of a human subject at a first point in time and a second point in time are measured by positron emission tomography (PET) imaging. In some embodiments, PET imaging identifies the brain of a human subject as amyloid negative at a second point in time. In some embodiments, “amyloid negative” is or comprises a beta amyloid plaque level that is not detected in the brain of a human subject. In some embodiments, “amyloid negative” is or comprises a beta amyloid plaque level that is present at low level in the brain of a human subject as compared to a reference. In some embodiments, a reference is or comprises a healthy control human subject. In some embodiments, a reference is or comprises a subject that has not been diagnosed with Alzheimer’s disease. In some embodiments, a reference is or comprises a subject that has not received one or more administrations of an anti -beta amyloid antibody and / or one or more administrations of an oligonucleotide or salt thereof.

[0032] In some embodiments, a method described herein comprises administering to a human subject an oligonucleotide or salt thereof in an amount that is equivalent to about 60 mg of an oligonucleotide or salt thereof. In some embodiments, a method described herein comprises administering to a human subject an oligonucleotide or salt thereof in an amount that is equivalent to about 115 mg of an oligonucleotide or salt thereof. In some embodiments, a method described herein comprises administering to a human subject an oligonucleotide or salt thereof in an amount that is equivalent to about 60 mg of an oligonucleotide once every 24 weeks. In some embodiments, a method described herein comprises administering to a human subject an oligonucleotide or salt thereof in an amount that is equivalent to about 115 mg of an oligonucleotide once every 24 weeks. In some embodiments, a method described herein comprises administering to a human subject an oligonucleotide or salt thereof in an amount that is equivalent to about 115 mg of an oligonucleotide once every 12 weeks.

[0033] In some embodiments, a method described herein comprises administering to a human subject suffering from Alzheimer’s disease a therapeutically effective amount of an anti-beta amyloid antibody. In some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a human subject in need thereof by administering to a human subject a therapeutically effective amount of an anti-beta amyloid antibody. In some embodiments, a human subject has received one or more administrations of an oligonucleotide or salt thereof. In some embodiments, a human subject has received one or more administrations of an oligonucleotide or salt thereof prior to initiation of treatment with an anti-beta amyloid antibody.

[0034] In some embodiments, the present disclosure provides a method of treating Alzheimer’ s disease in a human subject in need thereof by administering to a human subject a therapeutically effective amount of an anti-beta amyloid antibody, wherein the human subject has received one or more administrations of an oligonucleotide according

[0035] (nucleobase sequence of SEQ ID NO:4), or a salt thereof, wherein the human subject has received one or more administrations of the oligonucleotide or salt thereof prior to initiation of treatment with an anti-beta amyloid antibody. In some embodiments, the present disclosure provides a method of treating Alzheimer’ s disease in a human subject in need thereof by administering to a human subject a therapeutically effective amount of an anti-beta amyloid antibody, wherein the human subject has received one or more administrations of an oligonucleotide, wherein the oligonucleotide has the following chemical notation (5’ to 3’): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (nucleobase sequence of SEQ ID NO:4); wherein,

[0036] A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase, G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’ -MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar' moiety, s = a phosphoro thioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage.

[0037] In some embodiments, at least three months have elapsed between a first administration of an oligonucleotide or salt thereof and a last administration of an oligonucleotide or salt thereof prior to initiation of treatment with an anti-beta amyloid antibody. In some embodiments, at least six months have elapsed between a first administration of an oligonucleotide or salt thereof and a last administration of an oligonucleotide or salt thereof prior to initiation of treatment with an anti-beta amyloid antibody. In some embodiments, at least nine months have elapsed between a first administration of an oligonucleotide or salt there and a last administration of an oligonucleotide or salt thereof prior to initiation of treatment with an anti-beta amyloid antibody. In some embodiments, at least 12 months have elapsed between a first administration of an oligonucleotide or salt thereof and a last administration of an oligonucleotide or salt thereof prior to initiation of treatment with an anti-beta amyloid antibody. In some embodiments, at least 18 months have elapsed between a first administration of an oligonucleotide or salt thereof and a last administration of an oligonucleotide or salt thereof prior to initiation of treatment with an anti-beta amyloid antibody. In some embodiments, a method described herein comprises measuring Tan levels (e.g., Tau RNA levels and / or Tau protein levels) in a human subject. In some embodiments, a method described herein comprises measuring Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject. In some embodiments, a method described herein comprises measuring a reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject between a first point in time and a second point in time. In some embodiments, a first point in time is prior to a first administration of an oligonucleotide or salt thereof. In some embodiments, a reduction in Tau in the brain of a human subject has been measured between a first point in time and a second point in time, wherein a first point in time is prior to a first administration of an oligonucleotide or salt thereof. In some embodiments, a second point in time is after a last administration of an oligonucleotide or salt thereof prior to initiation of treatment with an anti-beta amyloid antibody. In some embodiments, a second point in time is prior to initiation of treatment with an anti-beta amyloid antibody.

[0038] In some embodiments, at least a 50% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 60% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels)in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 70% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least an 80% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels)in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 90% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 95% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time.

[0039] In some embodiments, Tau protein levels in the brain of a human subject is measured by positron emission tomography (PET) imaging. In some embodiments, Tau protein levels in the brain of a human subject at a first point in time and a second point in time are measured by positron emission tomography (PET) imaging. In some embodiments, PET imaging identifies the brain of a human subject as Tau negative at a second point in time. In some embodiments, “Tau negative” is or comprises a Tau level (e.g., Tau RNA level and / or Tau protein level) that is not detected in the brain of a human subject. In some embodiments, “Tau negative” is or comprises a Tau level (e.g., Tau RNA level and / or Tau protein level) that is present at low level in the brain of a human subject as compared to a reference. In some embodiments, a reference is or comprises a healthy control human subject. In some embodiments, a reference is or comprises a subject that has not been diagnosed with Alzheimer’s disease. In some embodiments, a reference is or comprises a subject that has not received one or more administrations of an anti-beta amyloid antibody and / or one or more administrations of an oligonucleotide or salt thereof.

[0040] In some embodiments, Tau levels (e.g., Tau RNA levels and / or Tau protein levels) are measured by analysis of cerebrospinal fluid samples. In some embodiments, Tau levels (e.g., Tau RNA levels and / or Tau protein levels) are measured by analysis of blood samples. In some embodiments, Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject are measured by analysis of cerebrospinal fluid and / or blood samples. In some embodiments, Tau levels (e.g., Tau RNA levels and / or Tau protein levels)in the brain of a human subject at a first point in time and a second point in time are measured by analysis of cerebrospinal fluid and / or blood samples. In some embodiments, Tau levels is or comprise Tau protein levels. In some embodiments, Tau levels is or comprise phospho-Tau levels. In some embodiments, Tau levels is or comprise phospho-Tau 181 (pTau-181) levels. In some embodiments, Tau levels is or comprise phosphor-Tau 217 (p-Tau 217) levels. In some embodiments, Tau levels is or comprise phospho-Tau 231 (p-Tau 231) levels. In some embodiments, Tau levels is or comprise MTBR-Tau containing residue 243 (MTBR-Tau243) levels. In some embodiments, Tau levels is or comprise MTBR-Tau containing residue 368 (MTBR- Tau368). In some embodiments, Tau levels is or comprise MTBR-Tau containing residue 275 (MTBR-Tau275). In some embodiments, Tau levels is or comprise MTBR-Tau containing residue 280 (MTBR-Tau280). In some embodiments, Tan levels is or comprise endogenously cleaved MTBR-Tau243 (cMTBR-Tau243).

[0041] In some embodiments, cerebrospinal fluid sample analysis identifies a human subject as Tau negative at the second point in time. In some embodiments, blood sample analysis identifies a human subject as Tau negative at the second point in time. In some embodiments, PET imaging identifies the brain of a human subject as Tau negative at a second point in time. In some embodiments, “Tau negative” is or comprises a Tau level (e.g., Tau RNA level and / or Tau protein level) that is not detected in the brain of a human subject. In some embodiments, “Tau negative” is or comprises a Tau level (e.g., Tau RNA level and / or Tau protein level) that is present at low level in the brain of a human subject as compared to a reference. In some embodiments, a reference is or comprises a healthy control human subject. In some embodiments, a reference is or comprises a subject that has not been diagnosed with Alzheimer’s disease. In some embodiments, a reference is or comprises a subject that has not received one or more administrations of an anti-beta amyloid antibody and / or one or more administrations of an oligonucleotide or salt thereof.

[0042] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti -beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody.

[0043] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0044] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0045] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti -beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month.

[0046] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months.

[0047] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months.

[0048] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, the present disclosure provides a method of treating

[0049] Alzheimer’s disease in a human subject in need thereof by administering one or more administrations of a therapeutically effective amount of an anti-beta amyloid antibody concurrently with one or more administrations of a therapeutically effective amount of an oligonucleotide to the human subject, wherein the oligonucleotide comprises the

[0050] (nucleobase sequence of SEQ ID NO:4), or a salt thereof. In some embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a human subject in need thereof, wherein the subject receives (i) one or more administrations of a therapeutically effective amount of an anti-beta amyloid antibody concurrently with (ii) one or more administrations of a therapeutically effective amount of an oligonucleotide to the human subject, wherein the oligonucleotide

[0051] (nucleobase sequence of SEQ ID NO:4), or a salt thereof.

[0052] In some embodiments, the disclosure also features a method of treating Alzheimer’s disease in a human subject in need thereof, the method comprising administering to the human subject a therapeutically effective amount of an anti-beta amyloid antibody concurrently with a therapeutically effective amount of an oligonucleotide, wherein an oligonucleotide has the following chemical notation (5’ to 3’): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCcs Tc (nuclcobasc sequence of SEQ ID NO:4); wherein,

[0053] A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,

[0054] G = a guanine nucleobase,

[0055] T = a thymine nucleobase, e = a 2’ -MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar moiety, s = a phosphoro thioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage.

[0056] In some embodiments, the disclosure provides a method of treating Alzheimer’s disease in a human subject in need thereof, wherein the subject receives (i) one or more administrations of a therapeutically effective amount of an anti-beta amyloid antibody concurrently with (ii) one or more administrations of a therapeutically effective amount of an oligonucleotide, wherein an oligonucleotide has the following chemical notation (5’ to 3’): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (nucleobase sequence of SEQ ID NO:4); wherein,

[0057] A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,

[0058] G = a guanine nucleobase,

[0059] T = a thymine nucleobase, e = a 2’ -MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar moiety, s = a phosphoro thioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage.

[0060] In some embodiments, beta amyloid plaque levels in a human subject is measured. In some embodiments, beta amyloid plaque levels in the brain of a human subject is measured. In some embodiments, a reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, a first point in time is prior to a first administration of an anti-beta amyloid antibody. In some embodiments, a second point in time is after a first administration of an anti-beta amyloid antibody. In some embodiments, a second point in time is after the last administration of an anti-beta amyloid antibody.

[0061] In some embodiments, at least a 50% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 60% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 70% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least an 80% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 90% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 95% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0062] In some embodiments, beta amyloid plaque levels in the brain of a human subject is measured by positron emission tomography (PET) imaging. In some embodiments, beta amyloid plaque levels in the brain of a human subject at a first point in time and a second point in time are measured by positron emission tomography (PET) imaging. In some embodiments, PET imaging identifies the brain of a human subject as amyloid negative at a second point in time. In some embodiments, “amyloid negative” is or comprises a beta amyloid plaque level that is not detected in the brain of a human subject. In some embodiments, “amyloid negative” is or comprises a beta amyloid plaque level that is present at low level in the brain of a human subject as compared to a reference. In some embodiments, a reference is or comprises a healthy control human subject. In some embodiments, a reference is or comprises a subject that has not been diagnosed with Alzheimer’s disease. In some embodiments, a reference is or comprises a subject that has not received one or more administrations of an anti -beta amyloid antibody and / or one or more administrations of an oligonucleotide or salt thereof.

[0063] In some embodiments, a method described herein comprises measuring Tau levels (e.g., Tau RNA levels and / or Tau protein levels). In some embodiments, a method described herein comprises measuring Tau levels (c.g., Tau RNA levels and / or Tau protein levels) in a human subject. In some embodiments, a method described herein comprises measuring Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject. In some embodiments, a method described herein comprises measuring a reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject between a first point in time and a second point in time. In some embodiments, a first point in time is prior to a first administration of an oligonucleotide or a salt thereof. In some embodiments, a reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, a first point in time is prior to a first administration of an oligonucleotide or a salt thereof. In some embodiments, a second point in time is after a first administration of an oligonucleotide or salt thereof. In some embodiments, a second point in time is after the last administration of an oligonucleotide or salt thereof.

[0064] In some embodiments, at least a 50% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 60% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 70% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least an 80% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 90% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, at least a 95% reduction in Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, Tan levels (e.g., Tan RNA levels and / or Tan protein levels) in the brain of a human subject at a first point in time and a second point in time are measured by positron emission tomography (PET) imaging.

[0065] In some embodiments, PET imaging identifies the brain of a human subject as Tau negative at a second point in time. In some embodiments, “Tau negative” is or comprises a Tau level (e.g., Tau RNA level and / or Tau protein level) that is not detected in the brain of a human subject. In some embodiments, “Tau negative” is or comprises a Tau level (e.g., Tau RNA level and / or Tau protein level) that is present at low level in the brain of a human subject as compared to a reference. In some embodiments, a reference is or comprises a healthy control human subject. In some embodiments, a reference is or comprises a subject that has not been diagnosed with Alzheimer’s disease. In some embodiments, a reference is or comprises a subject that has not received one or more administrations of an anti-beta amyloid antibody and / or one or more administrations of an oligonucleotide or salt thereof.

[0066] In some embodiments, Tau levels (e.g., Tau RNA levels and / or Tau protein levels) are measured by analysis of cerebrospinal fluid samples. In some embodiments, Tau levels (e.g., Tau RNA levels and / or Tau protein levels) are measured by analysis of blood samples. In some embodiments, Tau levels (e.g., Tau RNA levels and / or Tau protein levels)in the brain of a human subject are measured by analysis of cerebrospinal fluid and / or blood samples. In some embodiments, Tau levels (e.g., Tau RNA levels and / or Tau protein levels) in the brain of a human subject at a first point in time and a second point in time are measured by analysis of cerebrospinal fluid and / or blood samples. In some embodiments, Tau levels is or comprise Tau protein levels, phospho- Tau levels, phospho-Tau 181 (pTau-181) levels, phosphor-Tau 217 (p-Tau 217) levels, and / or phospho-Tau 231 (p-Tau 231) levels. In some embodiments, Tau levels is or comprise MTBR-Tau containing residue 243 (MTBR-Tau243) levels. In some embodiments, Tau levels is or comprise MTBR-Tau containing residue 368 (MTBR- Tau368). In some embodiments, Tau levels is or comprise MTBR-Tau containing residue 275 (MTBR-Tau275). In some embodiments, Tau levels is or comprise MTBR-Tau containing residue 280 (MTBR-Tau280). In some embodiments, Tau levels is or comprise endogenously cleaved MTBR-Tau243 (eMTBR-Tau243). In some embodiments, cerebrospinal fluid sample analysis identifies a human subject as Tau negative at the second point in time. In some embodiments, blood sample analysis identifies a human subject as Tau negative at the second point in time. In some embodiments, “Tau negative” is or comprises a Tau level (e.g., Tau RNA level and / or Tau protein level) that is not detected in the brain of a human subject. In some embodiments, “Tau negative” is or comprises a Tau level (e.g., Tau RNA level and / or Tau protein level) that is present at low level in the brain of a human subject as compared to a reference. In some embodiments, a reference is or comprises a healthy control human subject. In some embodiments, a reference is or comprises a subject that has not been diagnosed with Alzheimer’s disease. In some embodiments, a reference is or comprises a subject that has not received one or more administrations of an anti-beta amyloid antibody and / or one or more administrations of an oligonucleotide or salt thereof.

[0067] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody.

[0068] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0069] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0070] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti -beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every month.

[0071] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 3 months.

[0072] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 4 months.

[0073] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 6 months.

[0074] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year'. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year. In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every year.

[0075] In some embodiments, an Alzheimer’s disease is prcclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, mild Alzheimer’s disease, early Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease dementia, mild cognitive impairment due to Alzheimer’s disease, mid-stage Alzheimer’s disease, or latestage Alzheimer’s disease. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease. In some embodiments, an Alzheimer’s disease is presymptomatic Alzheimer’s disease. In some embodiments, an Alzheimer’s disease is early Alzheimer’s disease. In some embodiments, an Alzheimer’s disease is mild cognitive impairment due to Alzheimer’s disease. In some embodiments, an Alzheimer’s disease is mild Alzheimer’s disease dementia.

[0076] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an antibeta amyloid antibody is aducanumab, and at least a 50% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is aducanumab, and at least a 60% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is aducanumab, and at least a 70% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an antibeta amyloid antibody is aducanumab, and at least a 80% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is aducanumab, and at least a 90% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is aducanumab, and at least a 95% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0077] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is aducanumab, and beta amyloid plaque levels in the brain of a human subject at a first point in time and a second point in time are measured by PET imaging. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is aducanumab, and PET imaging identifies the brain of a human subject as amyloid negative at a second point in time.

[0078] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is lecanemab, and at least a 50% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is lecanemab, and at least a 60% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is lecanemab, and at least a 70% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is lecanemab, and at least a 80% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is lecanemab, and at least a 90% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is lecanemab, and at least a 95% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0079] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is lecanemab, and beta amyloid plaque levels in the brain of a human subject at a first point in time and a second point in time are measured by PET imaging. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an antibeta amyloid antibody is lecancmab, and PET imaging identifies the brain of a human subject as amyloid negative at a second point in time.

[0080] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an antibeta amyloid antibody is donanemab, and at least a 50% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0081] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is donanemab, and at least a 60% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0082] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is donanemab, and at least a 70% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is donanemab, and at least a 80% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’ s disease, presymptomatic Alzheimer’ s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is donanemab, and at least a 90% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is donanemab, and at least a 95% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0083] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an antibeta amyloid antibody is donanemab, and beta amyloid plaque levels in the brain of a human subject at a first point in time and a second point in time are measured by PET imaging. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’ s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an antibeta amyloid antibody is donanemab, and PET imaging identifies the brain of a human subject as amyloid negative at a second point in time.

[0084] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is bapineuzumab, and at least a 50% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is bapineuzumab, and at least a 60% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is bapineuzumab, and at least a 70% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is prcclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is bapineuzumab, and at least a 80% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is bapineuzumab, and at least a 90% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’ s disease is preclinical Alzheimer’ s disease, presymptomatic Alzheimer’ s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is bapineuzumab, and at least a 95% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0085] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is bapineuzumab, and beta amyloid plaque levels in the brain of a human subject at a first point in time and a second point in time are measured by PET imaging. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is bapineuzumab, and PET imaging identifies the brain of a human subject as amyloid negative at a second point in time.

[0086] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti- beta amyloid antibody is gantenerumab, and at least a 50% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is gantenerumab, and at least a 60% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is gantenerumab, and at least a 70% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is gantenerumab, and at least a 80% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is gantenerumab, and at least a 90% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is gantenerumab, and at least a 95% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0087] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is gantenerumab, and beta amyloid plaque levels in the brain of a human subject at a first point in time and a second point in time are measured by PET imaging. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is gantenerumab, and PET imaging identifies the brain of a human subject as amyloid negative at a second point in time.

[0088] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is solanezumab, and at least a 50% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is solanezumab, and at least a 60% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’ s disease is preclinical Alzheimer’ s disease, presymptomatic Alzheimer’ s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is solanezumab, and at least a 70% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an antibeta amyloid antibody is solanezumab, and at least a 80% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is solanezumab, and at least a 90% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is solanezumab, and at least a 95% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0089] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an antibeta amyloid antibody is solanezumab, and beta amyloid plaque levels in the brain of a human subject at a first point in time and a second point in time are measured by PET imaging. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’ s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is solanezumab, and PET imaging identifies the brain of a human subject as amyloid negative at a second point in time.

[0090] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is crenezumab, and at least a 50% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is crenezumab, and at least a 60% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. Tn some embodiments, an Alzheimer’ s disease is prcclinical Alzheimer’ s disease, prcsymptomatic Alzheimer’ s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti-beta amyloid antibody is crenezumab, and at least a 70% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an antibeta amyloid antibody is crenezumab, and at least a 80% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is crenezumab, and at least a 90% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time. In some embodiments, an Alzheimer’ s disease is preclinical Alzheimer’ s disease, presymptomatic Alzheimer’ s disease, early Alzheimer’ s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’s disease dementia, an anti-beta amyloid antibody is crenezumab, and at least a 95% reduction in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0091] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an antibeta amyloid antibody is crenezumab, and beta amyloid plaque levels in the brain of a human subject at a first point in time and a second point in time are measured by PET imaging. In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease, presymptomatic Alzheimer’s disease, early Alzheimer’s disease, mild cognitive impairment due to Alzheimer’ s disease, or mild Alzheimer’ s disease dementia, an anti- beta amyloid antibody is crenezumab, and PET imaging identifies the brain of a human subject as amyloid negative at a second point in time.

[0092] In some embodiments, a method described herein comprises administering a loading dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of BIIB080 once about every 4 weeks, and subsequently administering a maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of BIIB080 once about every 8 weeks, once about every 16 weeks, once about every 24 weeks, or once about every 6 months. In some embodiments, a method described herein comprises administering a loading dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of BIIB080 once about every 8 weeks, and subsequently administering a maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of BIIB080 once about every 16 weeks, once about every 24 weeks, or once about every 6 months. In some embodiments, a method described herein comprises administering a loading dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of BIIB080 once about every 12 weeks, and subsequently administering a maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of BIIB080 once about every 16 weeks, once about every 24 weeks, or once about every 6 months. In some embodiments, a method described herein comprises administering at least 2 loading doses, at least 3 loading doses, at least 4 loading doses, at least 5 loading doses, or at least 6 loading doses.

[0093] In some embodiments, a method described herein comprises administering a loading dose of about 60 mg to about 115 mg once about every 4 weeks, and subsequently administering a maintenance dose of about 60 mg to about 115 mg of BIIB080 once about every 8 weeks, once about every 16 weeks, once about every 24 weeks, or once about every 6 months. In some embodiments, a method described herein comprises administering a loading dose of about 60 mg to about 115 mg of BIIB080 once about every 8 weeks, and subsequently administering a maintenance dose of about 10 mg, about 30 mg, about 60 mg, about 90 mg, or about 115 mg of BIIB080 once about every 16 weeks, once about every 24 weeks, or once about every 6 months. In some embodiments, a method described herein comprises administering a loading dose of about 60 mg to about 115 mg of BIIB080 once about every 12 weeks, and subsequently administering a maintenance dose of about 60 mg to about 1 15 mg of BIIB080 once about every 16 weeks, once about every 24 weeks, or once about every 6 months.

[0094] In some embodiments, a method described herein comprises administering a loading dose of about 60 mg of BIIB080 once about every 12 weeks, and subsequently administering a maintenance dose of about 60 mg of BIIB080 once about every 6 months. In some embodiments, a method described herein comprises administering a loading dose of about 115 mg of BIIB080 once about every 12 weeks, and subsequently administering a maintenance dose of about 115 mg of BIIB080 once about every 6 months. In some embodiments, a method described herein comprises administering a loading dose of about 60 mg to about 115 mg of BIIB080 once about every 12 weeks, and subsequently administering a maintenance dose of about 60 mg to about 115 mg of BIIB080 once about every 6 months.

[0095] Among other things, the present disclosure provides a method for treating a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease. In some embodiments, a method described herein comprises treating a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease prior to receiving a diagnosis of Alzheimer’s disease. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease has not been diagnosed with Alzheimer’s disease.

[0096] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the ail to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the exemplary methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present application, including definitions, will control. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0097] Other features and advantages of the invention will be apparent from the following detailed description and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] The drawings are for illustration purposes only, not for limitation.

[0099] Figure 1 shows a schematic of quantitative systems pharmacology (QSP) model that accounts for changes in amyloid beta and Tau biomarkers, as well as capturing the interaction between both amyloid beta and Tau pathology by amyloid beta plaquedependent Tau hyperphosphorylation that drives neurofibrillary tangle formation in Braak region 1 / 2 (transentorhinal). QSP model also observes Tau pathology spreading to Braak regions 3 / 4 (limbic) and Braak regions 5 / 6 (neocortical).

[0100] Figure 2 shows QSP model evaluating amyloid positron emission tomography (PET) ccntiloids (also referred to herein as “plaque burden”) for >70 datasets involving subjects treated with either placebo, 10 mg / kg of an anti-amyloid antibody (AAA) dosed once every 2 weeks (Q2W), 115 mg of BIIB080 dosed once every 3 months (Q3M), or an AAA (10 mg / kg dosed Q2W) simultaneously with BIIB080 (115 mg dosed Q3M).

[0101] Figure 3 shows models evaluating change in standardized uptake value ratio (SUVR) of Tau PET from baseline as measured, from left to right, in the transentorhinal (“Region 1 / 2”), limbic (“Regions 3 / 4”), or neocortical (“Regions 5 / 6”) regions of subjects treated with either 115 mg of BIIB080 dosed Q3M, AAA (10 mg / kg dosed Q2W) simultaneously with BIIB080 (115 mg dosed Q3M), 10 mg / kg of an anti-amyloid antibody (AAA) dosed once (Q2W), or placebo.

[0102] Figure 4 shows QSP model evaluating amyloid PET centiloids involving subjects treated with either placebo, an AAA (10 mg / kg dosed Q2W) then BIIB080 (115 mg dosed Q3M), BIIB080 (115 mg dosed Q3M) then an AAA (10 mg / kg dosed Q2W), or an AAA (10 mg / kg dosed Q2W) simultaneously with BIIB080 (115 mg dosed Q3M).

[0103] Figure 5 shows models evaluating change in standardized uptake value ratio (SUVR) of Tau protein PET from baseline as measured, from left to right, Region 1 / 2, Region 3 / 4, or Region 5 / 6 of subjects treated with either placebo, an AAA (10 mg / kg dosed Q2W) then BIIB080 (115 mg dosed Q3M), BIIB080 (115 mg dosed Q3M) then an AAA (10 mg / kg dosed Q2W), or an AAA (10 mg / kg dosed Q2W) simultaneously with BIIB080 (115 mg dosed Q3M). Figures 6A and 6B show models evaluating changes in Clinical Dementia Rating scale Sum of Boxes (CDR-SB) and integrated Alzheimer’s Disease Rating Scale (iADRS) scores involving subjects treated with an AAA simultaneously with BIIB080, or only BIIB080. Dotted line marks the end of treatment. Figure 6A shows subjects treated with an AAA (10 mg / kg dosed Q2W) simultaneously with BIIB080 (115 mg dosed Q3M), or only BIIB080 (115 mg dosed Q3M). Figure 6B shows subjects treated with an AAA (10 mg / kg dosed Q4W) simultaneously with BIIB080 (115 mg dosed Q6M), or only BIIB080 (115 mg dosed Q6M).

[0104] Figure 7 shows models evaluating changes in CDR-SB and iADRS scores involving subjects treated with an AAA simultaneously with BIIB080. Subjects are treated with 10 mg / kg of an AAA Q2W for 18 months then Q4W and 115 mg of BIIB080 Q3M, or only 115 mg of BIIB080 Q3M .

[0105] Figure 8 shows models evaluating changes in CDR-SB and iADRS scores involving subjects treated with 10 mg / kg of an anti-amyloid antibody Q2W for 18 months then Q4W, and 115 mg of BIIB080 Q3M about 3 years, 4 years, or 5 years prior to onset of Alzheimer’s disease.

[0106] Figures 9A and 9B show models evaluating changes in CDR-SB (Figure 9A) and iADRS (Figure 9B) scores involving subjects with varying levels of Tau burden. Subjects were treated with 10 mg / kg of an anti-amyloid antibody Q2W for 18 months then Q4W indefinitely and 115 mg of BIIB080 Q3M about 4 years prior to an onset of Alzheimer’s disease.

[0107] Figures 10A and 10B show models evaluating changes in CDR-SB (Figure 10A) and iADRS (Figure 10B) scores involving presymptomatic Alzheimer’s disease subjects treated with 115 mg of BIIB080 Q12M, Q6M, or Q3M about 5 years, 10 years, or 15 years prior to onset of Alzheimer’s disease.

[0108] Figures 11A and 11B show models evaluating changes in CDR-SB and iADRS scores involving presymptomatic Alzheimer’s disease subjects treated with 115 mg of BIIB080 Q12M, Q6M, or Q3M about 5 years, 10 years, or 15 years prior to an onset of Alzheimer’s disease. Figure 12 shows models evaluating changes in CDR-SB and iADRS scores involving subjects treated with an AAA followed by BIIB080. Subjects were treated with either (i) 115 mg of BIIB080 Q3M only, (ii) 10 mg / kg of an AAA Q2W for 18 months then Q4W simultaneously with 115 mg of BIIB080 Q3M, (iii) or 10 mg / kg of an AAA Q2W for 18 months then Q4W, then with 115 mg of BIIB080 Q3M 1.5 year’s, 2.5 year, or 3.5 years after starting treatment with an AAA.

[0109] DEFINITIONS

[0110] Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well- known and commonly used in the art. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety.

[0111] Unless otherwise indicated, the following terms have the following meanings:

[0112] As used herein, “2’-deoxyribonucleoside” means a nucleoside comprising a 2’- H(H) deoxyribosyl sugar- moiety. In some embodiments, a 2’ -deoxyribonucleoside is a 2’ -P-D deoxyribonucleoside and comprises a 2’-P-D-deoxyribosyl sugar moiety, which has the P-D configuration as found in naturally occurring deoxyribonucleic acids (DNA). In some embodiments, a 2’ -deoxyribonucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (uracil).

[0113] As used herein, “2’-M0E” means a 2’-OCH2CH2OCH3 group in place of the 2’- OH group of a ribosyl sugar- moiety. A “2’ -MOE sugar moiety” is a sugar- moiety with a 2’-OCH2CH2OCH3 group in place of the 2’ -OH group of a ribosyl sugar moiety. Unless otherwise indicated, a 2’ -MOE sugar- moiety is in the P-D configuration. “MOE” means O-methoxyethyl.

[0114] As used herein, “2’-M0E nucleoside” means a nucleoside comprising a 2’-M0E sugar moiety.

[0115] As used herein, “5-methyl cytosine” means a cytosine modified with a methyl group attached to the 5 position. A 5-methyl cytosine is a modified nucleobase. As used herein, “about” refers to a value that is similar to a stated reference value. In general, the relevant degree of variance encompassed by “about” in that context. For example, in some embodiments, the term “about” may encompass a range of values that are within (i.e., ±) 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0116] As used herein, “administering” means providing a pharmaceutical agent to a human subject.

[0117] As used herein, “ameliorate” in reference to a treatment means improvement in at least one symptom or sign relative to the same symptom or sign in the absence of the treatment. In some embodiments, amelioration is the reduction in the severity or frequency of a symptom or sign, or the delayed onset or slowing of progression in the severity or frequency of a symptom or sign.

[0118] As used herein, “CAG repeat” means one of multiple contiguous trinucleotide units, wherein each trinucleotide unit consists of three contiguous nucleosides having a nucleobase sequence from 5’ to 3’ of cytosine (C), adenine (A), and guanine (G).

[0119] As used herein, “dose” means a quantity of a pharmaceutical agent administered.

[0120] As used herein, the term “intemucleoside linkage” means the covalent linkage between contiguous nucleosides in an oligonucleotide. As used herein “modified intemucleoside linkage” means any internucleoside linkage other than a phosphodiester intemucleoside linkage. “Phosphorothioate intemucleoside linkage” is a modified intemucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester intemucleoside linkage is replaced with a sulfur atom.

[0121] As used herein, “loading dose” means a therapeutically effective amount of a pharmaceutical agent administered during an initial dosing phase during which steady state concentration of the pharmaceutical agent is achieved. “Initial loading dose” means the first loading dose administered. “Last loading dose” means the loading dose administered most recently prior to administering a first maintenance dose.

[0122] As used herein, “maintenance dose” means a therapeutically effective amount of a pharmaceutical agent administered during a dosing phase after steady state concentration of the pharmaceutical agent has been achieved. As used herein, the terms “MAPTRX” and “ISIS 814907” and “BTIB080” are interchangeable.

[0123] As used herein, “nucleobase” means an unmodified nucleobase or modified nucleobase. An “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). A “modified nucleobase” is group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one unmodified nucleobase. A “5-methyl cytosine” is a modified nucleobase. As used herein, “nucleobase sequence” means the order of contiguous nucleobases in a target nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage modification.

[0124] As used herein, “nucleoside” means a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. As used herein, “modified nucleoside” means a nucleoside comprising a modified nucleobase and / or a modified sugar moiety. “Linked nucleosides” are nucleosides that are connected in a contiguous sequence (i.e., no additional nucleosides are presented between those that are linked). As used herein, “oligonucleotide” means a strand of linked nucleosides connected via internucleoside linkages, wherein each nucleoside and internucleoside linkage may be modified or unmodified. Unless otherwise indicated, oligonucleotides consist of 8-50 linked nucleosides. As used herein, “modified oligonucleotide” means an oligonucleotide, wherein at least one nucleoside or intemucleoside linkage is modified.

[0125] As used herein, the term “patient” includes any human subject who may benefit from therapy with an oligonucleotide or salt thereof described herein (e.g., BIIB080) and / or anti-beta amyloid antibody described herein (e.g., aducanumab, lecanemab, donanemab, bapineuzumab, gantenerumab, solanezumab, crenezumab, etc.).

[0126] As used herein, “pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to a human subject. Certain such carriers enable pharmaceutical compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension, and lozenges for the oral ingestion by a human subject. In some embodiments, a pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer solution, or sterile artificial cerebrospinal fluid (aCSF). As used herein, “pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds. Pharmaceutically acceptable salts retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

[0127] As used herein, “potassium salt” means a salt of a modified oligonucleotide, wherein the cation of the salt is potassium.

[0128] As used herein, “RNA” means an RNA transcript and includes pre-mRNA and mature mRNA unless otherwise specified.

[0129] As used herein, “sodium salt” means a salt of a modified oligonucleotide, wherein the cation of the salt is sodium.

[0130] As used herein, “subject” means a human or non-human animal. In some embodiments, the subject is a human subject. A “subject in need thereof,” is a subject who would benefit from administration of a modified oligonucleotide disclosed herein. In some embodiments, the subject in need thereof has Alzheimer’s disease (AD).

[0131] As used herein, “sugar moiety” means an unmodified sugar moiety or a modified sugar’ moiety. “Unmodified sugar’ moiety” means a 2’-0H(H) P-D ribosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2’-H(H) -D deoxyribosyl moiety, as found in DNA (an “unmodified DNA sugar moiety”). Unmodified sugar moieties have one hydrogen at each of the 1’, 3’, and 4’ positions, an oxygen at the 3’ position, and two hydrogens at the 5’ position. “Modified sugar moiety” or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate.

[0132] As used herein, “symptom or sign” means any physical feature or test result that indicates the existence or extent of a disease or disorder. In some embodiments, a symptom is apparent to a subject or to a medical professional examining or testing said subject. In some embodiments, a sign is apparent upon invasive diagnostic testing, including, but not limited to, post-mortem tests. In some embodiments, a sign is apparent on a brain MRI scan.

[0133] As used herein, “Tau RNA” is equivalent to “MAPT RNA” and is the RNA expression product of the human gene, MAPT. As used herein, “MAPT gene” refers to a genomic sequence encoding a Tau RNA.

[0134] As used herein, “Tau protein” is the protein expression product of Tau RNA. As used herein, “Tau neurofibrillary tangle” is the intracellular aggregate of hyperphosphorylated Tau protein.

[0135] As used herein, “therapeutically effective amount” means an amount of a pharmaceutical agent that provides a therapeutic benefit to a human subject. For example, a therapeutically effective amount improves a symptom or sign of a disease or disorder.

[0136] As used herein, the term “treat,” “treatment,” or “treating” refers to any method (or related agent or composition) used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. A treatment may be administered to a human subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, a treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0137] As used herein, “trough concentration” means the concentration of an analyte (e.g., Tau protein, and / or Tau neurofibrillary tangle) in a biological sample taken from a dosed human subject immediately prior to the human subject receiving a subsequent dose or the concentration of an analyte on the last study day.

[0138] As used herein, “week” means 7 days.

[0139] DETAILED DESCRIPTION

[0140] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and / or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

[0141] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, arc hereby expressly incorporatcd-by-rcfcrcncc for the portions of the document discussed herein, as well as in their entirety.

[0142] I. MAPT

[0143] Tau RNA is encoded by the human MAPT gene, located on human 17 ( 17q21.31 ). Tau protein is the protein expression product of Tau RNA. Tau protein is highly expressed in neurons relative to other cell types. A representative nucleobase sequence for a human MAPT gene is provided at GENBANK Accession No. NT_010783.14 truncated from nucleotides 2624000 to 2761000, incorporated herein as SEQ ID NO: 2. A representative nucleobase sequence for a human Tau RNA is provided at GENBANK Accession No. NM_001377265, incorporated herein as SEQ ID NO: 1. A representative protein sequence for a human Tau protein is provided at GENBANK Accession No. NP_001364194.1, incorporated here in as SEQ ID NO: 3.

[0144] II. Tau

[0145] Tau proteins form a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT (microtubule-associated protein Tau) (see, e.g., Buchholz S, Zempel H. The six brain-specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes. Alzheimers Dement. 2024;20(5):3606-3628. doi: 10.1002 / alz.13784, which is hereby incorporated by reference).

[0146] Tau neurofibrillary tangles are intracellular aggregates of hyperphosphorylated Tau protein. In some embodiments, Tau is phosphorylated (“p-Tau) at one or more positions selected from: Y18, S46, T50, S69, T71, SI 13, T123, T153, T175, T181, S184, S85, S 191, Y197, S198, S199, S202, T205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S289, S356, Y397, S400, T403, S404, S409, S412, S413, T414 / S416, S422, T427, S433, and S435. In some embodiments, Tau protein is or comprises phospho-Tau 181 (pTau-181). In some embodiments, Tau protein is or comprises phospho-Tau 217 (p-Tau 217). In some embodiments, Tau protein is or comprises phospho-Tau 231 (p-Tau 231). In some embodiments, Tan protein is or comprises microtubule-binding region (MTBR) -containing Tau. Without wishing to be bound by any particular theory, MTBR- containing Tau is enriched in aggregates in the brain of subjects (e.g., human subjects) suffering from Alzheimer’s Disease (see, e.g., Taniguchi- Watanabe, Sayuri et al. “Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau.” Acta neuropathologica vol. 131,2 (2016): 267-280.; and Roberts, Malcolm et al. “Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease.” Acta neuropathologica communications vol. 8,1 13. 4 Feb. 2020, each of which are hereby incorporated by reference).

[0147] In some embodiments, Tau protein is or comprises MTBR-Tau containing residue 243 (MTBR-Tau243). In some embodiments, Tau protein is or comprises MTBR-Tau containing residue 368 (MTBR-Tau368). In some embodiments, Tau protein is or comprises MTBR-Tau containing residue 275 (MTBR-Tau275). In some embodiments, Tau protein is or comprises MTBR-Tau containing residue 280 (MTBR-Tau280). In some embodiments, Tau protein is or comprises endogenously cleaved MTBR-Tau243 (eMTBR-Tau243).

[0148] III. BIIB080

[0149] In some embodiments, the present disclosure provides a method comprising administering a modified oligonucleotide to a subject in need thereof. In some embodiments, a modified oligonucleotide is or comprises BIIB080 (MAPTRX). In some embodiments, BIIB080 is characterized as a 5-8-5 MOE gapmer, having a sequence of (from 5’ to 3’) CCGTTTTCTTACCACCCT (incorporated herein as SEQ ID NO:4), wherein each of nucleosides 1-5 and 14-18 are 2’-M0E nucleosides and each of nucleosides 6-13 are 2’ -deoxynucleosides, wherein the internucleoside linkages between nucleoside 2 and nucleoside 3 and nucleoside 15 to nucleoside 16 are phosphodiester intemucleoside linkages and the remainder of the intemucleoside linkages are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5- methylcytosine. In some embodiments, BIIB080 is characterized by the following chemical notation: mCcs mCco Ges Tcs Tcs Tds Tds mCds Tds Tds Ads mCds mCds Acs mCco mCes mCes Te (nucleobase sequence of SEQ ID NO:4); wherein,

[0150] A = an adenine, mC = a 5-methylcytosine,

[0151] G = a guanine,

[0152] T = a thymine, e = a 2’ -MOE nucleoside, d = a 2’ -deoxy nucleoside, s = a phosphorothioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage.

[0153] In some embodiments, BIIB080 is characterized by the following chemical structure:

[0154]

[0155] (nucleobase sequence of SEQ ID NO:4).

[0156] Structure 1. BIIB080 In some embodiments, the sodium salt of BIIB080 is represented by the following chemical structure:

[0157]

[0158] (nucleobase sequence of SEQ ID NO:4).

[0159] Structure 2. Sodium salt of BIIB080 IV. Certain BIIB080 Pharmaceutical Compositions

[0160] In some embodiments, the present disclosure provides a method of administering to a subject a pharmaceutical composition comprising BIIB080. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable diluent or carrier. In some embodiments, a pharmaceutical composition comprises or consists essentially of a sterile saline solution and BIIB080. In some embodiments, a sterile saline is pharmaceutical grade saline. In some embodiments, a pharmaceutical composition comprises or consists essentially of sterile water and BIIB080. In some embodiments, the sterile water is pharmaceutical grade water. In some embodiments, the pharmaceutical composition comprises or consists essentially of artificial cerebrospinal fluid (aCSF) and BIIB080. In some embodiments, the artificial cerebrospinal fluid is pharmaceutical grade. In some embodiments, a pharmaceutical composition comprises a certain concentration of BIIB080 in aCSF, and is diluted in aCSF diluent to achieve the intended clinical dose. In some embodiments, BIIB080 is formulated in aCSF at 30 mg / mL and is diluted in aCSF diluent to achieve the intended clinical dose. In some embodiments, BIIB080 is formulated in aCSF at 20 mg / mL and is diluted in aCSF diluent to achieve the intended clinical dose. In some embodiments, aCSF is a solution designed to mimic the composition and properties (e.g., electrolyte concentrations) of natural cerebrospinal fluid.

[0161] In some embodiments, a pharmaceutical composition comprises one or more excipients and BIIB080. In some embodiments, an excipient is or comprises water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, or polyvinylpyrrolidone. In some embodiments, a pharmaceutical composition comprising BIIB080 encompass any pharmaceutically acceptable salt of BIIB080, esters of BIIB080, or salts of such esters. In some embodiments, a pharmaceutical composition comprising BIIB080 is capable of providing (directly or indirectly) a biologically active metabolite or residue thereof upon administration to a human subject. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of BIIB080, prodrugs of BIIB080, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.

[0162] In some embodiments, a pharmaceutical composition comprises one or more lipid moieties and BIIB080. In some embodiments, lipid moieties are used to increase distribution of BIIB080 to a particular cell or tissue. In certain such methods, BIIB080 is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids. In certain methods, DNA complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid.

[0163] In some embodiments, a pharmaceutical composition disclosed herein comprises a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing pharmaceutical compositions including those comprising hydrophobic compounds. In some embodiments, certain organic solvents such as dimethylsulfoxide are used.

[0164] In some embodiments, a pharmaceutical composition comprises one or more tissue-specific delivery molecules designed to deliver a modified oligonucleotide described herein to specific tissues or cell types. For example, in some embodiments, a pharmaceutical composition includes liposomes coated with a tissue- specific antibody.

[0165] In some embodiments, a pharmaceutical composition comprises a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In some embodiments, such co-solvent systems are used for hydrophobic compounds. A nonlimiting example of such a co-solvent system is a VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant Polysorbate 80™ and 65% w / v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

[0166] In some embodiments, a pharmaceutical composition is prepared for oral administration. In some embodiments, a pharmaceutical composition is prepared for buccal administration. In some embodiments, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, intrathecal (IT), intracerebroventricular (ICV)). In some embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as aCSF, water, or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In some embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In some embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection arc suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.

[0167] Under certain conditions, BIIB080 acts as an acid. Although BIIB080 may be drawn or described in protonated (free acid) form, or ionized and in association with a cation (salt) form, aqueous solutions of BIIB080 exist in equilibrium among such forms. For example, a phosphate linkage of BIIB080 in aqueous solution exists in equilibrium among free acid, anion, and salt forms. Unless otherwise indicated, the term, “BIIB080,” is intended to include all such forms. Moreover, BIIB080 has several such linkages, each of which is in equilibrium. Thus, BIIB080 exists in solution in an ensemble of forms at multiple positions all at equilibrium. The term “BIIB080” is intended to include all such forms. Drawn structures necessarily depict a single form. Nevertheless, unless otherwise indicated, such drawings are likewise intended to include corresponding forms. Herein, a structure depicting the free acid of BIIB080 followed by the term “or a salt thereof’ expressly includes all such forms that may be fully or partially protonated / de- protonated / in association with a cation. In certain instances, one or more specific cation is identified.

[0168] In some embodiments, BIIB080 is in aqueous solution with sodium. In some embodiments, BIIB080 is in aqueous solution with potassium. In some embodiments, BIIB080 is in PBS. In some embodiments, BIIB080 is in water. In certain such embodiments, the pH of the solution is adjusted with NaOH and / or HC1 to achieve a desired pH.

[0169] Herein, certain specific doses are described. For clarity, a dose of BIIB080 in milligrams indicates the mass of the free acid form of BIIB080. As described above, in aqueous solution, the free acid is in equilibrium with anionic and salt forms. However, for the purpose of calculating dose, it is assumed that BIIB080 exists as a solvent-free, sodium- acetate free, anhydrous, free acid. For example, where BIIB080 is in solution comprising sodium (e.g., saline), BIIB080 may be partially or fully de-protonated and in association with Na+ ions. However, the mass of the protons is nevertheless counted toward the weight of the dose, and the mass of the Na+ ions arc not counted toward the weight of the dose. Thus, for example, a dose of 60 mg of BIIB080 equals the number of fully protonated molecules that weighs 60 mg. This would be equivalent to 63.48 mg of solvent- free, sodium-acetate free, anhydrous sodiated BIIB080. Similarly, a dose of 115 mg of BIIB080 equals the number of fully protonated molecules that weighs 115 mg. This would be equivalent to 121.67 mg of solvent-free, sodium-acetate free, anhydrous sodiated BIIB080.

[0170] V. Certain BIIB080 Dosage Amounts

[0171] In some embodiments, the present disclosure provides a method comprising administering to a subject a therapeutically effective amount of BIIB080. In some embodiments, a therapeutically effective amount is 10 mg. In some embodiments, a therapeutically effective amount is 30 mg. In some embodiments, a therapeutically effective amount is 60 mg. In some embodiments, a therapeutically effective amount is 90 mg. In some embodiments, a therapeutically effective amount is 115 mg.

[0172] In some embodiments, a therapeutically effective amount is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg,

[0173] 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg,

[0174] 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg,

[0175] 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg,

[0176] 330 mg, 335 mg, 340 mg, 345 mg, or 350 mg.

[0177] In some embodiments, a therapeutically effective amount is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, or about 350 mg.

[0178] In some embodiments, a therapeutically effective amount is 50 mg, 50.1 mg, 50.2 mg, 50.3 mg, 50.4 mg, 50.5 mg, 50.6 mg, 50.7 mg, 50.8 mg, 50.9 mg, 51 mg, 51.1 mg,

[0179] 51.2 mg, 51.3 mg, 51.4 mg, 51.5 mg, 51.6 mg, 51.7 mg, 51.8 mg, 51.9 mg, 52 mg, 52.1 mg, 52.2 mg, 52.3 mg, 52.4 mg, 52.5 mg, 52.6 mg, 52.7 mg, 52.8 mg, 52.9 mg, 53 mg,

[0180] 53.1 mg, 53.2 mg, 53.3 mg, 53.4 mg, 53.5 mg, 53.6 mg, 53.7 mg, 53.8 mg, 53.9 mg, 54 mg, 54.1 mg, 54.2 mg, 54.3 mg, 54.4 mg, 54.5 mg, 54.6 mg, 54.7 mg, 54.8 mg, 54.9 mg, 55 mg, 55.1 mg, 55.2 mg, 55.3 mg, 55.4 mg, 55.5 mg, 55.6 mg, 55.7 mg, 55.8 mg, 55.9 mg, 56 mg, 56.1 mg, 56.2 mg, 56.3 mg, 56.4 mg, 56.5 mg, 56.6 mg, 56.7 mg, 56.8 mg, 56.9 mg, 57 mg, 57.1 mg, 57.2 mg, 57.3 mg, 57.4 mg, 57.5 mg, 57.6 mg, 57.7 mg, 57.8 mg, 57.9 mg, 58 mg, 58.1 mg, 58.2 mg, 58.3 mg, 58.4 mg, 58.5 mg, 58.6 mg, 58.7 mg, 58.8 mg, 58.9 mg, 59 mg, 59.1 mg, 59.2 mg, 59.3 mg, 59.4 mg, 59.5 mg, 59.6 mg, 59.7 mg, 59.8 mg, 59.9 mg, 60 mg, 60.1 mg, 60.2 mg, 60.3 mg, 60.4 mg, 60.5 mg, 60.6 mg, 60.7 mg, 60.8 mg, 60.9 mg, 61 mg, 61.1 mg, 61.2 mg, 61.3 mg, 61.4 mg, 61.5 mg, 61.6 mg, 61.7 mg, 61.8 mg, 61.9 mg, 62 mg, 62.1 mg, 62.2 mg, 62.3 mg, 62.4 mg, 62.5 mg, 62.6 mg, 62.7 mg, 62.8 mg, 62.9 mg, 63 mg, 63.1 mg, 63.2 mg, 63.3 mg, 63.4 mg, 63.5 mg, 63.6 mg, 63.7 mg, 63.8 mg, 63.9 mg, 64 mg, 64.1 mg, 64.2 mg, 64.3 mg, 64.4 mg, 64.5 mg, 64.6 mg, 64.7 mg, 64.8 mg, 64.9 mg, 65 mg, 65.1 mg, 65.2 mg, 65.3 mg, 65.4 mg, 65.5 mg, 65.6 mg, 65.7 mg, 65.8 mg, 65.9 mg, 66 mg, 66.1 mg, 66.2 mg, 66.3 mg, 66.4 mg, 66.5 mg, 66.6 mg, 66.7 mg, 66.8 mg, 66.9 mg, 67 mg, 67.1 mg, 67.2 mg, 67.3 mg, 67.4 mg, 67.5 mg, 67.6 mg, 67.7 mg, 67.8 mg, 67.9 mg, 68 mg, 68.1 mg, 68.2 mg,

[0181] 68.3 mg, 68.4 mg, 68.5 mg, 68.6 mg, 68.7 mg, 68.8 mg, 68.9 mg, 69 mg, 69.1 mg, 69.2 mg, 69.3 mg, 69.4 mg, 69.5 mg, 69.6 mg, 69.7 mg, 69.8 mg, 69.9 mg, 70 mg, 70.1 mg,

[0182] 70.2 mg, 70.3 mg, 70.4 mg, 70.5 mg, 70.6 mg, 70.7 mg, 70.8 mg, or 70.9 mg.

[0183] In some embodiments, a therapeutically effective amount is about 50 mg, about 50.1 mg, about 50.2 mg, about 50.3 mg, about 50.4 mg, about 50.5 mg, about 50.6 mg, about 50.7 mg, about 50.8 mg, about 50.9 mg, about 51 mg, about 51.1 mg, about 51 .2 mg, about 51.3 mg, about 51.4 mg, about 51.5 mg, about 51.6 mg, about 51.7 mg, about

[0184] 51.8 mg, about 51.9 mg, about 52 mg, about 52.1 mg, about 52.2 mg, about 52.3 mg, about 52.4 mg, about 52.5 mg, about 52.6 mg, about 52.7 mg, about 52.8 mg, about 52.9 mg, about 53 mg, about 53.1 mg, about 53.2 mg, about 53.3 mg, about 53.4 mg, about

[0185] 53.5 mg, about 53.6 mg, about 53.7 mg, about 53.8 mg, about 53.9 mg, about 54 mg, about 54.1 mg, about 54.2 mg, about 54.3 mg, about 54.4 mg, about 54.5 mg, about 54.6 mg, about 54.7 mg, about 54.8 mg, about 54.9 mg, about 55 mg, about 55.1 mg, about

[0186] 55.2 mg, about 55.3 mg, about 55.4 mg, about 55.5 mg, about 55.6 mg, about 55.7 mg, about 55.8 mg, about 55.9 mg, about 56 mg, about 56.1 mg, about 56.2 mg, about 56.3 mg, about 56.4 mg, about 56.5 mg, about 56.6 mg, about 56.7 mg, about 56.8 mg, about

[0187] 56.9 mg, about 57 mg, about 57.1 mg, about 57.2 mg, about 57.3 mg, about 57.4 mg, about 57.5 mg, about 57.6 mg, about 57.7 mg, about 57.8 mg, about 57.9 mg, about 58 mg, about 58.1 mg, about 58.2 mg, about 58.3 mg, about 58.4 mg, about 58.5 mg, about

[0188] 58.6 mg, about 58.7 mg, about 58.8 mg, about 58.9 mg, about 59 mg, about 59.1 mg, about 59.2 mg, about 59.3 mg, about 59.4 mg, about 59.5 mg, about 59.6 mg, about 59.7 mg, about 59.8 mg, about 59.9 mg, about 60 mg, about 60.1 mg, about 60.2 mg, about

[0189] 60.3 mg, about 60.4 mg, about 60.5 mg, about 60.6 mg, about 60.7 mg, about 60.8 mg, about 60.9 mg, about 61 mg, about 61.1 mg, about 61.2 mg, about 61.3 mg, about 61.4 mg, about 61.5 mg, about 61.6 mg, about 61.7 mg, about 61.8 mg, about 61.9 mg, about 62 mg, about 62.1 mg, about 62.2 mg, about 62.3 mg, about 62.4 mg, about 62.5 mg, about 62.6 mg, about 62.7 mg, about 62.8 mg, about 62.9 mg, about 63 mg, about 63.1 mg, about 63.2 mg, about 63.3 mg, about 63.4 mg, about 63.5 mg, about 63.6 mg, about

[0190] 63.7 mg, about 63.8 mg, about 63.9 mg, about 64 mg, about 64.1 mg, about 64.2 mg, about 64.3 mg, about 64.4 mg, about 64.5 mg, about 64.6 mg, about 64.7 mg, about 64.8 mg, about 64.9 mg, about 65 mg, about 65.1 mg, about 65.2 mg, about 65.3 mg, about

[0191] 65.4 mg, about 65.5 mg, about 65.6 mg, about 65.7 mg, about 65.8 mg, about 65.9 mg, about 66 mg, about 66.1 mg, about 66.2 mg, about 66.3 mg, about 66.4 mg, about 66.5 mg, about 66.6 mg, about 66.7 mg, about 66.8 mg, about 66.9 mg, about 67 mg, about 67.1 mg, about 67.2 mg, about 67.3 mg, about 67.4 mg, about 67.5 mg, about 67.6 mg, about 67.7 mg, about 67.8 mg, about 67.9 mg, about 68 mg, about 68.1 mg, about 68.2 mg, about 68.3 mg, about 68.4 mg, about 68.5 mg, about 68.6 mg, about 68.7 mg, about

[0192] 68.8 mg, about 68.9 mg, about 69 mg, about 69.1 mg, about 69.2 mg, about 69.3 mg, about 69.4 mg, about 69.5 mg, about 69.6 mg, about 69.7 mg, about 69.8 mg, about 69.9 mg, about 70 mg, about 70.1 mg, about 70.2 mg, about 70.3 mg, about 70.4 mg, about

[0193] 70.5 mg, about 70.6 mg, about 70.7 mg, about 70.8 mg, or about 70.9 mg.

[0194] In some embodiments, a therapeutically effective amount is 80 mg, 80.1 mg, 80.2 mg, 80.3 mg, 80.4 mg, 80.5 mg, 80.6 mg, 80.7 mg, 80.8 mg, 80.9 mg, 81 mg, 81.1 mg,

[0195] 81.2 mg, 81.3 mg, 81.4 mg, 81.5 mg, 81.6 mg, 81.7 mg, 81.8 mg, 81.9 mg, 82 mg, 82.1 mg, 82.2 mg, 82.3 mg, 82.4 mg, 82.5 mg, 82.6 mg, 82.7 mg, 82.8 mg, 82.9 mg, 83 mg, 83.1 mg, 83.2 mg, 83.3 mg, 83.4 mg, 83.5 mg, 83.6 mg, 83.7 mg, 83.8 mg, 83.9 mg, 84 mg, 84.1 mg, 84.2 mg, 84.3 mg, 84.4 mg, 84.5 mg, 84.6 mg, 84.7 mg, 84.8 mg, 84.9 mg, 85 mg, 85.1 mg, 85.2 mg, 85.3 mg, 85.4 mg, 85.5 mg, 85.6 mg, 85.7 mg, 85.8 mg, 85.9 mg, 86 mg, 86.1 mg, 86.2 mg, 86.3 mg, 86.4 mg, 86.5 mg, 86.6 mg, 86.7 mg, 86.8 mg,

[0196] 86.9 mg, 87 mg, 87.1 mg, 87.2 mg, 87.3 mg, 87.4 mg, 87.5 mg, 87.6 mg, 87.7 mg, 87.8 mg, 87.9 mg, 88 mg, 88.1 mg, 88.2 mg, 88.3 mg, 88.4 mg, 88.5 mg, 88.6 mg, 88.7 mg, 88.8 mg, 88.9 mg, 89 mg, 89.1 mg, 89.2 mg, 89.3 mg, 89.4 mg, 89.5 mg, 89.6 mg, 89.7 mg, 89.8 mg, 89.9 mg, 90 mg, 90.1 mg, 90.2 mg, 90.3 mg, 90.4 mg, 90.5 mg, 90.6 mg, 90.7 mg, 90.8 mg, 90.9 mg, 91 mg, 91.1 mg, 91.2 mg, 91.3 mg, 91.4 mg, 91.5 mg, 91.6 mg, 91.7 mg, 91.8 mg, 91.9 mg, 92 mg, 92.1 mg, 92.2 mg, 92.3 mg, 92.4 mg, 92.5 mg,

[0197] 92.6 mg, 92.7 mg, 92.8 mg, 92.9 mg, 93 mg, 93.1 mg, 93.2 mg, 93.3 mg, 93.4 mg, 93.5 mg, 93.6 mg, 93.7 mg, 93.8 mg, 93.9 mg, 94 mg, 94.1 mg, 94.2 mg, 94.3 mg, 94.4 mg, 94.5 mg, 94.6 mg, 94.7 mg, 94.8 mg, 94.9 mg, 95 mg, 95.1 mg, 95.2 mg, 95.3 mg, 95.4 mg, 95.5 mg, 95.6 mg, 95.7 mg, 95.8 mg, 95.9 mg, 96 mg, 96.1 mg, 96.2 mg, 96.3 mg, 96.4 mg, 96.5 mg, 96.6 mg, 96.7 mg, 96.8 mg, 96.9 mg, 97 mg, 97.1 mg, 97.2 mg, 97.3 mg, 97.4 mg, 97.5 mg, 97.6 mg, 97.7 mg, 97.8 mg, 97.9 mg, 98 mg, 98.1 mg, 98.2 mg,

[0198] 98.3 mg, 98.4 mg, 98.5 mg, 98.6 mg, 98.7 mg, 98.8 mg, 98.9 mg, 99 mg, 99.1 mg, 99.2 mg, 99.3 mg, 99.4 mg, 99.5 mg, 99.6 mg, 99.7 mg, 99.8 mg, 99.9 mg, 100 mg, 100.1 mg, 100.2 mg, 100.3 mg, 100.4 mg, 100.5 mg, 100.6 mg, 100.7 mg, 100.8 mg, 100.9 mg, 101 mg, 101.1 mg, 101.2 mg, 101.3 mg, 101.4 mg, 101.5 mg, 101.6 mg, 101.7 mg, 101.8 mg,

[0199] 101.9 mg, 102 mg, 102.1 mg, 102.2 mg, 102.3 mg, 102.4 mg, 102.5 mg, 102.6 mg, 102.7 mg, 102.8 mg, 102.9 mg, 103 mg, 103.1 mg, 103.2 mg, 103.3 mg, 103.4 mg, 103.5 mg, 103.6 mg, 103.7 mg, 103.8 mg, 103.9 mg, 104 mg, 104.1 mg, 104.2 mg, 104.3 mg, 104.4 mg, 104.5 mg, 104.6 mg, 104.7 mg, 104.8 mg, or 104.9 mg.

[0200] In some embodiments, a therapeutically effective amount is about 80 mg, about

[0201] 80.1 mg, about 80.2 mg, about 80.3 mg, about 80.4 mg, about 80.5 mg, about 80.6 mg, about 80.7 mg, about 80.8 mg, about 80.9 mg, about 81 mg, about 81.1 mg, about 81.2 mg, about 81.3 mg, about 81.4 mg, about 81.5 mg, about 81.6 mg, about 81.7 mg, about

[0202] 81.8 mg, about 81.9 mg, about 82 mg, about 82.1 mg, about 82.2 mg, about 82.3 mg, about 82.4 mg, about 82.5 mg, about 82.6 mg, about 82.7 mg, about 82.8 mg, about 82.9 mg, about 83 mg, about 83.1 mg, about 83.2 mg, about 83.3 mg, about 83.4 mg, about

[0203] 83.5 mg, about 83.6 mg, about 83.7 mg, about 83.8 mg, about 83.9 mg, about 84 mg, about 84.1 mg, about 84.2 mg, about 84.3 mg, about 84.4 mg, about 84.5 mg, about 84.6 mg, about 84.7 mg, about 84.8 mg, about 84.9 mg, about 85 mg, about 85.1 mg, about

[0204] 85.2 mg, about 85.3 mg, about 85.4 mg, about 85.5 mg, about 85.6 mg, about 85.7 mg, about 85.8 mg, about 85.9 mg, about 86 mg, about 86.1 mg, about 86.2 mg, about 86.3 mg, about 86.4 mg, about 86.5 mg, about 86.6 mg, about 86.7 mg, about 86.8 mg, about

[0205] 86.9 mg, about 87 mg, about 87.1 mg, about 87.2 mg, about 87.3 mg, about 87.4 mg, about 87.5 mg, about 87.6 mg, about 87.7 mg, about 87.8 mg, about 87.9 mg, about 88 mg, about 88.1 mg, about 88.2 mg, about 88.3 mg, about 88.4 mg, about 88.5 mg, about

[0206] 88.6 mg, about 88.7 mg, about 88.8 mg, about 88.9 mg, about 89 mg, about 89.1 mg, about 89.2 mg, about 89.3 mg, about 89.4 mg, about 89.5 mg, about 89.6 mg, about 89.7 mg, about 89.8 mg, about 89.9 mg, about 90 mg, about 90.1 mg, about 90.2 mg, about

[0207] 90.3 mg, about 90.4 mg, about 90.5 mg, about 90.6 mg, about 90.7 mg, about 90.8 mg, about 90.9 mg, about 91 mg, about 91.1 mg, about 91.2 mg, about 91.3 mg, about 91.4 mg, about 91.5 mg, about 91.6 mg, about 91.7 mg, about 91.8 mg, about 91.9 mg, about 92 mg, about 92.1 mg, about 92.2 mg, about 92.3 mg, about 92.4 mg, about 92.5 mg, about 92.6 mg, about 92.7 mg, about 92.8 mg, about 92.9 mg, about 93 mg, about 93.1 mg, about 93.2 mg, about 93.3 mg, about 93.4 mg, about 93.5 mg, about 93.6 mg, about

[0208] 93.7 mg, about 93.8 mg, about 93.9 mg, about 94 mg, about 94.1 mg, about 94.2 mg, about 94.3 mg, about 94.4 mg, about 94.5 mg, about 94.6 mg, about 94.7 mg, about 94.8 mg, about 94.9 mg, about 95 mg, about 95.1 mg, about 95.2 mg, about 95.3 mg, about

[0209] 95.4 mg, about 95.5 mg, about 95.6 mg, about 95.7 mg, about 95.8 mg, about 95.9 mg, about 96 mg, about 96.1 mg, about 96.2 mg, about 96.3 mg, about 96.4 mg, about 96.5 mg, about 96.6 mg, about 96.7 mg, about 96.8 mg, about 96.9 mg, about 97 mg, about

[0210] 97.1 mg, about 97.2 mg, about 97.3 mg, about 97.4 mg, about 97.5 mg, about 97.6 mg, about 97.7 mg, about 97.8 mg, about 97.9 mg, about 98 mg, about 98.1 mg, about 98.2 mg, about 98.3 mg, about 98.4 mg, about 98.5 mg, about 98.6 mg, about 98.7 mg, about 98.8 mg, about 98.9 mg, about 99 mg, about 99.1 mg, about 99.2 mg, about 99.3 mg, about 99.4 mg, about 99.5 mg, about 99.6 mg, about 99.7 mg, about 99.8 mg, about 99.9 mg, about 100 mg, about 101.1 mg, about 101.2 mg, about 101.3 mg, about 101.4 mg, about 101.5 mg, about 101.6 mg, about 101.7 mg, about 101.8 mg, about 101.9 mg, about 102 mg, about 102.1 mg, about 102.2 mg, about 102.3 mg, about 102.4 mg, about 102.5 mg, about 102.6 mg, about 102.7 mg, about 102.8 mg, about 102.9 mg, about 103 mg, about 103.1 mg, about 103.2 mg, about 103.3 mg, about 103.4 mg, about 103.5 mg, about

[0211] 103.6 mg, about 103.7 mg, about 103.8 mg, about 103.9 mg, about 104 mg, about 104.1 mg, about 104.2 mg, about 104.3 mg, about 104.4 mg, about 104.5 mg, about 104.6 mg, about 104.7 mg, about 104.8 mg, or about 104.9 mg.

[0212] In some embodiments, a therapeutically effective amount is 105 mg, 105.1 mg,

[0213] 105.2 mg, 105.3 mg, 105.4 mg, 105.5 mg, 105.6 mg, 105.7 mg, 105.8 mg, 105.9 mg, 106 mg, 106.1 mg, 106.2 mg, 106.3 mg, 106.4 mg, 106.5 mg, 106.6 mg, 106.7 mg, 106.8 mg, 106.9 mg, 107 mg, 107.1 mg, 107.2 mg, 107.3 mg, 107.4 mg, 107.5 mg, 107.6 mg, 107.7 mg, 107.8 mg, 107.9 mg, 108 mg, 108.1 mg, 108.2 mg, 108.3 mg, 108.4 mg, 108.5 mg,

[0214] 108.6 mg, 108.7 mg, 108.8 mg, 108.9 mg, 109 mg, 109.1 mg, 109.2 mg, 109.3 mg, 109.4 mg, 109.5 mg, 109.6 mg, 109.7 mg, 109.8 mg, 109.9 mg, 110 mg, 110.1 mg, 110.2 mg,

[0215] 110.3 mg, 110.4 mg, 110.5 mg, 110.6 mg, 110.7 mg, 110.8 mg, 110.9 mg, 111 mg, 111.1 mg, 111.2 mg, 111.3 mg, 111.4 mg, 111.5 mg, 111.6 mg, 111.7 mg, 111.8 mg, 111.9 mg, 112 mg, 112.1 mg, 112.2 mg, 112.3 mg, 112.4 mg, 112.5 mg, 112.6 mg, 112.7 mg, 112.8 mg, 112.9 mg, 113 mg, 113.1 mg, 113.2 mg, 113.3 mg, 113.4 mg, 113.5 mg, 113.6 mg,

[0216] 113.7 mg, 113.8 mg, 113.9 mg, 114 mg, 114.1 mg, 114.2 mg, 114.3 mg, 114.4 mg, 114.5 mg, 114.6 mg, 114.7 mg, 114.8 mg, 114.9 mg, 115 mg, 115.1 mg, 115.2 mg, 115.3 mg,

[0217] 115.4 mg, 115.5 mg, 115.6 mg, 115.7 mg, 115.8 mg, 115.9 mg, 116 mg, 116.1 mg, 116.2 mg, 116.3 mg, 116.4 mg, 116.5 mg, 116.6 mg, 116.7 mg, 116.8 mg, 116.9 mg, 117 mg,

[0218] 117.1 mg, 117.2 mg, 117.3 mg, 117.4 mg, 117.5 mg, 117.6 mg, 117.7 mg, 117.8 mg, 117.9 mg, 118 mg, 118.1 mg, 118.2 mg, 1 18.3 mg, 1 18.4 mg, 118.5 mg, 118.6 mg, 118.7 mg, 118.8 mg, 118.9 mg, 119 mg, 119.1 mg, 119.2 mg, 119.3 mg, 119.4 mg, 119.5 mg,

[0219] 119.6 mg, 119.7 mg, 119.8 mg, 119.9 mg, 120 mg, 120.1 mg, 120.2 mg, 120.3 mg, 120.4 mg, 120.5 mg, 120.6 mg, 120.7 mg, 120.8 mg, 120.9 mg, 121 mg, 121.1 mg, 121.2 mg,

[0220] 121.3 mg, 121.4 mg, 121.5 mg, 121.6 mg, 121.7 mg, 121.8 mg, 121.9 mg, 122 mg, 122.1 mg, 122.2 mg, 122.3 mg, 122.4 mg, 122.5 mg, 122.6 mg, 122.7 mg, 122.8 mg, 122.9 mg, 123 mg, 123.1 mg, 123.2 mg, 123.3 mg, 123.4 mg, 123.5 mg, 123.6 mg, 123.7 mg, 123.8 mg, 123.9 mg, 124 mg, 124.1 mg, 124.2 mg, 124.3 mg, 124.4 mg, 124.5 mg, 124.6 mg,

[0221] 124.7 mg, 124.8 mg, 124.9 mg, or 125 mg.

[0222] In some embodiments, a therapeutically effective amount is about 105 mg, about

[0223] 105.1 mg, about 105.2 mg, about 105.3 mg, about 105.4 mg, about 105.5 mg, about 105.6 mg, about 105.7 mg, about 105.8 mg, about 105.9 mg, about 106 mg, about 106.1 mg, about 106.2 mg, about 106.3 mg, about 106.4 mg, about 106.5 mg, about 106.6 mg, about

[0224] 106.7 mg, about 106.8 mg, about 106.9 mg, about 107 mg, about 107.1 mg, about 107.2 mg, about 107.3 mg, about 107.4 mg, about 107.5 mg, about 107.6 mg, about 107.7 mg, about 107.8 mg, about 107.9 mg, about 108 mg, about 108.1 mg, about 108.2 mg, about

[0225] 108.3 mg, about 108.4 mg, about 108.5 mg, about 108.6 mg, about 108.7 mg, about 108.8 mg, about 108.9 mg, about 109 mg, about 109.1 mg, about 109.2 mg, about 109.3 mg, about 109.4 mg, about 109.5 mg, about 109.6 mg, about 109.7 mg, about 109.8 mg, about

[0226] 109.9 mg, about 110 mg, about 110.1 mg, about 110.2 mg, about 110.3 mg, about 110.4 mg, about 110.5 mg, about 110.6 mg, about 110.7 mg, about 110.8 mg, about 110.9 mg, about 111 mg, about 111.1 mg, about 111.2 mg, about 111.3 mg, about 111.4 mg, about 111.5 mg, about 111.6 mg, about 111.7 mg, about 111.8 mg, about 111.9 mg, about 112 mg, about 112.1 mg, about 112.2 mg, about 112.3 mg, about 112.4 mg, about 112.5 mg, about 112.6 mg, about 112.7 mg, about 112.8 mg, about 112.9 mg, about 113 mg, about

[0227] 113.1 mg, about 113.2 mg, about 113.3 mg, about 113.4 mg, about 113.5 mg, about 113.6 mg, about 113.7 mg, about 113.8 mg, about 113.9 mg, about 114 mg, about 114.1 mg, about 114.2 mg, about 114.3 mg, about 114.4 mg, about 114.5 mg, about 114.6 mg, about

[0228] 114.7 mg, about 114.8 mg, about 114.9 mg, about 115 mg, about 115.1 mg, about 115.2 mg, about 115.3 mg, about 115.4 mg, about 115.5 mg, about 115.6 mg, about 115.7 mg, about 115.8 mg, about 115.9 mg, about 116 mg, about 116.1 mg, about 116.2 mg, about 116.3 mg, about 1 16.4 mg, about 116.5 mg, about 116.6 mg, about 116.7 mg, about 1 16.8 mg, about 116.9 mg, about 117 mg, about 117.1 mg, about 117.2 mg, about 117.3 mg, about 117.4 mg, about 117.5 mg, about 117.6 mg, about 117.7 mg, about 117.8 mg, about 117.9 mg, about 118 mg, about 118.1 mg, about 118.2 mg, about 118.3 mg, about 118.4 mg, about 118.5 mg, about 118.6 mg, about 118.7 mg, about 118.8 mg, about 118.9 mg, about 119 mg, about 119.1 mg, about 119.2 mg, about 119.3 mg, about 119.4 mg, about

[0229] 119.5 mg, about 119.6 mg, about 119.7 mg, about 119.8 mg, about 119.9 mg, about 120 mg, about 120.1 mg, about 120.2 mg, about 120.3 mg, about 120.4 mg, about 120.5 mg, about 120.6 mg, about 120.7 mg, about 120.8 mg, about 120.9 mg, about 121 mg, about 121.1 mg, about 121.2 mg, about 121.3 mg, about 121.4 mg, about 121.5 mg, about 121.6 mg, about 121.7 mg, about 121.8 mg, about 121.9 mg, about 122 mg, about 122.1 mg, about 122.2 mg, about 122.3 mg, about 122.4 mg, about 122.5 mg, about 122.6 mg, about 122.7 mg, about 122.8 mg, about 122.9 mg, about 123 mg, about 123.1 mg, about 123.2 mg, about 123.3 mg, about 123.4 mg, about 123.5 mg, about 123.6 mg, about 123.7 mg, about 123.8 mg, about 123.9 mg, about 124 mg, about 124.1 mg, about 124.2 mg, about

[0230] 124.3 mg, about 124.4 mg, about 124.5 mg, about 124.6 mg, about 124.7 mg, about 124.8 mg, about 124.9 mg, or about 125 mg.

[0231] In some embodiments, a therapeutically effective amount is 40 mg to 200 mg, 40 mg to 190 mg, 40 mg to 180 mg, 40 mg to 170 mg, from 40 mg to 160 mg, 40 mg to 150 mg, 40 mg to 140 mg, 40 mg to 120 mg, 40 mg to 110 mg, 40 mg to 100 mg, 40 mg to 80 mg, 40 mg to 70 mg, 40 mg to 60 mg, 40 mg to 50 mg, 50 mg to 200 mg, 50 mg to 190 mg, 50 mg to 180 mg, 50 mg to 170 mg, 50 mg to 160 mg, 50 mg to 150 mg, 50 mg to 140 mg, 50 mg to 120 mg, 50 mg to 110 mg, 50 mg to 100 mg, 50 mg to 80 mg, 50 mg to 70 mg, 50 mg to 60 mg, 60 mg to 200 mg, 60 mg to 190 mg, 60 mg to 180 mg, 60 mg to 170 mg, 60 mg to 160 mg, 60 mg to 150 mg, 60 mg to 140 mg, 60 mg to 120 mg, 60 mg to 115 mg, 60 mg to 110 mg, 60 mg to 100 mg, 60 mg to 80 mg, 60 mg to 70 mg, 70 mg to 200 mg, 70 mg to 190 mg, 70 mg to 180 mg, 70 mg to 170 mg, 70 mg to 160 mg, 70 mg to 150 mg, 70 mg to 140 mg, 70 mg to 120 mg, 70 mg to 110 mg, 70 mg to 100 mg, 70 mg to 80 mg, 80 mg to 200 mg, 80 mg to 190 mg, 80 mg to 180 mg, 80 mg to 170 mg, 80 mg to 160 mg, 80 mg to 150 mg, 80 mg to 140 mg, 80 mg to 120 mg, 80 mg to 110 mg, 80 mg to 100 mg, 80 mg to 90 mg, 90 mg to 200 mg, 90 mg to 190 mg, 90 mg to 180 mg, 90 mg to 170 mg, 90 mg to 160 mg, 90 mg to 150 mg, 90 mg to 140 mg, 90 mg to 120 mg, 90 mg to 110 mg, 90 mg to 100 mg, 100 mg to 200 mg, 100 mg to 190 mg, 100 mg to 180 mg, 100 mg to 170 mg, 100 mg to 160 mg, 100 mg to 150 mg, 100 mg to 140 mg, 100 mg to 120 mg, 100 mg to 110 mg, 110 mg to 200 mg, 110 mg to 190 mg, 110 mg to 180 mg, 110 mg to 170 mg, 110 mg to 160 mg, 110 mg to 150 mg, 110 mg to 140 mg, 110 mg to 130 mg, 110 mg to 120 mg, 120 mg to 200 mg, 120 mg to 190 mg, 120 mg to 180 mg, 120 mg to 170 mg, 120 mg to 160 mg, 120 mg to 150 mg, 120 mg to 140 mg, 120 mg to 130 mg, 130 mg to 200 mg, 130 mg to 190 mg, 130 mg to 180 mg, 130 mg to 170 mg, 130 mg to 160 mg, 130 mg to 150 mg, 130 mg to 140 mg, 140 mg to 200 mg, 140 mg to 190 mg, 140 mg to 180 mg, 140 mg to 170 mg, 140 mg to 160 mg, 140 mg to 150 mg, 150 mg to 200 mg, 150 mg to 190 mg, 150 mg to 180 mg, 150 mg to 170 mg, 150 mg to 160 mg, 160 mg to 200 mg, 160 mg to 190 mg, 160 mg to 180 mg, 160 mg to 170 mg, 180 mg to 200 mg, 180 mg to 190 mg, 190 mg to 200 mg, 105 mg to 135 mg, 105 mg to 130 mg, 105 mg to 125 mg 105 mg to 120 mg, 110 mg to 135 mg, 110 mg to 130 mg, 110 mg to 125 mg, 110 mg to 120 mg, 115 mg to 135 mg, 115 mg to 130 mg, 115 mg to 125 mg, 115 mg to 120 mg, 115 mg to 125 mg, 115 mg to 120 mg, 120 mg to 135 mg, 120 mg to 125 mg, 125 mg to 140 mg, 125 mg to 130 mg, 130 mg to 135 mg, 135 mg to 140 mg, 120 mg to 129 mg, 120 mg to 128 mg, 120 mg to 127 mg, 120 mg to 86 mg, 120 mg to 124 mg, 120 mg to 123 mg, 120 mg to 122 mg, 120 mg to 121 mg, 121 mg to 130 mg, 122 mg to 129 mg, 122 mg to 128 mg, 122 mg to 127 mg, 122 mg to 126 mg, 122 mg to 125 mg, 122 mg to 124 mg, 122 mg to 123 mg, 123 mg to 130 mg, 123 mg to 129 mg, 123 mg to 128 mg, 123 mg to 127 mg, 123 mg to 126 mg, 123 mg to 125 mg, 123 mg to 124 mg, 124 mg to 130 mg, 124 mg to 129 mg, 124 mg to 128 mg, 124 mg to 127 mg, 124 mg to 126 mg, 124 mg to 125 mg, 125 mg to 129 mg, 125 mg to 128 mg, 125 mg to 127 mg, 125 mg to 126 mg, 126 mg to 130 mg, 126 mg to 129 mg, 126 mg to 128 mg, 126 mg to 127 mg, 127 mg to 130 mg, 127 mg to 129 mg, 127 mg to 128 mg, 128 mg to 130 mg, 128 mg to 129 mg, or 129 mg to 130 mg.

[0232] In some embodiments, a therapeutically effective amount is less than 350 mg, less than 345 mg, less than 340 mg, less than 335 mg, less than 330 mg, less than 325 mg, less than 320 mg, less than 315 mg, less than 310 mg, less than 305 mg, less than 300 mg, less than 295 mg, less than 290 mg, less than 285 mg, less than 280 mg, less than 275 mg, less than 270 mg, less than 265 mg, less than 260 mg, less than 255 mg, less than 250 mg, less than 245 mg, less than 240 mg, less than 235 mg, less than 230 mg, less than 225 mg, less than 220 mg, less than 215 mg, less than 210 mg, less than 205 mg, less than 200 mg, less than 195 mg, less than 190 mg, less than 185 mg, less than 180 mg, less than 175 mg, less than 170 mg, less than 165 mg, less than 160 mg, less than 150 mg, less than 145 mg, less than 140 mg, less than 135 mg, less than 130 mg, less than 125 mg, less than 120 mg, less than 115 mg, less than 110 mg, less than 105 mg, less than 100 mg, less than 95 mg, less than 90 mg, less than 85 mg, less than 80 mg, less than 75 mg, less than 70 mg, less than 65 mg, less than 60 mg, less than 55 mg, less than 50 mg, less than 45 mg, less than 40 mg, less than 35 mg, less than 30 mg, less than 25 mg, less than 20 mg, less than 15 mg, less than 10 mg, or less than 5 mg.

[0233] In some embodiments, a therapeutically effective amount is less than about 350 mg, less than about 345 mg, less than about 340 mg, less than about 335 mg, less than about 330 mg, less than about 325 mg, less than about 320 mg, less than about 315 mg, less than about 310 mg, less than about 305 mg, less than about 300 mg, less than about 295 mg, less than about 290 mg, less than about 285 mg, less than about 280 mg, less than about 275 mg, less than about 270 mg, less than about 265 mg, less than about 260 mg, less than about 255 mg, less than about 250 mg, less than about 245 mg, less than about 240 mg, less than about 235 mg, less than about 230 mg, less than about 225 mg, less than about 220 mg, less than about 215 mg, less than about 210 mg, less than about 205 mg, less than about 200 mg, less than about 195 mg, less than about 190 mg, less than about 185 mg, less than about 180 mg, less than about 175 mg, less than about 170 mg, less than about 165 mg, less than about 160 mg, less than about 150 mg, less than about 145 mg, less than about 140 mg, less than about 135 mg, less than about 130 mg, less than about 125 mg, less than about 120 mg, less than about 115 mg, less than about 110 mg, less than about 105 mg, less than about 100 mg, less than about 95 mg, less than about 90 mg, less than about 85 mg, less than about 80 mg, less than about 75 mg, less than about 70 mg, less than about 65 mg, less than about 60 mg, less than about 55 mg, less than about 50 mg, less than about 45 mg, less than about 40 mg, less than about 35 mg, less than about 30 mg, less than about 25 mg, less than about 20 mg, less than about 15 mg, less than about 10 mg, or less than about 5 mg. In some embodiments, a therapeutically effective amount is at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg, at least 150 mg, at least 155 mg, at least 160 mg, at least 165 mg, at least 170 mg, at least 175 mg, at least 180 mg, at least 185, at least 190 mg, at least 195 mg, or at least 200 mg.

[0234] In some embodiments, a therapeutically effective amount is at least about 5 mg, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 25 mg, at least about 30 mg, at least about 35 mg, at least about 40 mg, at least about 45 mg, at least about 50 mg, at least about 55 mg, at least about 60 mg, at least about 65 mg, at least about 70 mg, at least about 75 mg, at least about 80 mg, at least about 85 mg, at least about 90 mg, at least about 95 mg, at least about 100 mg, at least about 105 mg, at least about 115 mg, at least about 120 mg, at least about 125 mg, at least about 130 mg, at least about 135 mg, at least about 140 mg, at least about 145 mg, or at least about 150 mg, at least about 155 mg, at least about 160 mg, at least about 165 mg, at least about 170 mg, at least about 175 mg, at least about 180 mg, at least about 185, at least about 190 mg, at least about 195 mg, or at least about 200 mg.

[0235] VI. Certain BIIB080 Dosing Regimens

[0236] In some embodiments, the present disclosure provides a method comprising administering to a subject a therapeutically effective amount of BIIB080 one or more times. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 times. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once every 4 weeks. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once every 8 weeks. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BTIBO8O once every 12 weeks. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once every 16 weeks. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once every 20 weeks. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once every 24 weeks. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once every 6 months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 monthly. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once every two months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once every three months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 quarterly. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 semiannually. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 annually. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once every two years.

[0237] In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 about every 1 week, about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, about every 12 weeks, about every 13 weeks, about every 14 weeks, about every 15 weeks, about every 16 weeks, about every 17 weeks, about every 18 weeks, about every 19 weeks, about every 20 weeks, about every 21 weeks, about every 22 weeks, about every 23 weeks, about every 24 weeks, or about every 6 months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 about monthly. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once about every two months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once about every three months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 about quarterly. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 about semiannually. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 about annually. In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 once about every two years.

[0238] In some embodiments, a method described herein comprises administering a therapeutically effective amount of BIIB080 for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months.

[0239] In some embodiments, a method described herein comprises administering BIIB080 at a dose of 10 mg once monthly. In some embodiments, a method described herein comprises administering BIIB080 at a dose of 30 mg once monthly. In some embodiments, a method described herein comprises administering BIIB080 at a dose of 60 mg once monthly. In some embodiments, a method described herein comprises administering BIIB080 at a dose of 115 mg once every quarter. In some embodiments, a human subject has mild Alzheimer’s disease. In some embodiments, a human subject has MCI due to Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease dementia.

[0240] In some embodiments, a method described herein comprises administering BIIB080 at a dose of 10 mg once every four weeks. In some embodiments, a method described herein comprises administering BIIB080 at a dose of 30 mg once every four weeks. In some embodiments, a method described herein comprises administering BIIB080 at a dose of 60 mg once every four weeks. In some embodiments, a method described herein comprises administering BIIB080 at a dose of 115 mg once every three months. In some embodiments, a method described herein comprises administering BIIB080 at a dose of 115 mg four times per year. In some embodiments, a human subject has mild Alzheimer’s disease. In some embodiments, a human subject has MCI due to Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease dementia.

[0241] In some embodiments, a method described herein comprises administering BIIB080 at a dose of 60 mg once every 24 weeks. In some embodiments, a method described herein comprises administering BIIB080 at a dose of 115 mg once every 24 weeks. In some embodiments, a method described herein comprises administering BIIB080 at a dose of 115 mg once every 12 weeks. In some embodiments, a human subject has mild Alzheimer’s disease. In some embodiments, a human subject has MCI due to Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease dementia.

[0242] In some embodiments, a method described herein comprises administering BIIB080 at a dose of 60 mg twice per year (e.g., biannually). In some embodiments, a method described herein comprises administering BIIB080 at a dose of 115 mg twice per year (e.g., biannually). In some embodiments, a method described herein comprises administering BIIB080 at a dose of 115 mg once every three months (e.g., four times per year). In some embodiments, a human subject has preclinical Alzheimer’s disease. In some embodiments, a human subject has presymptomatic Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease. In some embodiments, a human subject has MCI due to Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease dementia.

[0243] Loading and Maintenance Doses

[0244] In certain embodiment, a therapeutically effective amount is administered as a loading dose. In certain embodiment, a therapeutically effective amount is administered as a maintenance dose. In certain embodiment, a therapeutically effective amount is administered as a loading dose and a maintenance dose. In some embodiments, a method described herein comprises administering a loading dose or doses and subsequently administering a maintenance dose or doses. In some embodiments, a method described herein comprises administering a loading dose once about every 4 weeks, and subsequently administering a maintenance dose once about every 4 weeks, about every 8 weeks, about every 12 weeks, about every 16 weeks, about 20 weeks, about 24 weeks, or about 6 months. In some embodiments, a method described herein comprises administering a loading dose once about every 4 weeks, and subsequently administering a maintenance dose once about every 6 months. In some embodiments, a method described herein comprises administering a loading dose once about every 12 weeks, and subsequently administering a maintenance dose once about every 6 months.

[0245] In some embodiments, a method described herein comprises administering at least 2 loading doses, at least 3 loading doses, at least 4 loading doses, at least 5 loading doses, or at least 6 loading doses. In some embodiments, a method described herein comprises administering 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 loading doses. In some embodiments, a method described herein comprises administering a loading dose or doses about every 1 week, about every 2 weeks, about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, or about every 12 weeks. In some embodiments, a method described herein comprises administering an initial loading dose and administering a second loading dose about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, or about 12 weeks after administering the initial loading dose.

[0246] In some embodiments, a method described herein comprises administering at least 2 maintenance doses, at least 3 maintenance doses, at least 4 maintenance doses, at least 5 maintenance doses, or at least 6 maintenance doses. In some embodiments, a method described herein comprises administering 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 maintenance doses. In some instances, a method described herein comprises administering a maintenance dose or doses about every 4 weeks, about every 5 weeks, about every 6 weeks, about every 7 weeks, about every 8 weeks, about every 9 weeks, about every 10 weeks, about every 11 weeks, about every 12 weeks, about every 13 weeks, about every 14 weeks, about every 15 weeks, about every 16 weeks, about every 17 weeks, about every 18 weeks, about every 19 weeks, about every 20 weeks, about every 21 weeks, about every 22 weeks, about every 23 weeks, about every 24 weeks, or about every 6 months. In some embodiments, a method described herein comprises administering a first maintenance dose and administering a second maintenance dose about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, or about 6 months after administering the first maintenance dose.

[0247] In some embodiments, a method described herein comprises administering a first maintenance dose or doses about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, or about 24 weeks after administering the last loading dose.

[0248] VII. Potency and Efficacy

[0249] In some embodiments, a method described herein comprises reducing a level of Tau RNA and / or Tau protein in a cell or biological fluid of a human subject, wherein the method comprises administering a therapeutically effective amount of BIIB080 to the subject. In some embodiments, a method described herein comprises reducing a level of Tau RNA and / or Tau protein in the cerebrospinal fluid of the human subject. One may determine whether or not a method described herein reduces a level of Tau RNA and / or Tau protein, e.g., by detecting / quantifying a first amount of Tau RNA or Tau protein in a first biological sample obtained before administering and detecting / quantifying a second amount of Tau RNA or Tau protein in a second biological sample obtained after administering, and detecting or quantifying a reduction in Tau RNA or Tau protein by comparing the first amount to the second amount.

[0250] In some embodiments, a method described herein comprises reducing a level of Tau RNA and / or Tau protein by 1-100%, or a range defined by any two of these values. In some embodiments, a method described herein comprises reducing a level of Tau RNA and / or Tau protein by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51 %, 52%, 53%, 54%, 55%, 56%, 57%,

[0251] 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%,

[0252] 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,

[0253] 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0254] In some embodiments, a method described herein comprises reducing a level of Tan RNA or Tau protein by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25 %, at least about 30%, at least about 35 %, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%.

[0255] In some embodiments, a method described herein comprises reducing a level of Tau RNA or Tau protein by about 5% to about 10%, about 10% to about 15%, about 15% to about 20%, about 20% to about 25%, about 25% to about 30%, about 30% to about 35%, about 35% to about 40%, about 40% to about 45%, about 45% to about 50%, about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, or about 95% to 100%.

[0256] In some embodiments, a method described herein comprises administering BIIB080 to a subject and detecting or quantifying an amount of Tau RNA or Tau protein in a cell or a biological fluid of the subject. In some embodiments, a method described herein comprises detecting / quantifying a first amount of Tau RNA or Tau protein in a first biological sample obtained before administering and detecting / quantifying a second amount of Tau RNA or Tau protein in a second biological sample obtained after administering, and detecting or quantifying a reduction in Tau RNA or Tau protein by comparing the first amount to the second amount. In some embodiments, the second biological sample is obtained less than about 24 hours after administering. In some embodiments, the second biological sample is obtained less than about 1 week after administering. In some embodiments, the second biological sample is obtained about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, or about 18 weeks after administering. Tn some embodiments, a method described herein comprises increasing or decreasing the dose after comparing the first amount to the second amount. In some embodiments, a method described herein comprises administering more frequently or less frequently after comparing the first amount to the second amount.

[0257] Assessing Efficacy 0 / BIIBO8O

[0258] In some embodiments, a method described herein comprises ameliorating at least one symptom or sign of a disease or disorder associated with Tau protein in a human subject. In some embodiments, a method described herein comprises preventing or decreasing a rate of progression, or delaying an onset of at least one symptom or sign associated with Tau protein in a human subject as compared to an appropriate reference (e.g., healthy human control subject, a human subject not administered BIIB080). In some embodiments, at least one symptom or sign is loss of memory, cognitive decline, loss of ability to understand or express speech, abnormal behavior, impaired motor function, falls, impaired balance, impaired swallowing, impaired eating, feeding tube placement, hospitalization, death, increase in the number and / or volume of neurofibrillary inclusions, loss of memory, loss of cognitive function, neuropsychiatric behavior dysfunction, or loss of motor function. In some embodiments, at least one symptom or sign is loss of cognitive function, neuropsychiatric behavior dysfunction, impaired global function, impaired loss of motor function, impaired cognitive function, impaired neuropsychiatric function, impaired daily function, impaired attention, impaired visuoperceptual processing, impaired working memory, impaired psychomotor speed, impaired verbal motor output, impaired degree of independence, increased apathy, impaired learning ability, impaired mental concentration, impaired understanding and expression of speech, impaired behavior, depression, irritability, anger, impaired mobility, impaired self-care, pain, discomfort, anxiety, seizures, suicidal ideation, or suicidal behavior. In some embodiments, a disease or disorder associated with Tau protein is a neurodegenerative disease or disorder. In some embodiments, a disease or disorder associated with Tau protein is a Tauopathy. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease (e.g., mild AD, MCI due to AD, or mild AD dementia) or Fronto-temporal Dementia (FTD). Clinical criteria for MCI due to AD or mild AD dementia are according to the National Institute on Aging at National Institutes of Health and the Alzheimer’s Association (NIA-AA). In some embodiments, a disease or disorder associated with Tau protein is Frontotemporal Dementia, MAPT-related frontotemporal dementia (MAPT- FTD), Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), non-fluent primary progressive aphasia, Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Pick Disease, Argyrophilic Grain Disease (AGD), Globular- Glial Tauopathies, Epilepsy, and / or Dravet’s Syndrome. In some embodiments, a disease or disorder associated with Tau protein is Down syndrome, Prion diseases (sCJD, vCJD, gCJD, GSS, FFI), Diffuse neurofibrillary tangles with calcification, Familial British and Danish dementia, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis, Myotonic dystrophy (DM1) and PROMM (DM2), Aging-related tau astrogliopathy, Traumatic brain injury, Chronic traumatic encephalopathy, IgLON5-related tauopathy, Guadeloupean parkinsonism, Parkinson-dementia complex of Guam, Non-Guamanian motor neuron disease with NFTs, Amyotrophic lateral sclerosis of Guam, X-linked parkinsonism with spasticity, Cerebrotendinous xanthomatosis, Niemann-Pick disease type C, PANK2-associated Neurodegeneration with Brain Iron Accumulation (NBIA), PLA2G6-assiciated NBIA, SLC9A6 mental retardation, or diseases or disorders associated with gene mutations in LRRK2, PRKN, SNCA, TARDBP, or C9orf72. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease or FTD.

[0259] In some embodiments, a method described herein comprises maintaining memory, improving memory, maintaining cognitive function, improving cognitive function, maintaining neuropsychiatric behaviors, improving neuropsychiatric behaviors, maintaining motor function, improving motor function, reducing falls, improving balance, improving swallowing, improving eating, reducing feeding tube placement, reducing hospitalization, prolonging life, maintaining a number and / or volume of neurofibrillary inclusions, or reducing a number and / or volume of neurofibrillary inclusions in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises maintaining memory in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises improving memory in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises maintaining cognitive function in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises improving cognitive function in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises maintaining neuropsychiatric behaviors in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises improving neuropsychiatric behaviors in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises maintaining motor function in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises improving motor function in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises reducing falls in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises improving balance in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises improving swallowing in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises improving eating in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises reducing feeding tube placement in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises reducing hospitalization in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises prolonging life in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises maintaining a number and / or volume of neurofibrillary inclusions in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080). In some embodiments, a method described herein comprises reducing a number and / or volume of neurofibrillary inclusions in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080).

[0260] In some embodiments, a disease or disorder associated with Tau protein is a Tauopathy. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease (e.g., mild AD, MCI due to AD, mild AD dementia) or Frontotemporal Dementia (FTD). In some embodiments, a disease or disorder associated with Tau protein is Frontotemporal Dementia, MAPT-related frontotemporal dementia (MAPT-FTD), Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Pick Disease, Argyrophilic Grain Disease (AGD), Globular Glial Tauopathies, Epilepsy, and / or Dravet’s Syndrome. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease or FTD. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease.

[0261] In some embodiments, a method described herein comprises ameliorating at least one symptom or sign of a disease or disorder associated with Tau protein in a human subject having the disease or disorder associated with Tau protein relative to a healthy control subject. In some embodiments, a method described herein comprises preventing or decreasing a rate of progression, or delaying an onset of at least one symptom or sign of a disease or disorder associated with Tau protein in a human subject having a disease or disorder associated with Tau protein relative to a healthy control subject. In some embodiments, a disease or disorder associated with Tau protein is a Tauopathy. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease (e.g., mild AD, MCI due to AD, or mild AD dementia) or Fronto-temporal Dementia (FTD). In some embodiments, a disease or disorder associated with Tau protein is Frontotemporal Dementia, MAPT-related frontotemporal dementia (MAPT-FTD), Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Pick Disease, Argyrophilic Grain Disease (AGD), Globular Glial Tauopathies, Epilepsy, and / or Dravet’s Syndrome. In some embodiments, the disease or disorder associated with Tau protein is Down syndrome, Prion diseases (sCJD, vCJD, gCJD, GSS, FFI), Diffuse neurofibrillary tangles with calcification, Familial British and Danish dementia, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis, Myotonic dystrophy (DM1) and PROMM (DM2), Aging-related tau astrogliopathy, Traumatic brain injury, Chronic traumatic encephalopathy, IgLON5 -related tauopathy, Guadeloupean parkinsonism, Parkinson-dementia complex of Guam, Non-Guamanian motor neuron disease with NFTs, Amyotrophic lateral sclerosis of Guam, X-linked parkinsonism with spasticity, Cerebrotendinous xanthomatosis, Niemann-Pick disease type C, PANK2-associated Neurodegeneration with Brain Iron Accumulation (NBIA), PLA2G6-assiciatcd NBIA, SLC9A6 mental retardation, or diseases or disorders associated with gene mutations in LRRK2, PRKN, SNCA, TARDBP, or C9orf72. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease. In some embodiments, a healthy control subject is a subject that does not have a disease or disorder associated with Tau protein.

[0262] In some embodiments, a subject (e.g., human subject) may be genetically predisposed to Alzheimer’s Disease but has not exhibited any symptoms or been diagnosed with Alzheimer’s Disease.

[0263] In some embodiments, a method described herein comprises ameliorating an increase in an amount or concentration of total Tau protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference. In some embodiments, a method described herein comprises ameliorating an increase in an amount or concentration of phosphorylated Tau protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference. In some embodiments, a method described herein comprises ameliorating an increase in an amount or concentration of neurofilament protein (e.g., light (NfL) or heavy (NfH)) in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference. In some embodiments, a method described herein comprises ameliorating an increase in an amount or concentration of amyloid beta protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference. In some embodiments, an appropriate reference is or comprises a healthy human control subject or a human subject not administered BIIB080. In some embodiments, an amount or concentration of total Tau protein, phosphorylated Tau protein, neurofilament protein (e.g., light (NfL) or heavy (NfH)), or amyloid beta protein in the cerebral spinal fluid of a human subject is determined by CSF analysis.

[0264] In some embodiments, a method described herein comprises maintaining an amount or concentration of total Tau protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein. In some embodiments, a method described herein comprises maintaining an amount or concentration of phosphorylated Tau protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein. In some embodiments, a method described herein comprises maintaining an amount or concentration of amyloid beta protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein. In some embodiments, an amount or concentration of total Tau protein, phosphorylated Tau protein, or amyloid beta protein in the cerebral spinal fluid of a human subject is determined by CSF analysis.

[0265] In some embodiments, a method described herein comprises delaying an increase of the amount or concentration of total Tau protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference. In some embodiments, a method described herein comprises delaying an increase of the amount or concentration of phosphorylated Tau protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference. In some embodiments, a method described herein comprises delaying an increase of the amount or concentration of amyloid beta protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference. In some embodiments, an appropriate reference is or comprises a healthy human control subject or a human subject not administered BIIB080. In some embodiments, an amount or concentration of total Tau protein, phosphorylated Tau protein, or amyloid beta protein in the cerebral spinal fluid of a human subject is determined by CSF analysis.

[0266] In some embodiments, a method described herein comprises reducing an amount or concentration of total Tau protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference. In some embodiments, a method described herein comprises reducing an amount or concentration of phosphorylated Tau protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference. In some embodiments, a method described herein comprises reducing an amount or concentration of or amyloid beta protein in the cerebral spinal fluid of a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference. In some embodiments, an appropriate reference is or comprises a healthy human control subject or a human subject not administered BIIB080. In some embodiments, an amount or concentration of total Tau protein, phosphorylated Tau protein, or amyloid beta protein in the cerebral spinal fluid of a human subject is determined by CSF analysis.

[0267] In some embodiments, a method described herein comprises ameliorating an increase in the number and / or volume of neurofibrillary inclusions in a human subject having a disease or disorder associated with Tau protein as determined by performing magnetic resonance imaging (MRI) and / or Positron Emission Tomography (PET) on the human subject. In some embodiments, a method described herein comprises maintaining a number and / or volume of neurofibrillary inclusions, delaying an onset of an increase in a number and / or volume of neurofibrillary inclusions, slowing an increase in the number and / or volume of neurofibrillary inclusions, or reducing an number and / or volume of neurofibrillary inclusions in a human subject having a disease or disorder associated with Tau protein as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080), as determined by performing magnetic resonance imaging (MRI) and / or Positron Emission Tomography (PET) on the human subject. In some embodiments, a disease or disorder associated with Tau protein is a tauopathy. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease (e.g., mild AD, MCI due to AD, or mild AD dementia) or Frontotemporal Dementia (FTD). In some embodiments, a disease or disorder associated with Tau protein is Frontotemporal Dementia, MAPT-related frontotemporal dementia (MAPT-FTD), Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Pick Disease, Argyrophilic Grain Disease (AGD), Globular Glial Tauopathies, Epilepsy, and / or Dravet’s Syndrome. In some embodiments, a disease or disorder associated with Tau protein is Down syndrome, Prion diseases (sCJD, vCJD, gCJD, GSS, FFI), Diffuse neurofibrillary tangles with calcification, Familial British and Danish dementia, Postencephalitic parkinsonism, Subacute sclerosing panencephalitis, Myotonic dystrophy (DM1) and PROMM (DM2), Aging- related Tau astrogliopathy, Traumatic brain injury, Chronic traumatic encephalopathy, IgL0N5-related Tauopathy, Guadeloupean parkinsonism, Parkinson-dementia complex of Guam, Non-Guamanian motor neuron disease with NFTs, Amyotrophic lateral sclerosis of Guam, X-linked parkinsonism with spasticity, Cerebrotendinous xanthomatosis, Niemann-Pick disease type C, PANK2-associated Neurodegeneration with Brain Iron Accumulation (NBIA), PLA2G6-assiciated NBIA, SLC9A6 mental retardation, or diseases or disorders associated with gene mutations in LRRK2, PRKN, SNCA, TARDBP, or C9orf72. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease. In some embodiments, a method described herein comprises reducing a number of neurofibrillary inclusions or reduce the volume of neurofibrillary inclusions by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% as compared to an appropriate reference (e.g., a healthy human control subject, a human subject not administered BIIB080).

[0268] In some embodiments, a method described herein comprises ameliorating at least one symptom or sign of a disease or disorder associated with Tau protein in a human subject as assessed by a clinically relevant test, score or scale. In some embodiments, a disease or disorder associated with Tau protein is a Tauopathy. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease (e.g., mild AD, MCI due to AD, or mild AD dementia) or Fronto-temporal Dementia (FTD). In some embodiments, a disease or disorder associated with Tau protein is Frontotemporal Dementia, MAPT-related frontotemporal dementia (MAPT-FTD), Frontotemporal Dementia with Parkinsonism- 17 (FTDP-17), Progressive Supranuclear Palsy (PSP), Chronic Traumatic Encephalopathy (CTE), Corticobasal Ganglionic Degeneration (CBD), Pick Disease, Argyrophilic Grain Disease (AGD), Globular Glial Tauopathies, Epilepsy, and / or Dravet’s Syndrome. In some embodiments, a disease or disorder associated with Tau protein is Down syndrome, Prion diseases (sCID, vCID, gCID, GSS, FFI), Diffuse neurofibrillary tangles with calcification, Familial British and Danish dementia, Postencephalitic parkinsonism, Subacute sclerosing pancnccphalitis, Myotonic dystrophy (DM1) and PROMM (DM2), Aging-related Tau astrogliopathy, Traumatic brain injury, Chronic traumatic encephalopathy, IgLON5-related Tauopathy, Guadeloupean parkinsonism, Parkinson-dementia complex of Guam, Non-Guamanian motor neuron disease with NFTs, Amyotrophic lateral sclerosis of Guam, X-linked parkinsonism with spasticity, Cerebrotendinous xanthomatosis, Niemann-Pick disease type C, PANK2-associated Neurodegeneration with Brain Iron Accumulation (NBIA), PLA2G6-assiciated NBIA, SLC9A6 mental retardation, or diseases or disorders associated with gene mutations in LRRK2, PRKN, SNCA, TARDBP, or C9orf72. In some embodiments, a disease or disorder associated with Tau protein is Alzheimer’s disease. In some embodiments, at least one symptom or sign is loss of memory, cognitive decline, loss of ability to understand or express speech, abnormal behavior, impaired motor function, or increase in the number and / or volume of neurofibrillary inclusions. In some embodiments, at least one symptom or sign is loss of cognitive function, neuropsychiatric behavior dysfunction, impaired global function, loss of motor function, impaired cognitive function, impaired neuropsychiatric function, impaired daily function, impaired attention, impaired visuoperceptual processing, impaired memory, impaired degree of independence, increased apathy, impaired learning ability, impaired mental concentration, impaired understanding and expression of speech, impaired behavior, depression, irritability, anger, impaired mobility, impaired self-care, pain, discomfort, anxiety, seizures, suicidal ideation, or suicidal behavior. Non-limiting examples of such clinically relevant tests, scores and scales include the following.

[0269] Symbol Digit Modalities Test

[0270] In some embodiments, a method described herein comprises ameliorating impaired attention, impaired visuoperceptual processing, impaired working memory, impaired psychomotor speed, or a combination thereof, in a subject having a disease or disorder associated with Tau protein, as assessed by the Symbol Digit Modalities Test (SDMT). In SMDT, a subject pairs abstract symbols with specific numbers according to a translation key. The test measures the number of items correctly paired (maximum of 110 correct pairs) in 90 seconds. SDMT has been shown to have strong reliability and validity. SDMT is described in greater detail by Smith, A. Symbol Digit Modalities Test (SDMT). Manual (rev.) Los Angeles: Western Psychological Services, 1982. In some embodiments, methods improve the number of items correctly paired by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 items.

[0271] Stroop Word Reading Test

[0272] In some embodiments, a method described herein comprises ameliorating impaired attention, impaired processing, impaired psychomotor speed, impaired verbal motor output, or a combination thereof, in a subject having a disease or disorder associated with Tau protein, as assessed by the Stroop Word Reading Test (SWR) Test. During a SWR Test, a subject is presented with a page of color names (e.g., "BLUE," "RED," or "GREEN") printed in black ink and is asked to read aloud as many words as possible within a given amount of time (in 45 seconds). The number of words read correctly is counted, with a higher score indicating better cognitive performance. See Stroop, J. R., J. Exp. Psychol. 1935, 18, 643-662 for additional description of the SWR Test. In some embodiments, methods improve the number of words the subject can read aloud in the given amount of time by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 words.

[0273] Global Impression, Severity’ and Change Scales

[0274] In some embodiments, a method described herein comprises improving a subject’s score on a Global Impression, Severity and Change Scale. This assessment can be conducted by a clinician (CGLS), a companion (CrGLS), or the subject (PGLS). The subject is assessed using an 11-point numeric rating scale (NRS), where higher scores indicate greater severity. The CGI-S is described in greater detail by Guy W: ECDEU Assessment Manual for Psychopharmacology Rockville, MD: U. S. Department of Health, Education, and Welfare; 1976. In some embodiments, methods reduce the subject’s NRS score by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points.

[0275] Montreal Cognitive Assessment

[0276] In some embodiments, a method described herein comprises ameliorating impaired cognitive function in a subject having a disease or disorder associated with Tau protein, as assessed by the Montreal Cognitive Assessment (MoCA). The MoCA is a subject-completed assessment used to detect cognitive impairment. It contains a series of basic assessments, including attention and visuospatial tasks. The total score ranges from 0 to 30, where lower scores indicate greater impairment. The MoCA is described in greater detail by Nasreddine et al., 2015, J. Am. Geriatr. Soc. 53:695-9. In some embodiments, methods increase the subject’s MoCA score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points.

[0277] Work Productivity and Activity Impairment Test

[0278] In some embodiments, a method described herein comprises ameliorating impaired global function in a subject having a disease or disorder associated with Tau protein, as assessed by the Work Productivity and Activity Impairment Test (WPAI). The WPAI contains 6 items assessing the impact of disease on employment status (yes / no), hours missed due to disease, hours missed due to other reasons, hours worked, and impact on productivity and on daily activities (both using an 11 -point NRS, where higher scores indicate greater impact). The WPAI is described in greater detail by Reilly et al., 1993, Pharmacoeconomics 4:353-65. In some embodiments, methods reduce the subject’s WPAI score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points.

[0279] Apathy Evaluation Scale

[0280] In some embodiments, a method described herein comprises ameliorating increased apathy in a subject having a disease or disorder associated with Tau protein, as assessed by the Apathy Evaluation Scale (AES). The AES is an 18-item assessment of apathy, including overt behavior, cognitive aspects of motivation, and emotional responsivity. Each item is scored on a 4-point Likert scale, from 1 ("Not at all") to 4 ("A lot"). A total score is created by summing the 18 items (scores range from 18 to 72; 3 items are reverse scored), with higher scores indicating greater apathy. The AES is described in greater detail by Marin et al., 1991, Psychiatry Res. 38:143-62. In some embodiments, methods decrease the subject’s AES score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points. Neuro-Qol Cognition Function Short Form, Version 2

[0281] In some embodiments, a method described herein comprises ameliorating impaired mental concentration and / or impaired learning ability in a subject having a disease or disorder associated with Tau protein, as assessed by the Neuro-Qol Cognition Function Short Form. The Neuro-Qol Cognition Function Short Form contains 8 items (including "trouble concentrating" and difficulty "learning new tasks or instructions"), each assessed using a 5-point Likert scale, where lower scores indicate greater difficulty (4 items) or greater frequency (4 items). The raw sum score is converted to a T-score distribution (mean of 50, standard deviation of 10). See National Institute of Neurological Disorders and Stroke (NINDS). User Manual for the Quality of Life in Neurological Disorders (Neuro-QoL) Measures, Version 2.0, March 2015.

[0282] Symptoms of Major Depressive Disorder Scale

[0283] In some embodiments, a method described herein comprises ameliorating depression in a subject having a disease or disorder associated with Tau protein, as assessed by the Symptoms of Major Depressive Disorder Scale (SMDDS). SMDDS is a self-report assessment of depression (McCarrier et al., 2016, Patient 9:117-134). It contains 16 items, measuring concepts such as sadness, irritability, worry, and sleep disturbance. Each item is assessed on a 5-point Likert scale, from "Not at all" to "Extremely" (9 items) and from "Never" to "Always" (7 items). Item scores from 15 of the items (the least severe of the two eating items is not included) are summed to create a 0 to 60 score, where higher scores indicate more severe depressive symptomatology. The SMDDS is described in greater detail by Bushnell et al., 2019, Value in Health 22:906- 915. In some embodiments, methods reduce the subject’s score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 points.

[0284] EuroQol 5 -Dimension, 5-Level Questionnaire

[0285] In some embodiments, m a method described herein comprises ameliorating impaired mobility, impaired self-care, impaired global function, pain / discomfort, anxiety, depression, or a combination thereof, in a subject having a disease or disorder associated with Tau protein, as assessed by the EuroQol 5-Dimension, 5-Level Questionnaire (EQ- 5D-5L). EQ-5D-5L is a validated self-report health status questionnaire used to calculate a health status utility score for use in health economic analyses (Brooks, 1996, Health Policy 37:53-72 and Herdman et al., 2011, Qual Life Res. 20:1727-36). There are two components to the EQ-5D-5L: a 5-item health state profile that assesses mobility, self- care, usual activities, pain / discomfort, and anxiety / depression, as well as a visual analog scale (VAS) that measures health state. Published weighting systems allow for creation of a single composite score of the subject's health status (Index score) from the 5-item scores (e.g., does not include the VAS). In some embodiments, methods improve the subject’s EQ-5D-5L score.

[0286] Health Utilities Index

[0287] In some embodiments, a method described herein comprises improving a health status of a subject having a disease or disorder associated with Tau protein, as assessed by the Health Utilities Index (HUI). The HUI is a multi-attribute system of health status (Feeny et al., 1995, Pharmacoeconomics 7:490-502). The HUI2 and HUB questionnaire (commonly referred to as HUI2 / 3) contains 15 items with Likert-type response options. From these items, two scores can be produced: HUB (7 items) and HUB (8 items). Both scores are health utility indexes, where 0 = death, and 1 = perfect health. In some embodiments, methods improve the subject’s HUI score.

[0288] Columbia-Suicide Severity Rating Scale

[0289] In some embodiments, a method described herein comprises ameliorating suicidal ideation or suicidal behavior of a subject having a disease or disorder associated with Tau protein, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS). The C- SSRS is a structured tool to assess suicidal ideation and behavior. Four constructs are measured: severity of ideation, intensity of ideation, behavior, and lethality of actual suicide attempts. Binary (yes / no) data are collected for 10 categories, and composite endpoints based on the categories are followed over time to monitor subject safety (Posner et al., 2011, Am. J. Psychiatry 168:1266-77). It maps to the Columbia- Classification Algorithm for Suicide Assessment and meets the criteria listed in the U.S. FDA draft guidance for assessment of suicidality in clinical trials (FDA 2012). In some embodiments, methods improve the subject’s C-SSRS score.

[0290] Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)

[0291] In some embodiments, a method described herein comprises ameliorating loss of memory, cognitive decline, impaired cognitive function or loss of cognitive function of a subject having a disease or disorder associated with Tau protein, as assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) assessment. The RBANS is a neurological assessment designed to identify abnormal cognitive decline in older adults and to differentiate between different dementia etiologies (Randolph et al., J. Clin. Exp. Neuropsychol. 1998 20: 310-319). The RBANS has been shown to correlate with functional limitations in dementia populations (Hobson et al., 2010, Int. J. Geriatr. Psychiatry 25:525-530) and to adequately detect cognitive impairment associated with AD (Duff et al., Arch. Clin. Neuropsychol. 2008 23:603- 612).

[0292] The assessment yields 5 index scores, 1 for each of the domains tested: attention, visuospatial / constructional abilities, language, immediate memory and delayed memory. The index scores for the domains can be used to determine a total scale score.

[0293] Mini-mental state examination (MMSE)

[0294] In some embodiments, a method described herein comprises ameliorating loss of memory, cognitive decline, impaired cognitive function or loss of cognitive function of a subject having a disease or disorder associated with Tau protein, as assessed by the MiniMental State Examination (MMSE) (Tombaugh et al., 2996, Psychological Assessment 8:48-59). The MMSE is used to quantify cognitive function and to screen for cognitive loss. It is a severity scale, not a diagnostic scale, and can be confounded by level of education such that dementia may be present and diagnosed despite relatively high MMSE score. The test administrator presents the patient with a series of questions and tests related to orientation, attention, calculation, recall, language and motor skills with a maximum possible score of 30 points. N europsychiatric Inventory - Questionnaire (NPI-Q)

[0295] In some embodiments, a method described herein comprises ameliorating abnormal behavior, neuropsychiatric behavior dysfunction, or impaired neuropsychiatric function, of a subject having a disease or disorder associated with Tau protein, as assessed by the Neuropsychiatric Inventory (NPI). The NPI assesses behavioral disturbances occurring in dementia patients to evaluate a wide range of psychopathology and distinguish among different etiologies of dementia (Cummings et al., 1997, Neurology 71:337-343). The NPI-Questionnaire (NPI-Q) is a brief questionnaire form of the NPI intended to identify clinically-significant neuropsychiatric disturbances and their associated impact on caregivers (Kaufer et al., 2000, J. Neuropsychiatry Clin. Neuro. 12:233-239). It is completed by the test administrator after discussion with the trial partner about the presence / absence in the patient of 12 behaviors (e.g., anxiety, disinhibition, agitation / aggression) and, for each behavior that is present, its severity (scale of 1-3, with 3 being the most severe) and the associated caregiver distress (scale of 0-5, representing no distress through extreme distress).

[0296] Functional Activities Questionnaire (FAQ)

[0297] In some embodiments, a method described herein comprises ameliorating impaired degree of independence, impaired mobility, or impaired self-care of a subject having a disease or disorder associated with Tau protein, as assessed by the Functional Activities Questionnaire (FAQ). The FAQ is a widely-used scale to assess activities of daily living in patients with mild AD (Brown et al., 2011, Arch. Gen. Psychiatry 68:617- 626; Marshall et al., 2011, Alzheimers Dement. 7:300-308). It is a brief questionnaire in which the trial partner rates the patient’s abilities in ten areas, such as keeping track of current events and preparing a balanced meal, on a scale of 0 (normal) to 3 (dependent). A score of 30 represents maximal dependence, and a score of 0 represents complete independence (Pfeffer et al., 1982, J. Gerontol. 37:323-329).

[0298] Clinical Dementia Rating ( CDR) Scale

[0299] In some embodiments, a method described herein comprises ameliorating loss of memory, cognitive decline, impaired cognitive function or loss of cognitive function of a subject having a disease or disorder associated with Tau protein, as assessed by the Clinical Dementia Rating (CDR). The CDR is a global scale used to categorize the severity of Alzheimer’s type dementia (Morris, 1993, Neurol. 43:2412-2414; Morris, 1997, Int. Psychogeriatr. 9 Suppl 1:173-173). It utilizes a semi- structured test administrator interview with the patient and the trial partner to obtain the information necessary to rate the patient’s cognitive performance in 6 domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Categorical scores for each domain are 0 (none), 0.5 (questionable), 1 (mild), 2 (moderate) and 3 (severe). A summed total score (sum of boxes) is produced, and a global score (using the same 5 grades of dementia) is derived from the category scores according to the practice described by Morris (Morris 1993).

[0300] In some embodiments, a method described herein comprises ameliorating a symptom or sign of a disease or disorder associated with Tau protein, as assessed by one or more of the following assessments known to those of skill in the art: Alzheimer’s Disease Cooperative Study Activities of Daily Living for Mild Cognitive Impairment ADCS-(ADL MCI); Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS Cog 13); Alzheimer’s Disease Composite Score (ADCOMS); Integrated Alzheimer’s Disease Rating Scale (iADRS); Zarit Burden Interview (ZB I); Resource Utilization in Dementia (RUD-Lite); PSP Rating Scale (PSPRS); Movement Disorder Society (MDS)- sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part II; Clinical Global Impression (CGI) of Severity and Change; Progressive Supranuclear Palsy Quality of Life scale (PSP-QoL); Schwab and England Activities of Daily Living (SEADL) scale; Phonemic Fluency; Letter-Number Sequencing; Color Trails Test; The Montreal Cognitive Assessment (MoCA); European Quality of Life (EuroQol); and Short Form Survey (SF-36).

[0301] VIII. Certain Anti-Beta Amyloid Antibody Pharmaceutical Compositions

[0302] In some embodiments, a method described herein comprises administering to a subject a pharmaceutical composition comprising an anti-beta amyloid antibody. In some embodiments, an anti-beta amyloid antibody is or comprises aducanumab, lecanemab, donanemab, bapineuzumab, gantenerumab, solanezumab, crenezumab, or any combination thereof. Tn some embodiments, an anti-beta amyloid antibody is or comprises aducanumab. In some embodiments, an anti-beta amyloid antibody is or comprises Iccancmab. In some embodiments, an anti-beta amyloid antibody is or comprises donanemab. In some embodiments, an anti-beta amyloid antibody is or comprises bapineuzumab. In some embodiments, an anti-beta amyloid antibody is or comprises gantenerumab. In some embodiments, an anti-beta amyloid antibody is or comprises solanezumab. In some embodiments, an anti-beta amyloid antibody is or comprises crenezumab.

[0303] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable diluent or carrier. In some embodiments, a pharmaceutical composition comprises or consists essentially of a sterile saline solution and the anti-beta amyloid antibody. In some embodiments, a sterile saline is pharmaceutical grade saline. In some embodiments, the pharmaceutical composition comprises or consists essentially of sterile water and an anti-beta amyloid antibody. In some embodiments, sterile water is pharmaceutical grade water. In some embodiments, a pharmaceutical composition comprises or consists essentially of artificial cerebrospinal fluid (aCSF) and an anti-beta amyloid antibody. In some embodiments, artificial cerebrospinal fluid is pharmaceutical grade. In some embodiments, a pharmaceutical composition comprises a certain concentration of anti-beta amyloid antibody in aCSF, and is diluted in aCSF diluent to achieve the intended clinical dose.

[0304] In some embodiments, a pharmaceutical composition comprises an anti-beta amyloid antibody. In some embodiments, an anti-beta amyloid antibody can be formulated according to methods known in the art (Remington: The Science and Practice of Pharmacy, 2000). Pharmaceutical compositions disclosed herein comprise of a pharmaceutical carrier including, but not limited to, phosphate buffered saline solutions, water, emulsions (e.g., oil / water), liposomes, and a co-solvent system. In some embodiments, certain organic solvents such as dimethylsulfoxide are used.

[0305] In some embodiments, a pharmaceutical composition comprises a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In some embodiments, such co-solvent systems are used for hydrophobic compounds. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.

[0306] In some embodiments, a pharmaceutical composition is prepared for oral administration. In some embodiments, a pharmaceutical composition is prepared for buccal administration. In some embodiments, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, intraperitoneal (IP), subcutaneous, intramuscular, intrathecal (IT), intracerebroventricular (ICV)). In some embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as aCSF, water, or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In some embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In some embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.

[0307] In some embodiments, a pharmaceutical composition is prepared for administration by topical or intradermal administration. In some embodiments, a pharmaceutical composition is prepared for administration through an aerosol formulation. In some embodiments, an aerosol formulation is a nasal spray.

[0308] IX. Certain Anti-Beta Amyloid Antibody Dosage Amounts

[0309] In some embodiments, a method described herein comprises administering to a subject a therapeutically effective amount of an anti-beta amyloid antibody. In some embodiments, a therapeutically effective amount is 10 mg / kg of a subject's weight. In some embodiments, a therapeutically effective amount is 15 mg / kg of a subject’s weight. In some embodiments, a therapeutically effective amount is 60 mg / kg of a subject’s weight.

[0310] In some embodiments, a dosage regimen will be determined by the attending physician and a subject’s clinical factors. Dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. A typical dose can be, for example, in the range of 0.01 to 60 mg / kg; however, doses below or above this exemplary range are envisioned, especially considering the aforementioned factors. Generally, a dose can range, e.g., from about 0.25 to 60 mg / kg, and more usually 0.25 to 5 mg / kg (e.g., 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1 mg / kg, 2 mg / kg, etc.), of the subject’s weight. For example, dosages can be 1 mg / kg body weight or 10 mg / kg body weight or within the range of 1-10 mg / kg, preferably at least 1 mg / kg. Doses intermediate in the above ranges are also intended to be within the scope of the invention. Subjects can be administered such doses weekly, bi-weekly, once every month, once every 3 months, once every 4 months, once every 6 months, or once a year according to any other schedule determined by empirical analysis. In some embodiments, subjects can be administered such doses over a duration of an hour (e.g., lOmg / kg of a subject’s weight over a course of an hour).

[0311] In some embodiments, a therapeutically effective amount is 0.25 mg / kg, 0.75 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, or 60 mg / kg of a subject’s weight.

[0312] In some embodiments, a therapeutically effective amount is about 0.25 mg / kg, about 0.75 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 60 mg / kg of a subject’s weight.

[0313] In some embodiments, a therapeutically effective amount is 10 mg / kg, 10.1 mg / kg, 10.2 mg / kg, 10.3 mg / kg, 10.4 mg / kg, 10.5 mg / kg, 10.6 mg / kg, 10.7 mg / kg, 10.8 mg / kg, 10.9 mg / kg, 15.1 mg / kg, 15.2 mg / kg, 15.3 mg / kg, 15.4 mg / kg, 15.5 mg / kg, 15.6 mg / kg, 15.7 mg / kg, 15.8 mg / kg, 15.9 mg / kg, 60 mg / kg, 60.1 mg / kg, 60.2 mg / kg, 60.3 mg / kg, 60.4 mg / kg, 60.5 mg / kg, 60.6 mg / kg, 60.7 mg / kg, 60.8 mg / kg, or 60.9 mg / kg of a subject’s weight.

[0314] In some embodiments, a therapeutically effective amount is about 10 mg / kg, about 10.1 mg / kg, about 10.2 mg / kg, about 10.3 mg / kg, about 10.4 mg / kg, about 10.5 mg / kg, about 10.6 mg / kg, about 10.7 mg / kg, about 10.8 mg / kg, about 10.9 mg / kg, about 15.1 mg / kg, about 15.2 mg / kg, about 15.3 mg / kg, about 15.4 mg / kg, about 15.5 mg / kg, about 15.6 mg / kg, about 15.7 mg / kg, about 15.8 mg / kg, about 15.9 mg / kg, about 60 mg / kg, about 60.1 mg / kg, about 60.2 mg / kg, about 60.3 mg / kg, about 60.4 mg / kg, about 60.5 mg / kg, about 60.6 mg / kg, about 60.7 mg / kg, about 60.8 mg / kg, or about 60.9 mg / kg of a subject’s weight.

[0315] X. Certain Anti-Beta Amyloid Antibody Dosing Regimens

[0316] In some embodiments, a method described herein comprises administering to a subject a therapeutically effective amount of an anti-beta amyloid antibody one or more times. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody amount at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 times. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody once every week. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody once every 2 weeks. In some embodiments a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody once every 3 months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody monthly. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody once every two months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an antibeta amyloid antibody once every three months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an antibeta amyloid antibody quarterly. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody semiannually. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody annually. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody once every two years.

[0317] In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody about every 1 week, about every 2 weeks, about every month, about every three months, about every four months, about every six months, or about a year. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an antibeta amyloid antibody about monthly. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody once about every two months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody once about every three months. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody about quarterly. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody about semiannually. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody about annually. In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody once about every two years.

[0318] In some embodiments, a method described herein comprises administering a therapeutically effective amount of an anti-beta amyloid antibody for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months.

[0319] In some embodiments, a method described herein comprises administering an anti-beta amyloid antibody at a dose of 10 mg / kg of a human subject’s weight once every week. In some embodiments, a method described herein comprises administering an antibeta amyloid antibody at a dose of 15 mg / kg of a human subject’s weight once every week. In some embodiments, a method described herein comprises administering an antibeta amyloid antibody at a dose of 60 mg / kg of a human subject’s weight once every week. In some embodiments, a human subject has mild Alzheimer’s disease. In some embodiments, a human subject has MCI due to Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease dementia. In some embodiments, a human subject has presymptomatic Alzheimer’s disease.

[0320] In some embodiments, a method described herein comprises administering an anti-beta amyloid antibody at a dose of 10 mg / kg of a human subject’s weight once every 2 weeks. In some embodiments, a method described herein comprises administering an anti-beta amyloid antibody at a dose of 15 mg / kg of a human subject’s weight once every 2 weeks. In some embodiments, a method described herein comprises administering an anti-beta amyloid antibody at a dose of 60 mg / kg of a human subject’s weight once every

[0321] 2 weeks. In some embodiments, a human subject has mild Alzheimer’s disease. In some embodiments, a human subject has MCI due to Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease dementia. In some embodiments, a human subject has presymptomatic Alzheimer’s disease.

[0322] In some embodiments, a method described herein comprises administering an anti-beta amyloid antibody at a dose of 10 mg / kg of a human subject’s weight once every month. In some embodiments, a method described herein comprises administering an anti -beta amyloid antibody at a dose of 15 mg / kg of a human subject’s weight once every month. In some embodiments, a method described herein comprises administering an anti -beta amyloid antibody at a dose of 60 mg / kg of a human subject’s weight once every month. In some embodiments, a human subject has mild Alzheimer’s disease. In some embodiments, a human subject has MCI due to Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease dementia. In some embodiments, a human subject has presymptomatic Alzheimer’s disease.

[0323] In some embodiments, a method described herein comprises administering an anti-beta amyloid antibody at a dose of 10 mg / kg of a human subject’s weight once every

[0324] 3 months. In some embodiments, a method described herein comprises administering an anti-beta amyloid antibody at a dose of 15 mg / kg of a human subject’s weight once every 3 months. In some embodiments, a method described herein comprises administering an anti-beta amyloid antibody at a dose of 60 mg / kg of a human subject’s weight once every 3 months. In some embodiments, a human subject has mild Alzheimer’s disease. In some embodiments, a human subject has MCI due to Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease dementia. In some embodiments, a human subject has presymptomatic Alzheimer’s disease.

[0325] In some embodiments, a method described herein comprises administering an anti-beta amyloid antibody at a dose of 10 mg / kg of a human subject’s weight once every 6 months. In some embodiments, a method described herein comprises administering an anti -beta amyloid antibody at a dose of 15 mg / kg of a human subject’s weight once every 6 months. In some embodiments, a method described herein comprises administering an anti -beta amyloid antibody at a dose of 60 mg / kg of a human subject’s weight once every 6 months. In some embodiments, a human subject has mild Alzheimer’s disease. In some embodiments, a human subject has MCI due to Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease dementia. In some embodiments, a human subject has presymptomatic Alzheimer’s disease.

[0326] In some embodiments, a method described herein comprises administering an anti-beta amyloid antibody at a dose of 10 mg / kg of a human subject’s weight once every year. In some embodiments, a method described herein comprises administering an antibeta amyloid antibody at a dose of 15 mg / kg of a human subject’s weight once every year. In some embodiments, a method described herein comprises administering an antibeta amyloid antibody at a dose of 60 mg / kg of a human subject’s weight once every year. In some embodiments, a human subject has mild Alzheimer’s disease. In some embodiments, a human subject has MCI due to Alzheimer’s disease. In some embodiments, a human subject has mild Alzheimer’s disease dementia. In some embodiments, a human subject has presymptomatic Alzheimer’s disease.

[0327] XI. Combination Therapy with an Anti-Beta Amyloid Antibody

[0328] Current treatment options targeting Alzheimer’s disease are limited, with only a small portion considered disease-modifying. Emerging evidence suggests that Alzheimer’s disease has complex interplay between two pathogenic signs, one being aberrant hyperphosphorylated Tau protein aggregates and another being beta-amyloid plaques. The methods described herein may be used in treatment of multifactorial progressive neurodegenerative disorders such as Alzheimer’s disease. One characteristic of Alzheimer’s disease results from aberrant aggregation of hyperphosphorylated Tau protein into intrancuronal neurofibrillary tangles (NFT). Development of NFTs result in loss of cytoskeletal microtubules and tubulin-associated proteins within neurons which instigates further progression of Alzheimer’s disease (Metaxas et al., 2016). In some embodiments, a method described herein comprises use of modified oligonucleotides or salts thereof (e.g., BIIB080) to inhibit Tau mRNA and protein expression thereof. In some embodiments, use of the methods described herein are sufficiently effective in reduction of Tau mRNA and protein expression thereof. In some embodiments, use of the methods described herein are sufficiently effective in reduction of NFTs. In some embodiments, the methods described herein may be used for treatment and improvement of Alzheimer’s disease in a human subject.

[0329] Another characteristic associated with pathogenesis of Alzheimer’s disease is accumulation of beta-amyloid plaques. Beta-amyloid plaques disrupt cell-to-cell communication and may activate immune cell inflammation that causes neuronal death. Thus, both the temporal and spatial progression of beta-amyloid plaques appeared to underlie the cognitive and functional decline associated with Alzheimer’s disease. In some embodiments, the methods described herein entail the use of anti-beta amyloid antibodies (e.g., aducanumab, lecanemab, donanemab, bapineuzumab, gantenerumab, solanezumab, crenezumab, etc.) to reduce and / or inhibit the formation of beta- amyloid plaques. In some embodiments, use of the methods described herein are sufficiently effective in reduction of beta- amyloid plaques. In some embodiments, a method described may be used for treatment and improvement of Alzheimer’s disease in a human subject.

[0330] In some embodiments, a method described herein comprises a method of treatment that entail co-administering BIIB080 with an anti-beta amyloid antibody to a human subject in need thereof. In some embodiments, a human subject has received one or more administrations of an anti-beta amyloid antibody prior to initiation of treatment with BIIB080. In some embodiments, a human subject has received one or more administrations of BIIB080 prior to initiation of treatment with an anti-beta amyloid antibody. In some embodiments, a human subject has received one or more administrations of BIIB080 in combination with one or more administrations with an anti-beta amyloid antibody. In some embodiments, a human subject has received one or more administrations of an anti-beta amyloid antibody prior to initiation of treatment with BIIB080.

[0331] In some embodiments, a method described herein comprises treatment of one or both pathogenic signs of Alzheimer’s disease: hyperphosphorylated Tau protein aggregates and beta-amyloid plaques. In some embodiments, use of the methods described herein are sufficiently effective in reduction of Tau mRNA and protein expression thereof. In some embodiments, use of the methods described herein are sufficiently effective in reduction of NFTs. In some embodiments, use of the methods described herein are sufficiently effective in reduction of beta- amyloid plaques. In some embodiments, use of the methods described herein are sufficiently effective in reduction of Tau mRNA, protein expression thereof, NFTs, and / or beta- amyloid plaques. In some embodiments, use of the methods described herein may result in amelioration of symptoms associated with Alzheimer’s disease in a human subject. In some embodiments, a method described herein may be used for treatment and improvement of Alzheimer’s disease in a human subject.

[0332] In some embodiments, a subject (e.g., a human subject) is a patient. In some embodiments, a patient has a disease and / or disorder. In some embodiments, a disease and / or disorder is or comprises preclinical Alzheimer’s disease, presymptomatic Alzheimer’ s disease, mild Alzheimer’ s disease, early Alzheimer’ s disease, prodromal Alzheimer’ s disease, mild Alzheimer’ s disease dementia, mild cognitive impairment due to Alzheimer’s disease, mid-stage Alzheimer’s disease, or late-stage Alzheimer’s disease. In some embodiments, a disease and / or disorder is or comprises preclinical Alzheimer’ s disease. In some embodiments, a disease and / or disorder is or comprises presymptomatic Alzheimer’s disease. In some embodiments, a disease and / or disorder is or comprises mild Alzheimer’s disease. In some embodiments, a disease and / or disorder is or comprises early Alzheimer’s disease. In some embodiments, a disease and / or disorder is or comprises prodromal Alzheimer’s disease. In some embodiments, a disease and / or disorder is or comprises mild Alzheimer’s disease dementia. In some embodiments, a disease and / or disorder is or comprises mild cognitive impairment due to Alzheimer’s disease. In some embodiments, a disease and / or disorder is or comprises mid-stage Alzheimer’s disease. In some embodiments, a disease and / or disorder is or comprises late-stage Alzheimer’s disease. The present disclosure provides the recognition that administering one or more therapeutic agents described herein to a subject (c.g., a human subject, c.g., a patient) may be preventative and / or therapeutic. For example, a subject (e.g., a human subject, e.g., a patient) may have early indicators that they are at risk for developing Alzheimer’s disease. In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) has a genetic predisposition to Alzheimer's disease. In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) has a mutation in the Microtubule- Associated Protein Tau gene (MAP ). In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) has a mutation in the Amyloid Precursor Protein gene PP). In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) has a mutation in the Presenilin-1 gene (PSENI). In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the human subject (e.g., a human subject, e.g., a patient) has a mutation in the Presenilin 2 gene (PSEN2). In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) has a mutation in the Leucine-rich repeat kinase 2 gene (LRRK2). In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) has a mutation in the Syntaxin 6 gene (STX6). In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) has a mutation in the Eukaryotic translation initiation factor 2-alpha kinase 3 gene (EIF2AK3). In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) has a mutation in the Myelin-associated oligodendrocyte basic protein gene (MOBP). In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) has a mutation in MAPT, APP, PSENI, PSEN2. LRRK2, STX6, EIF2AK3, MOBP, or any combination thereof. In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) is a carrier of ApoE E4. In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) is homozygous for ApoE E4.

[0333] In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) is aged > 65 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) is aged 65 to 74 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the subject (e.g., a human subject, e.g., a patient) is aged > 75 years.

[0334] In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the human subject (e.g., a human subject, e.g., a patient) is amyloid positive. In some embodiments, amyloid positive is or comprises determining a presence of amyloid beta plaques in a sample from a subject (e.g., a human subject, e.g., a patient). In some embodiments, amyloid positive is or comprises determining an increased level of amyloid beta plaques in a sample from a subject (e.g., a human subject, e.g., a patient) as compared to a reference. In some embodiments, amyloid positive is or comprises determining an abnormal level of amyloid beta plaques in a sample from a subject (e.g., a human subject, e.g., a patient) as compared to a reference. In some embodiments, a reference is or comprises a healthy control human subject. In some embodiments, a reference is or comprises a subject that has not been diagnosed with Alzheimer’s disease. In some embodiments, a reference is or comprises a subject that has not received one or more administrations of an anti-beta amyloid antibody and / or one or more administrations of an oligonucleotide or salt thereof. In some embodiments, a sample is or comprises plasma, cerebrospinal fluid (CSF), a skin biopsy, urine or an imaging sample. In some embodiments, a sample is or comprises CSF. In some embodiments, a sample is or comprises a skin biopsy. In some embodiments, a sample is or comprises urine. In some embodiments, a sample is or comprises an imaging sample. In some embodiments, an imaging sample is or comprises a positron emission tomography (PET) image. In some embodiments, a PET image is or comprises an amyloid PET image. In some embodiments, a PET image is or comprises an amyloid PET image of brain tissue from the subject (e.g., the human subject, e.g., the patient).

[0335] In some embodiments, a subject (e.g., a human subject, e.g., a patient) is at risk for developing Alzheimer’s disease if the human subject (e.g., a human subject, e.g., a patient) is Tau positive. In some embodiments, Tau positive is or comprises a determining a presence of neurofibrillary tangles in a sample from a subject (e.g., a human subject, e.g., a patient). In some embodiments, Tau positive is or comprises determining an increased level or Tau (e.g., total Tau level, e.g., plasma p-Tau level, e.g., CSF p-Tau level, e.g., plasma MTBR-containing Tau level, e.g., CSF MTBR-containing Tau level) in a sample from a subject (e.g., a human subject, e.g., a patient) as compared to a reference. In some embodiments, Tau positive is or comprises determining an abnormal Tau level (e.g., plasma p-Tau, e.g., CSF p-Tau, e.g., plasma MTBR-containing Tau, e.g., CSF MTBR-containing Tau) in a sample from a subject (e.g., a human subject, e.g., a patient) as compared to a reference. In some embodiments, a reference is or comprises a healthy control human subject. In some embodiments, a reference is or comprises a subject that has not been diagnosed with Alzheimer’s disease. In some embodiments, a reference is or comprises a subject that has not received one or more administrations of an anti-beta amyloid antibody and / or one or more administrations of an oligonucleotide or salt thereof. In some embodiments, a sample is or comprises plasma, cerebrospinal fluid (CSF), a skin biopsy, urine or an imaging sample. In some embodiments, a sample is or comprises CSF. In some embodiments, a sample is or comprises a skin biopsy. In some embodiments, a sample is or comprises urine. In some embodiments, a sample is or comprises an imaging sample. In some embodiments, an imaging sample is or comprises a positron emission tomography (PET) image. In some embodiments, a PET image is or comprises a Tau PET image. In some embodiments, a PET image is or comprises a Tau PET image of brain tissue from the subject (e.g., the human subject, e.g., the patient) . Methods comprising administering one or more therapeutic agents to a patient at risk for developing Alzheimer ’s disease

[0336] Among other things, the present disclosure provides a method for treating a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease. In some embodiments, a method described herein comprises treating a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease prior to receiving a diagnosis of Alzheimer’s disease. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease has not been diagnosed with Alzheimer’s disease. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease exhibits at least one symptom or sign of Alzheimer’s disease. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease exhibits at least one symptom or sign of Alzheimer’s disease and has not been diagnosed with Alzheimer’s disease. In some embodiments, at least one symptom or sign is loss of memory, cognitive decline, loss of ability to understand or express speech, abnormal behavior, impaired motor function, falls, impaired balance, impaired swallowing, impaired eating, feeding tube placement, hospitalization, death, increase in the number and / or volume of neurofibrillary inclusions, loss of memory, loss of cognitive function, neuropsychiatric behavior dysfunction, or loss of motor function. In some embodiments, at least one symptom or sign is loss of cognitive function, neuropsychiatric behavior dysfunction, impaired global function, impaired loss of motor function, impaired cognitive function, impaired neuropsychiatric function, impaired daily function, impaired attention, impaired visuoperceptual processing, impaired working memory, impaired psychomotor speed, impaired verbal motor output, impaired degree of independence, increased apathy, impaired learning ability, impaired mental concentration, impaired understanding and expression of speech, impaired behavior, depression, irritability, anger, impaired mobility, impaired self-care, pain, discomfort, anxiety, seizures, suicidal ideation, or suicidal behavior

[0337] In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease has presymptomatic Alzheimer’s disease. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease has preclinical Alzheimer’s disease. Tn some embodiments, a subject (c.g., a human subject, c.g., a patient) at risk for developing Alzheimer’s disease has prodromal Alzheimer’s disease. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease has mild cognitive impairment (e.g., mild cognitive impairment due to Alzheimer’s disease).

[0338] In some embodiments, a method described herein comprises administering an a therapeutically effective amount of oligonucleotide or salt thereof (e.g., BIIB080) and / or a therapeutically effective amount of an anti-beta amyloid antibody to a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease and the subject has not been diagnosed with Alzheimer’s disease, wherein the subject (e.g., a human subject, e.g., a patient) has a mutation in MAPT, APP, PSEN1, PSEN2, LRRK2. STX6, EIE2AK3, MOBP, or any combination thereof.

[0339] In some embodiments, a method described herein comprises administering a therapeutically effective amount of oligonucleotide or salt thereof (e.g., BIIB080) and / or a therapeutically effective amount of an anti-beta amyloid antibody to a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease and the subject has not been diagnosed with Alzheimer’s disease, wherein the subject (e.g., a human subject, e.g., a patient) is a carrier of ApoE s4 or homozygous for ApoE s4.

[0340] In some embodiments, a method described herein comprises administering a therapeutically effective amount of oligonucleotide or salt thereof (e.g., BIIB080) and / or a therapeutically effective amount of an anti-beta amyloid antibody to a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease and the subject has not been diagnosed with Alzheimer’s disease, wherein the subject (e.g., a human subject, e.g., a patient) is aged > 65 years, 65 to 74 years, or > 75 years.

[0341] In some embodiments, a method described herein comprises administering a therapeutically effective amount of oligonucleotide or salt thereof (e.g., BIIB080) and / or a therapeutically effective amount of an anti-beta amyloid antibody to a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease and the subject has not been diagnosed with Alzheimer’s disease, wherein the subject (e.g., a human subject, e.g., a patient) is amyloid positive.

[0342] In some embodiments, a method described herein comprises administering a therapeutically effective amount of oligonucleotide or salt thereof (e.g., BTIB080) and / or a therapeutically effective amount of an anti-beta amyloid antibody to a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease and the subject has not been diagnosed with Alzheimer’s disease, wherein the subject (e.g., a human subject, e.g., a patient) is Tau positive.

[0343] In some embodiments, a method described herein comprises administering a therapeutically effective amount of oligonucleotide or salt thereof (e.g., BIIB080) and / or a therapeutically effective amount of an anti-beta amyloid antibody to a subject (e.g., a human subject, e.g., a patient) prior to being diagnosed with Alzheimer’s disease, wherein the subject (e.g., a human subject, e.g., a patient) exhibits at least one symptom or sign of Alzheimer’s disease.

[0344] In some embodiments, a method described herein comprises administering a therapeutically effective amount of oligonucleotide or salt thereof (e.g., BIIB080) and / or a therapeutically effective amount of an anti-beta amyloid antibody to a subject (e.g., a human subject, e.g., a patient) prior to being diagnosed with Alzheimer’s disease. In some embodiment, a method described herein comprises determining when a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease will be diagnosed with Alzheimer’s disease. In some embodiment, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease about 6 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 15 years, or about 20 years following the determination. For example, in some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 6 months. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 1 year, about 2 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 3 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 4 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 5 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 6 year's. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 7 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 8 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 9 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 10 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 15 years. In some embodiments, a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease is determined to be diagnosed with Alzheimer’s disease in about 20 years. In some embodiments, a method described herein comprises administering a therapeutically effective amount of oligonucleotide or salt thereof (e.g., BIIB080) and / or a therapeutically effective amount of an anti-beta amyloid antibody about 6 months, about 1 year, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 15 years, or about 20 years to a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease prior to a diagnosis with Alzheimer’s disease.

[0345] In some embodiments, the present disclosure provides a method comprising administering a therapeutically effective amount of an oligonucleotide to a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease after a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease has received one or more administrations of an anti-beta amyloid antibody. In some embodiments, the present disclosure provides a method comprising administering a therapeutically effective amount of an oligonucleotide to a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease prior to the subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease receiving one or more administrations of an anti-beta amyloid antibody. In some embodiments, the present disclosure provides a method comprising administering an anti-beta amyloid antibody to a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease after the subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease has received one or more administrations of a therapeutically effective amount of an oligonucleotide or salt thereof. In some embodiments, the present disclosure provides a method comprising administering an anti-beta amyloid antibody to a subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease prior to the subject (e.g., a human subject, e.g., a patient) at risk for developing Alzheimer’s disease receiving one or more administrations of an oligonucleotide or salt thereof.

[0346] In some embodiments, an anti-beta amyloid antibody is or comprises aducanumab. In some embodiments, an anti-beta amyloid antibody is or comprises lecanemab. In some embodiments, an anti-beta amyloid antibody is or comprises donanemab. In some embodiments, an anti-beta amyloid antibody is or comprises bapineuzumab. In some embodiments, an anti-beta amyloid antibody is or comprises gantenerumab. In some embodiments, an anti-beta amyloid antibody is or comprises solanezumab. In some embodiments, an anti-beta amyloid antibody is or comprises crenezumab. In some embodiments, an anti-beta amyloid antibody is or comprises aducanumab, lecanemab, donanemab, bapineuzumab, gantenerumab, solanezumab, crenezumab, or any combination thereof.

[0347] In some embodiments, an oligonucleotide has the following chemical structure:

[0348]

[0349] (nucleobase sequence of SEQ ID NO:4), or a salt thereof.

[0350] In some embodiments, an oligonucleotide has the following chemical notation (5’ to 3’): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (nucleobase sequence of SEQ ID NO:4); wherein,

[0351] A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,

[0352] G = a guanine nucleobase,

[0353] T = a thymine nucleobase, e = a 2’ -MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar moiety, s = a phosphoro thioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage. Methods comprising administering BIIB080 to a patient who has received anti-beta amyloid antibody

[0354] In some embodiments, a method of treatment comprises administering to a human subject a therapeutically effective amount of an oligonucleotide according to the following chemical structure:

[0355] (nucleobase sequence of SEQ ID NO: 4), or a salt thereof, wherein the human subject has received one or more administrations of an anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof.

[0356] In some embodiments, a method of treatment comprising administering to a human subject a therapeutically effective amount of an oligonucleotide, wherein the oligonucleotide has the following chemical notation (5’ to 3’): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Acs mCeo mCcs mCes Tc (nuclcobasc sequence of SEQ ID NO:4); wherein,

[0357] A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,

[0358] G = a guanine nucleobase,

[0359] T = a thymine nucleobase, e = a 2’ -MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar moiety, s = a phosphorothioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage, wherein the human subject has received one or more administrations of an anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide (e.g., BIIB080).

[0360] In some embodiments, one or more administrations of an anti-beta amyloid antibody comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10, or at least 15 administrations of an anti-beta amyloid antibody. In some embodiments, one or more administrations of an anti-beta amyloid antibody continues until there is a reduction or clearance of beta amyloid plaque levels in the brain of a human subject.

[0361] In some embodiments, at least three months (e.g., at least four months, at five months, at least six months, at least seven months, at least eight months, at least nine months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or at least 30 months, at least 36 months, at least 42 months, or at least 48 months) have elapsed between a first administration of an anti-beta amyloid antibody and a last administration of an anti-beta amyloid antibody prior to initiation of treatment with an oligonucleotide or salt thereof (e.g., BIIB080).

[0362] In some embodiments, a reduction in beta amyloid plaque levels in the brain of a human subject is measured between a first point in time and a second point in time, wherein the first point in time is prior to the first administration of an anti-beta amyloid antibody and the second point in time is (i) after the last administration of the anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof and (ii) prior to initiation of treatment with the oligonucleotide or salt thereof.

[0363] In some embodiments, at least a 50% reduction (c.g., at least a 60% reduction, at least a 70% reduction, at least a 80% reduction, at least a 90% reduction, or at least a 95% reduction) in beta amyloid plaque levels in the brain of a human subject has been measured between a first point in time and a second point in time.

[0364] In some embodiments, beta amyloid plaque levels in the brain of a human subject at a first point in time and a second point in time are measured by positron emission tomography (PET) imaging. In some embodiments, beta amyloid plaque levels are assessed by [18F]-florbetapir PET imaging. In some embodiments, beta amyloid plaque levels are assessed by [18F]-fhitemetomol PET imaging. In some embodiments, beta amyloid plaque levels are assessed by [18F]-florbetaben PET imaging. In some embodiments, PET imaging identifies the brain of a human subject as amyloid negative at a second point in time (e.g., by the method described in Clark et al., 2011, JAMA ;305(3):275-83).

[0365] In some embodiments, a method described herein comprises administering to a human subject an oligonucleotide or salt thereof in an amount that is equivalent to about 60 mg of the oligonucleotide or salt thereof

[0366] In some embodiments, a method described herein comprises administering to a human subject an oligonucleotide or salt thereof in an amount that is equivalent to about 115 mg of the oligonucleotide or salt thereof.

[0367] In some embodiments, a method described herein comprises administering to a human subject an oligonucleotide or salt thereof in an amount that is equivalent to about 60 mg of the oligonucleotide or salt thereof once every 24 weeks.

[0368] In some embodiments, a method described herein comprises administering to a human subject an oligonucleotide or salt thereof in an amount that is equivalent to about 115 mg of the oligonucleotide or salt thereof once every 24 weeks.

[0369] In some embodiments, a method described herein comprises administering to a human subject an oligonucleotide or salt thereof in an amount that is equivalent to about 115 mg of the oligonucleotide or salt thereof once every 12 weeks.

[0370] In some embodiments, an anti-beta amyloid antibody is aducanumab.

[0371] In some embodiments, an anti-beta amyloid antibody is lecanemab. In some embodiments, an anti-beta amyloid antibody is donanemab.

[0372] In some embodiments, an anti-beta amyloid antibody is bapincuzumab.

[0373] In some embodiments, an anti-beta amyloid antibody is gantenerumab.

[0374] In some embodiments, an anti-beta amyloid antibody is solanezumab.

[0375] In some embodiments, an anti-beta amyloid antibody is crenezumab.

[0376] In some embodiments, an Alzheimer’s disease is preclinical Alzheimer’s disease.

[0377] In some embodiments, an Alzheimer’s disease is presymptomatic Alzheimer’s disease.

[0378] In some embodiments, an Alzheimer’s disease is mild Alzheimer’s disease.

[0379] In some embodiments, an Alzheimer’s disease is early Alzheimer’s disease.

[0380] In some embodiments, an Alzheimer’s disease is prodromal Alzheimer’s disease.

[0381] In some embodiments, an Alzheimer’s disease is mild Alzheimer’s disease dementia.

[0382] In some embodiments, an Alzheimer’s disease is mild cognitive impairment due to Alzheimer’s disease.

[0383] In some embodiments, an Alzheimer’s disease is mid-stage Alzheimer’s disease.

[0384] In some embodiments, an Alzheimer’s disease is late-stage Alzheimer’s disease.

[0385] In some embodiments, a human subject is at risk for developing Alzheimer’s disease. In some embodiments, a human subject is at risk for developing Alzheimer’s disease and has not been diagnosed with Alzheimer’s disease.

[0386] Methods comprising administering anti-beta amyloid antibody to a patient who has received BIIB080

[0387] In some embodiments, a method of treatment comprises administering to the human subject in need thereof a therapeutically effective amount of an anti-beta amyloid antibody, wherein the human subject has received one or more administrations of an oligonucleotide according to the following chemical structure:

[0388] (nucleobase sequence of SEQ ID NO: 4), or a salt thereof.

[0389] In some embodiments, a method of treatment comprises administering to the human subject a therapeutically effective amount of an anti-beta amyloid antibody, wherein the human subject has received one or more administrations of an oligonucleotide, wherein the oligonucleotide has the following chemical notation (5’ to 3’): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (nucleobase sequence of SEQ ID NO:4); wherein,

[0390] A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,

[0391] G = a guanine nucleobase, T = a thymine nucleobase, e = a 2’ -MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar moiety, s = a phosphorothioatc intcmuclcosidc linkage, and o = a phosphodiester intemucleoside linkage.

[0392] In some embodiments, the one or more administrations of an oligonucleotide or salt thereof comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10, or at least 15 administrations of the oligonucleotide or salt thereof. In some embodiments, the one or more administrations of an oligonucleotide or salt thereof continues until there is a reduction or clearance of Tau in the brain of a human subject.

[0393] In some embodiments, at least three months (e.g., at least four months, at five months, at least six months, at least seven months, at least eight months, at least nine months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or at least 30 months, at least 36 months, at least 42 months, or at least 48 months) have elapsed between the first administration of the oligonucleotide or salt thereof (e.g., BIIB080) and the last administration of the oligonucleotide or salt thereof (e.g., BIIB080) prior to initiation of treatment with an anti-beta amyloid antibody.

[0394] In some embodiments, a reduction in Tau in the brain of the human subject is measured between a first point in time and a second point in time, wherein the first point in time is prior to the first administration of the oligonucleotide or salt thereof (e.g., BIIB080) and the second point in time is (i) after the last administration of the oligonucleotide or salt thereof (e.g., BIIB080) prior to initiation of treatment with an antibeta amyloid antibody and (ii) prior to initiation of treatment with an anti-beat amyloid antibody.

[0395] In some embodiments, at least a 50% reduction (e.g., at least a 60% reduction, at least a 70% reduction, at least a 80% reduction, at least a 90% reduction, or at least a 95% reduction) in Tau in the brain of the human subject has been measured between the first point in time and the second point in time.

[0396] In some embodiments, Tau in the brain of the human subject at the first point in time and the second point in time are measured by positron emission tomography (PET) imaging. In some embodiments, Tau protein plaque levels are assessed by [18F]- florbetapir PET imaging. In some embodiments, Tau is assessed by [18F]-flutemetomol PET imaging. In some embodiments, Tau is assessed by [18F]-florbetaben PET imaging. In some embodiments, PET imaging identifies the brain of the human subject as Tau negative at the second point in time (e.g., by the method described in Clark el al., 2011, JAMA ;305(3):275-83).

[0397] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0398] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0399] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0400] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0401] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0402] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0403] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0404] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0405] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0406] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0407] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0408] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0409] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0410] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0411] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 60 mg / kg of the human subject weight for an anti-beta amyloid antibody once every week.

[0412] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.25 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0413] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0414] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 0.75 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0415] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 1 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0416] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 2 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0417] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 3 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0418] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 4 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0419] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 5 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0420] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 6 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0421] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 7 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0422] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 8 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0423] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 9 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0424] In some embodiments, a method described herein comprises administering to a human subject an anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0425] In some embodiments, a method described herein comprises administering to a human subject an anti -beta amyloid antibody in an amount that is equivalent to about 15 mg / kg of the human subject weight for an anti-beta amyloid antibody once every 2 weeks.

[0426] In some embodiments, a method described herein comprises administering to a human subject an anti-beta...

Claims

WHAT IS CLAIMED IS:

1. A method comprising administering to a human subject a therapeutically effective amount of an oligonucleotide according to the following chemical structure:(nucleobase sequence of SEQ ID NO:4), or a salt thereof, wherein the human subject has received one or more administrations of an anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof.

2. A method of comprising administering to a human subject a therapeutically effective amount of an oligonucleotide, wherein the oligonucleotide has the following chemical notation (5’ to 3’): mCes mCeo Ges Tes Tes Tds Tds mCds Tds Tds Ads mCds mCds Aes mCeo mCes mCes Te (nucleobase sequence of SEQ ID NO:4); wherein,A = an adenine nucleobase,mC = a 5-methyl cytosine nucleobase,G = a guanine nucleobase,T = a thymine nucleobase, e = a 2’ -MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar’ moiety, s = a phosphoro thioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage, wherein the human subject has received one or more administrations of an anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide.

3. The method of claim 1 or 2, wherein at least three months have elapsed between the first administration of the anti-beta amyloid antibody and the last administration of the anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof.

4. The method of claim 1 or 2, wherein at least six months have elapsed between the first administration of the anti-beta amyloid antibody and the last administration of the anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof.

5. The method of claim 1 or 2, wherein at least nine months have elapsed between the first administration of the anti-beta amyloid antibody and the last administration of the anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof.

6. The method of claim 1 or 2, wherein at least 12 months have elapsed between the first administration of the anti-beta amyloid antibody and the last administration of the anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof.

7. The method of claim 1 or 2, wherein at least 18 months have elapsed betweenthe first administration of the anti-heta amyloid antibody and the last administration of the anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof.

8. The method of any one of claims 1 to 7, wherein a reduction in beta amyloid plaque levels in the brain of the human subject has been measured between a first point in time and a second point in time, wherein the first point in time is prior to the first administration of the anti-beta amyloid antibody and the second point in time is (i) after the last administration of the anti-beta amyloid antibody prior to initiation of treatment with the oligonucleotide or salt thereof and (ii) prior to initiation of treatment with the oligonucleotide or salt thereof.

9. The method of claim 8, wherein at least a 50% reduction in beta amyloid plaque levels in the brain of the human subject has been measured between the first point in time and the second point in time.

10. The method of claim 8, wherein at least a 60% reduction in beta amyloid plaque levels in the brain of the human subject has been measured between the first point in time and the second point in time.

11. The method of claim 8, wherein at least a 70% reduction in beta amyloid plaque levels in the brain of the human subject has been measured between the first point in time and the second point in time.

12. The method of claim 8, wherein at least a 80% reduction in beta amyloid plaque levels in the brain of the human subject has been measured between the first point in time and the second point in time.

13. The method of claim 8, wherein at least a 90% reduction in beta amyloid plaque levels in the brain of the human subject has been measured between the first point in time and the second point in time.

14. The method of claim 8, wherein at least a 95% reduction in beta amyloid plaque levels in the brain of the human subject has been measured between the first point in time and the second point in time.

15. The method of any one of claims 8 to 14, wherein beta amyloid plaque levels in the brain of the human subject at the first point in time and the second point in time are measured by positron emission tomography (PET) imaging.

16. The method of claim 15, wherein PET imaging identifies the brain of the human subject as amyloid negative at the second point in time.

17. The method of any one of the preceding claims, comprising administering to the human subject the oligonucleotide or salt thereof in an amount that is equivalent to about 60 mg of the oligonucleotide.

18. The method of any one of claims 8 to 16, comprising administering to the human subject the oligonucleotide or salt thereof in an amount that is equivalent to about 115 mg of the oligonucleotide.

19. The method of any one of claims 8 to 16, comprising administering to the human subject the oligonucleotide or salt thereof in an amount that is equivalent to about 60 mg of the oligonucleotide once every 24 weeks.

20. The method of any one of claims 8 to 16, comprising administering to the human subject the oligonucleotide or salt thereof in an amount that is equivalent to about 115 mg of the oligonucleotide once every 24 weeks.

21. The method of any one of claims 8 to 16, comprising administering to the human subject the oligonucleotide or salt thereof in an amount that is equivalent to about 115 mg of the oligonucleotide once every 12 weeks.

22. A method of comprising administering to a human subject a therapeutically effective amount of an anti-beta amyloid antibody, wherein the human subject has received one or more administrations of an oligonucleotide according to the following chemical structure:(nucleobase sequence of SEQ ID NO:4), or a salt thereof.

23. A method comprising administering to a human subject a therapeutically effective amount of an anti-beta amyloid antibody, wherein the human subject has received one or more administrations of an oligonucleotide, wherein the oligonucleotide has the following chemical notation (5’ to 3’): mCes mCeo Ges Tes Tes Tds Tds mCdsTds Tds Ads mCds mCds Aes mCeo mCes mCes Te (nucleobase sequence of SEQ ID NO:4); wherein,A = an adenine nucleobase, mC = a 5-methyl cytosine nucleobase,G = a guanine nucleobase,T = a thymine nucleobase, e = a 2’ -MOE sugar moiety, d = a 2’-P-D-deoxyribosyl sugar moiety, s = a phosphoro thioate intemucleoside linkage, and o = a phosphodiester intemucleoside linkage.

24. The method of claim 22 or 23, wherein at least three months have elapsed between the first administration of the oligonucleotide or salt thereof and the last administration of the oligonucleotide or salt thereof prior to initiation of treatment with the anti-beta amyloid antibody.

25. The method of claim 22 or 23, wherein at least six months have elapsed between the first administration of the oligonucleotide or salt thereof and the last administration of the oligonucleotide or salt thereof prior to initiation of treatment with the anti-beta amyloid antibody.

26. The method of claim 22 or 23, wherein at least nine months have elapsed between the first administration of the oligonucleotide or salt thereof and the last administration of the oligonucleotide or salt thereof prior to initiation of treatment with the anti-beta amyloid antibody.

27. The method of claim 22 or 23, wherein at least 12 months have elapsed between the first administration of the oligonucleotide or salt thereof and the last administration of the oligonucleotide or salt thereof prior to initiation of treatment withthe anti-beta amyloid antibody.

28. The method of claim 22 or 23, wherein at least 18 months have elapsed between the first administration of the oligonucleotide or salt thereof and the last administration of the oligonucleotide or salt thereof prior to initiation of treatment with the anti-beta amyloid antibody.

29. The method of any one of claims 22 to 28, wherein a reduction in Tau in the brain of the human subject has been measured between a first point in time and a second point in time, wherein the first point in time is prior to the first administration of the oligonucleotide or salt thereof and the second point in time is (i) after the last administration of the oligonucleotide or salt thereof prior to initiation of treatment with the anti-beta amyloid antibody and (ii) prior to initiation of treatment with the anti-beta- amyloid antibody.

30. The method of claim 29, wherein at least a 50% reduction in Tau in the brain of the human subject has been measured between the first point in time and the second point in time.

31. The method of claim 29, wherein at least a 60% reduction in Tau in the brain of the human subject has been measured between the first point in time and the second point in time.

32. The method of claim 29, wherein at least a 70% reduction in Tau in the brain of the human subject has been measured between the first point in time and the second point in time.

33. The method of claim 29, wherein at least an 80% reduction in Tau in the brainof the human subject has been measured between the first point in time and the second point in time.

34. The method of claim 29, wherein at least a 90% reduction in Tau in the brain of the human subject has been measured between the first point in time and the second point in time.

35. The method of claim 29, wherein at least a 95% reduction in Tau in the brain of the human subject has been measured between the first point in time and the second point in time.

36. The method of any one of claims 29 to 35, wherein Tau in the brain of the human subject at the first point in time and the second point in time are measured by positron emission tomography (PET) imaging.

37. The method of claim 36, wherein PET imaging identifies the brain of the human subject as Tau negative at the second point in time.

38. The method of any one of claims 29 to 35, wherein Tau in the brain of the human subject at the first point in time and the second point in time are measured by analysis of cerebrospinal fluid and / or blood samples.

39. The method of 38, wherein Tau measured by analysis of cerebrospinal fluid and / or blood samples comprises Tau protein, phospho-Tau, phospho-Tau 181 (pTau- 181), phosphor-Tau 217 (p-Tau 217), phospho-Tau 231 (p-Tau 231), MTBR-Tau containing residue 243 (MTBR-Tau243), MTBR-Tau containing residue 368 (MTBR- Tau368), MTBR-Tau containing residue 275 (MTBR-Tau275), MTBR-Tau containing residue 280 (MTBR-Tau280), endogenously cleaved MTBR-Tau243 (eMTBR-Tau243).

40. The method of 38, wherein cerebrospinal fluid and / or blood sample analysis identifies the brain of the human subject as Tau negative at the second point in time.

41. The method of any one of the claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg of the human subject weight for the anti-beta amyloid antibody.

42. The method of any one of the claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for the anti-beta amyloid antibody.

43. The method of any one of claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 60 mg / kg of the human subject weight for the anti-beta amyloid antibody once every week.

44. The method of any one of claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for the anti-beta amyloid once every week.

45. The method of any one of claims 22 to 40, comprising administering to the human subject the anti -beta amyloid antibody in an amount that is equivalent to about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 60 mg / kg of the human subject weight for the anti-beta amyloid antibody once every two weeks.

46. The method of any one of claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for the anti-beta amyloid once every two weeks.

47. The method of any one of claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 60 mg / kg of the human subject weight for the anti-beta amyloid antibody once every month.

48. The method of any one of claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for the anti-beta amyloid once every month.

49. The method of any one of claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 60 mg / kg of the human subject weight for the anti-beta amyloid antibody once every 3 months.

50. The method of any one of claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for the anti-beta amyloid once every 3 months.

51. The method of any one of claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 60 mg / kg of the human subject weight for the anti -beta amyloid antibody once every 6 months.

52. The method of any one of claims 22 to 40, comprising administering to thehuman subject the anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for the anti-beta amyloid once every 6 months.

53. The method of any one of claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 60 mg / kg of the human subject weight for the anti-beta amyloid antibody once every year-.

54. The method of any one of claims 22 to 40, comprising administering to the human subject the anti-beta amyloid antibody in an amount that is equivalent to about 10 mg / kg of the human subject weight for the anti-beta amyloid once every year.

55. The method of any one of the preceding claims, wherein the anti-beta amyloid antibody is aducanumab, lecanemab, donanemab, bapineuzumab, gantenerumab, solanezumab, or crenezumab.

56. The method of any one of the preceding claims, wherein human subject has a disease and / or disorder.

57. The method of claim 56, wherein the disease and / or disorder is or comprises preclinical Alzheimer’ s disease, presymptomatic Alzheimer’ s disease, mild Alzheimer’ s disease, early Alzheimer’s disease, prodromal Alzheimer’s disease, mild Alzheimer’s disease dementia, mild cognitive impairment due to Alzheimer’ s disease, mid-stage Alzheimer’s disease, or late-stage Alzheimer’s disease.

58. The method of claim 56 or 57, wherein the disease and / or disorder is or comprises early Alzheimer’s disease.

59. The method of claim 56 or 57, wherein the disease and / or disorder is orcomprises mild cognitive impairment due to Alzheimer’s disease.

60. The method of claim 56 or 57, wherein the disease and / or disorder is or comprises mild Alzheimer’s disease dementia.

61. The method of claim 56 or 57, wherein the disease and / or disorder is or comprises presymptomatic Alzheimer’ s disease.

62. The method of any one of claim 1-55, wherein the human subject is at risk for developing Alzheimer’s disease.

63. The method of any one of claim 1-55, wherein the human subject is at risk for developing Alzheimer’ s disease and has not been diagnosed with Alzheimer’ s disease.

64. The method of claim 62 or 63, wherein the human subject exhibits at least one symptom or signs of Alzheimer’s disease.

65. The method of any one of claims 62-64, wherein the human subject is treated following an onset of at least one symptom or signs of Alzheimer’s disease.

66. The method of any one of claims 62-65, wherein the human subject is treated following:(i) an increase in amyloid beta plaques in a sample from the human subject as compared to a reference,(ii) an increase in CSF and / or plasma Tau protein levels in a sample from the human subject as compared to a reference,(iii) an increase in CSF and / or plasma phospho-Tau protein levels in a sample from the human subject as compared to a reference,(iv) an increase in CSF and / or plasma MTBR containing Tau levels in a sample from the human subject as compared to a reference, or(v) any combination thereof.

67. The method of claim 66, wherein the reference is or comprises:(i) a healthy control human subject,(ii) a subject that has not been diagnosed with Alzheimer’s disease, (iii) a subject that has been diagnosed with presymptomatic Alzheimer’s disease, and / or(iv) a subject that has not received one or more administrations of an antibeta amyloid antibody and / or one or more administrations of an oligonucleotide or salt thereof.