Methods of diagnosing and treating neurodegenerative disorders

Abstract

Provided herein are methods of diagnosing and treating neurodegenerative disorders, specifically compositions and methods related to improved assays for determining the status of a neurodegenerative disease and providing treatment. Also provided herein are compositions and methods comprising improved antibodies for use in assays, including immunoassays, for diagnosing Alzheimer's disease and providing treatment.

Description

[0001] This application is a divisional application of Chinese patent application No. 202480032852.0, filed on March 15, 2024, entitled "Method for Diagnosing and Treating Neurodegenerative Diseases" (the corresponding PCT application was filed on March 15, 2024, and has the application number PCT / US2024 / 020266). Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 490,773, filed March 16, 2023, which is incorporated herein by reference in its entirety. Background Technology

[0003] Biomarker discovery and screening technologies for Alzheimer's disease (AD) and other tau protein disorders are an ongoing field of development in which these tools can be applied to screening populations to identify which non-demented individuals are at greatest risk of developing AD dementia and to assess disease progression in patients. Proteins reflecting AD pathology have been detected using various methods, including amyloid β42 (Aβ). 42 Tau protein isoforms include neurofilament light chains and various tau protein isoforms. Abnormal or excessive phosphorylation of tau is associated with the transformation of pathologically normal tau molecules into paired helical filaments (PHF), tau, and neurofibrillary tangles (NFT), which indicate various tau protein pathologies. Sequence list reference merge

[0004] This application is submitted together with an electronic sequence list. The sequence list is provided as a file named 58484-707_601_SL.xml, created on March 15, 2024, and is 106,132 bytes in size. Information from the electronic sequence list is incorporated in its entirety by reference. Summary of the Invention

[0005] In one aspect, this document describes a method for treating a neurodegenerative disease in a subject, wherein the neurodegenerative disease is characterized by the accumulation of β-amyloid (Aβ) peptide in the subject's brain, the method comprising: administering a therapeutic agent to the subject for treating the neurodegenerative disease, the therapeutic agent comprising (i) an inhibitor of the Aβ peptide or a modified form of the Aβ peptide or (ii) an inhibitor of phosphorylated tau protein, wherein the subject is identified for the treatment based at least in part on: a level of phosphorylated tau 217 (p-Tau 217) measured in a sample obtained from the subject being higher than a level of p-Tau 217 measured in samples with standard values ​​of p-Tau 217 levels derived from multiple reference samples from reference subjects not suffering from the neurodegenerative disease, which predicts with a sensitivity greater than or equal to about 85% that the subject has abnormal tau protein deposition in the brain. In some embodiments, p-Tau 217 in a sample is measured by a method comprising immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the immunoassay is a digital immunoassay configured to measure p-Tau 217 in a sample as a fluid sample. In some embodiments, the digital immunoassay is a single-molecule array (SIMOA). In some embodiments, the immunoassay includes enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), fluorescence immunoassay (FIA), chemiluminescent immunoassay (CLIA), or counting immunoassay (CIA). In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises: a) a heavy chain comprising a variable heavy chain (VH) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23; and b) a light chain comprising a variable light chain (VL) domain, wherein the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR3 sequence selected from SEQ ID NO: 37-43. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 2, the HCDR2 sequence contains SEQ ID NO: 11, and the HCDR3 sequence contains SEQ ID NO: 19; and the LCDR1 sequence contains SEQ ID NO: 25, the LCDR2 sequence contains SEQ ID NO: 33, and the LCDR3 sequence contains SEQ ID NO: 38.In some embodiments, the HCDR1 sequence contains SEQ ID NO: 1, the HCDR2 sequence contains SEQ ID NO: 10, and the HCDR3 sequence contains SEQ ID NO: 18; and the LCDR1 sequence contains SEQ ID NO: 24, the LCDR2 sequence contains SEQ ID NO: 32, and the LCDR3 sequence contains SEQ ID NO: 37. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 2, the HCDR2 sequence contains SEQ ID NO: 11, and the HCDR3 sequence contains SEQ ID NO: 19; and the LCDR1 sequence contains SEQ ID NO: 26, the LCDR2 sequence contains SEQ ID NO: 34, and the LCDR3 sequence contains SEQ ID NO: 39. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 3, the HCDR2 sequence contains SEQ ID NO: 12, and the HCDR3 sequence contains SEQ ID NO: 18; and the LCDR1 sequence contains SEQ ID NO: 27, the LCDR2 sequence contains SEQ ID NO: 32, and the LCDR3 sequence contains SEQ ID NO: 40. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 4, the HCDR2 sequence contains SEQ ID NO: 11, and the HCDR3 sequence contains SEQ ID NO: 20; and the LCDR1 sequence contains SEQ ID NO: 28, the LCDR2 sequence contains SEQ ID NO: 35, and the LCDR3 sequence contains SEQ ID NO: 41. In some embodiments, the HCDR1 sequence comprises SEQ ID NO: 5, the HCDR2 sequence comprises SEQ ID NO: 13, and the HCDR3 sequence comprises SEQ ID NO: 21; and the LCDR1 sequence comprises SEQ ID NO: 29, the LCDR2 sequence comprises SEQ ID NO: 33, and the LCDR3 sequence comprises SEQ ID NO: 42. In some embodiments, the anti-tau antibody comprises a heavy chain (HC) sequence comprising SEQ ID NO: 57 and a light chain (LC) sequence comprising SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC sequence comprising SEQ ID NO: 57 and an LC sequence comprising SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC sequence comprising SEQ ID NO: 60 and an LC sequence comprising SEQ ID NO: 61.In some embodiments, the anti-tau antibody comprises an HC sequence containing SEQ ID NO: 62 and an LC sequence containing SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC sequence containing SEQ ID NO: 64 and an LC sequence containing SEQ ID NO: 65. In some embodiments, the anti-tau antibody comprises an HC sequence containing SEQ ID NO: 55 and an LC sequence containing SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises a variable heavy chain (VH) domain, the VH domain comprising a sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with sequences selected from SEQ ID NO: 44-48. In some embodiments, the anti-tau antibody comprises a variable light chain (VL) domain, the VL domain comprising a sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microbodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or endoantibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the p-Tau 217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the p-Tau 217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a phosphorylated tau polypeptide comprising site pT217-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a phosphorylated tau polypeptide comprising sites pT217-tau and pT231-tau. In some embodiments, the subject has or is suspected of having Alzheimer's disease (AD). In some embodiments, AD causes, is associated with, or exhibits tau proteinopathy in the subject. In some embodiments, the tau proteinopathy includes secondary tau proteinopathy, which includes neurofibrillary tangles (NTF) pathology in the subject's brain, wherein the tau proteinopathy is secondary to β-amyloid plaques in the subject's brain. In some embodiments, according to the method of claim 30, the AD includes variant AD selected from: early-onset Alzheimer's disease, late-onset Alzheimer's disease, familial Alzheimer's disease (FAD), mixed dementia including Alzheimer's disease and vascular dementia, oligophagia, posterior cortical atrophy, frontal lobe variant Alzheimer's disease, and Alzheimer's disease with corticobasal ganglia syndrome (AD-CBS). In some embodiments, the tau proteinopathy includes hyperphosphorylated tau, misfolded tau, oligotau, aggregated paired helical filaments of tau (PFH), neurofibrillary tangles (NFT), or any combination thereof. In some embodiments, the subject is a person 60 years of age or older.In some implementations, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tauinosis (PART), argyrophilic granulomatosis (AGD), glioblastomatosis (GGT), vacuoletomatosis, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jacob disease, boxing dementia, Down syndrome, and Gerstmann-Staussler-Scheinker disease. The neurodegenerative disease includes, but is not explicitly defined as, Alzheimer's disease. Other neurodegenerative diseases include, but are not explicitly defined as, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallevorden-Spatz disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakoff syndrome, prions, vascular dementia, Alzheimer's disease-related dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the neurodegenerative disease is Alzheimer's disease. In some embodiments, the prodromal phase of Alzheimer's disease is characterized by mild cognitive impairment (MCI). In some embodiments, the prodromal phase of Alzheimer's disease is characterized by at least Braak stage I by tau-PET spatial determination. In some embodiments, the prodromal phase of Alzheimer's disease is characterized by at least Braak stage II by tau-PET spatial determination. In some embodiments, the neurodegenerative disease is a tau proteinopathy, which includes hyperphosphorylated tau, misfolded tau, oligomeric tau, aggregated paired helical filaments of tau (PFH), neurofibrillary tangles (NFT), or any combination thereof.In some embodiments, the inhibitor of the Aβ peptide or a modified form of the Aβ peptide includes: ABvac40, ABBV-916, ACU193, AD-35, Aducanumab (Aduhelm®), APH-1105, BPN14770, Bapineuzumab, BMS-984923, Contraloid acetate, CNP520 (AMG520), Crenzumab, Donanemab (LY3002813), Donepezil (Aricept), Elenbecestat (E2609), Gantenerumab, Brain Shutle Gantenerumab (RO7126209), GV-971, HT-ALZ, and KHK. 66401, Lanabesetate, Lecanemab (BAN2401) (Leqembi®), Lu AF20513, MEDI 1814, Ponezumab, Remternetumab (LY3372993), Rivastigmine, SHR-1707, Simufilam (PTI-125), Sodium Mannoside The inhibitors include oligomannate, solanezumab, scyllo-inositol, UB-311, valiltramiprosate (ALZ-801), varoglutamstat (PQ912), verubecestat (MK-8931), VGH-AD1, antisense RNA targeting human β-amyloid isoform, siRNA targeting human β-amyloid isoform, antisense oligonucleotides targeting human β-amyloid isoform, LNA oligonucleotides targeting human β-amyloid isoform, CRISPRn-based therapeutic agents targeting the human APP locus, or CRISPRi-based therapeutic agents targeting the human APP locus. In some embodiments, the inhibitor of the Aβ peptide or a modified form of the Aβ peptide includes donepemumab. In some embodiments, the inhibitor of the Aβ peptide or a modified form of the Aβ peptide includes lencanetumab. In some embodiments, the inhibitor of the Aβ peptide or a modified form of the Aβ peptide includes remenetatumab. In some embodiments, the inhibitor of the Aβ peptide or a modified form of the Aβ peptide includes aducamab.In some embodiments, the inhibitor of the Aβ peptide or a modified form of the Aβ peptide is selected from Table 10. In some embodiments, the inhibitor of phosphorylated tau protein includes inhibitors targeting p-Tau 217 or a modified form of p-Tau 217, p-Tau181, p-Tau 212, p-Tau 220, p-Tau 231, or phosphorylated serine (pS) 214-tau. In some embodiments, the inhibitor of phosphorylated tau protein includes an inhibitor of p-Tau 217. In some embodiments, the sensitivity is greater than or equal to about 90%. In some embodiments, the sensitivity is greater than or equal to about 92%. In some embodiments, the measured level of p-Tau 217 predicts that the subject has abnormal tau protein deposition in the brain, and the area under the curve (AUC) of this prediction is greater than or equal to about 0.85. In some embodiments, the AUC is greater than or equal to about 0.90. In some embodiments, the measured p-Tau 217 level predicts that the subject has abnormal tau protein deposition in the brain, with a specificity greater than or equal to about 81%. In some embodiments, the specificity is greater than or equal to about 85%. In some embodiments, the measured p-Tau 217 level predicts that the subject has abnormal tau protein deposition in the brain, with a positive predictive value (PPV) greater than or equal to about 51%. In some embodiments, the PPV is greater than or equal to about 70%. In some embodiments, the measured p-Tau 217 level predicts that the subject has abnormal tau protein deposition in the brain, with a negative predictive value (NPV) greater than or equal to about 51%. In some embodiments, the NPV is greater than or equal to about 70%. In some embodiments, the measured p-Tau 217 level predicts that the subject will exhibit a positive therapeutic response to the therapeutic agent, with a specificity greater than or equal to about 70%. In some embodiments, the measured level of p-Tau 217 predicts that the subject will exhibit a positive therapeutic response to the treatment agent, with a prediction sensitivity greater than or equal to about 70%. In some embodiments, the measured level of p-Tau 217 predicts that the subject will exhibit a positive therapeutic response to the treatment agent, with a predicted PPV greater than or equal to about 70%. In some embodiments, the measured level of p-Tau 217 predicts that the subject will exhibit a positive therapeutic response to the treatment agent, with a predicted NPV greater than or equal to about 70%. In some embodiments, the measured level of p-Tau 217 predicts that the subject will exhibit a positive therapeutic response to the treatment agent, with a predicted AUC greater than or equal to about 0.70. In some embodiments, the sample is a cerebrospinal fluid (CSF) sample, a plasma sample, a blood sample, or a serum sample. In some embodiments, the sample is a plasma sample.In some embodiments, the method includes determining the likelihood of a clinical diagnosis of a neurodegenerative disease in the subject based at least in part on the level of p-Tau 217 measured in the sample. In some embodiments, the method includes determining an early prognosis of the neurodegenerative disease in the subject based at least in part on the level of p-Tau 217 measured in the sample, wherein the early prognosis precedes providing a diagnosis of the prodromal stage of the neurodegenerative disease in the subject. In some embodiments, the neurodegenerative disease is Alzheimer's disease, and determining an early prognosis of Alzheimer's disease includes determining the likelihood of the subject's Alzheimer's disease progressing to Alzheimer's dementia based at least in part on the level of p-Tau 217 measured in the sample. In some embodiments, the method includes identifying an increased risk that the neurodegenerative disease will lead to pathological memory impairment and cognitive decline in the subject based at least in part on the level of p-Tau 217 measured in the sample. In some embodiments, the method includes improving one or more symptoms of the subject's neurodegenerative disease. In some embodiments, the method includes slowing the progression of one or more symptoms of the subject's neurodegenerative disease. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of a neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of a neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered intravenously to the subject at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered intravenously to the subject at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered intravenously to the subject at a dose of about 10 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administering the therapeutic agent approximately every 2 weeks (q2w). In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administering the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the therapeutic agent is administered to the subject in multiple doses, wherein the first three doses are administered to the subject at a dose containing approximately 700 mg per dose. In some embodiments, the doses administered to the subject after the first three doses are doses containing approximately 1400 mg per dose. In some embodiments, the administration is systemic.In some embodiments, the systemic administration includes intravenous administration. In some embodiments, the systemic administration includes subcutaneous administration. In some embodiments, the systemic administration includes oral administration. In some embodiments, the method includes: a) repeating the method after the introduction of the therapeutic agent, thereby measuring a second level of p-Tau 217 in a second sample obtained from the subject after the introduction of the therapeutic agent, wherein the second level of p-Tau 217 is lower than the level of p-Tau 217 measured before the introduction of the therapeutic agent; and b) administering another dose of the therapeutic agent to the subject.

[0006] In the aspects described herein, a kit for selecting a subject to treat neurodegenerative diseases is provided, the kit comprising: a) an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment comprising: i) a heavy chain comprising a variable heavy chain (VH) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23; and ii) a light chain comprising a variable light chain (VL) domain, wherein the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR3 sequence selected from SEQ ID NO: 37-43; ii) a heavy chain (HC) sequence comprising any one of SEQ ID NO: 57, 60, 62, 64, or 55; and comprising SEQ ID NO: The kit comprises: b) a light chain (LC) sequence of any one of SEQ ID NO: 58, 59, 63, 65, or 56; or a variable heavy chain (VH) domain comprising a sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 44-48; and a variable light chain (VL) domain comprising a sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54; c) a specification for analyzing samples obtained from a subject using the anti-tau antibody or its antigen-binding fragment in an immunoassay; d) a specification for treating a subject with a neurodegenerative disease using a therapeutic agent comprising (i) an inhibitor of the Aβ peptide or a modified form of the Aβ peptide or (ii) an inhibitor of phosphorylated tau protein; and d) optionally, the therapeutic agent. In some embodiments, the kit comprises a therapeutic agent. In some embodiments, the kit comprises one or more immunoassay components, wherein the immunoassay includes a single-molecule array (SIMOA), enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), fluorescence immunoassay (FIA), chemiluminescent immunoassay (CLIA), or count immunoassay (CIA). In some embodiments, the kit comprises a system for performing the immunoassay, wherein the immunoassay includes a single-molecule array (SIMOA), enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), fluorescence immunoassay (FIA), chemiluminescent immunoassay (CLIA), or count immunoassay (CIA).In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises: a heavy chain containing a variable heavy chain (VH) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23; and a light chain containing a variable light chain (VL) domain, wherein the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR3 sequence selected from SEQ ID NO: 37-43. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises: a heavy chain (HC) sequence comprising any one of SEQ ID NO: 57, 60, 62, 64, or 55; and a light chain (LC) sequence comprising any one of SEQ ID NO: 58, 59, 63, 65, or 56. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises: a variable heavy chain (VH) domain containing a sequence having at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO: 44-48; and a variable light chain (VL) domain containing a sequence having at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54.In some embodiments, the inhibitors in the therapeutic agent include: ABvac40, ABBV-916, ACU193, AD-35, aducarumab (Aduhelm®), APH-1105, BPN14770, bavinzizumab, BMS-984923, Contraloid acetate, CNP520 (AMG520), cremastrabin, donepezil (LY3002813), donepezil (Aricept), elembestat (E2609), gantenatumab, Brain Shutle gantenatumab (RO7126209), GV-971, HT-ALZ, KHK 66401, labestat, lencanemab (BAN2401) (Leqembi®), Lu AF20513, MEDI 1814, Ponaizumab, Remenetatumab (LY3372993), Ristimin, SHR-1707, Simulfil (PTI-125), Sodium Mannoside, Sorapizumab, Squalinosin, UB-311, Valiltramiprosate (ALZ-801), Varoglutamstat (PQ912), Verositol (MK-8931), VGH-AD1, Antisense RNA against human β-amyloid isoform, siRNA against human β-amyloid isoform, Antisense oligonucleotide against human β-amyloid isoform, LNA oligonucleotide against human β-amyloid isoform, CRISPRn-based therapeutic agent targeting the human APP locus, or CRISPRi-based therapeutic agent targeting the human APP locus. In some embodiments, the therapeutic agent includes donepemab. In some embodiments, the therapeutic agent includes lencanetumab. In some embodiments, the therapeutic agent includes remenetatumab. In some embodiments, the therapeutic agent comprises aducamab. In some embodiments, the therapeutic agent is selected from Table 10. In some embodiments, the therapeutic agent is an inhibitor of phosphorylated tau protein. In some embodiments, the inhibitor of phosphorylated tau protein is an inhibitor targeting p-Tau 217 or a modified form of p-Tau 217, p-Tau 181, p-Tau 212, p-Tau 220, p-Tau 231, or phosphorylated serine (pS) 214-tau. In some embodiments, the inhibitor of phosphorylated tau protein includes an inhibitor of p-Tau 217. In some embodiments, the specification for the analytical sample also includes standardized values ​​of p-Tau 217 levels derived from multiple reference samples from reference subjects who do not have neurodegenerative diseases.

[0007] In some respects, this document discloses a method for treating a neurodegenerative disease in a subject, the method comprising: (a) detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with a standard value of pT217 tau level from a plurality of reference samples, wherein the detection comprises immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR2 sequence selected from SEQ ID NO: 18-23. (a) the LCDR3 sequence of 37-43; (b) determining the likelihood of a clinical diagnosis of neurodegenerative disease of the subject based at least in part on the detection; (c) determining an early prognosis of neurodegenerative disease of the subject based at least in part on the determination, wherein the early prognosis is earlier than providing a diagnosis of the prodromal stage of neurodegenerative disease of the subject; and (d) initiating treatment comprising administration of a formulation containing a therapeutic agent, wherein the determination of initiation is based at least in part on the determination, wherein the therapeutic agent is selected from: ABvac40LY3002813, AADvac-1, ACI-35, AAV-Htert, ACU193, ASN51, ACI-242, AD-35, aducamab, AGB101, AL002, allopregnanolone, APH-1105, and azaginsat. Instat (COR388), AVP-786, AXS-05, Baricitinib, Bepranemeb, BCG, BEIY2153, BPN14770, Bromocriptine, Bryostatin 1, BXCL-501, Blarcamesine (ANAVEX2-73), Bavizumab, BIIB092 (BMS-986168, IPN007, Gosuranemab), BIIB080 / IONIS-MAPTRx, BIIB076, BPDO-1603, BMS-984923, BDPP (Bioactive Dietary Polyphenols), Bripiprazole, Caffeine, CAD1063, Canakinumab, Contraloid acetate, COR588, CORT108297, CNP520 (AMG520), C2N-8E12 (ABBV-8E12), Crizotinib, CST-2032, Curcumin, CY6463, Dabigatran, DAOIB, Dapagliflozin, Daratumumab, Dasatinib, Deferiprone, Donepezil (LY3002813), Donepezil (Aricept) Dronabinol, Dutanumab, Edicotinib (JNJ-40346527), Efavirenz, Emtricitabine, Empagliflozin, Elenbesta (E2609), E2814, Ednerpic (T-817mA), Elayta (CT1812), ExPlas, Escitalopram, Fosgonimeton (ATH01017), Galantamine, Gantrinumab, Brain Shuttle Gantenafil (RO7126209), GB301, Grape Seed Extract, GV1001, Guanfacine, GV-971, Intranasal Insulin, HT-ALZ, Huperzine A, Hydralazine, IGC AD1, Ethyl Eicosapentaenoic Acid (IPE), JNJ-63733657, KHK 66401, LuAF87908, Lu AF20513, Lamivudine (3TC), Labestat, Lenalidomide, Levetiracetam, L-Serine, Lupron, Remenetatumab (LY3372993), LY3372689, LMTX, LY3303560 (Zagotenemab), Lencanemab (BAN2401), Losartan, LX1001, MEDI 1814, Memantine, Metformin, MK-1942, MIB-626, Montelukast, MW150. Neflamimod (VX-745), Nabilone, NE3107, Nicotinamide, Nicotine, NNI-362, Nilotinib BE, Octohydro-aminoacridine Succinate), Obicetrapib, Omega-3 (DHA+EPA), Perindopril, Pepinemab (VX15), Posiphen, Prazosin, Ponaizumab, Protollin, PQ912, PNT001, PU-AD, Quercetin, Rapamycin, REM0046127, RG7345 (RO6926496), Ristimin, RG6100, RO7105705 (MTAU9937A, RG6100, Semorinemab), Dihydrate Salsalate, Sargramostim, Cirrenamide, Senicapoc, Semaglutide, SHR-1707, Simurafil (PTI-125), Sodium Mannoside, Solatumab, Squalane, Sovateltide (PMZ-1620), Suvorexant, T3D-959, TB006, Telmisartan, Trehalose, Tdap vaccine, THC-free CBD oil, Thiethylperazine (TEP), Troluzole (BHV4157), TPI 2871, Tricaprilin (AC-1202), TRx0237, UB-311, UCB0107 valiltramiprosate (ALZ-801), Valacyclovir varoglutamstat(PQ912), VGH-AD1, Vorinostat, VT301, XPro1595, Xanamem, Yangxue Qingao pills, antisense RNA targeting human tau mRNA subtypes or human β-amyloid isoforms, siRNA targeting human tau mRNA subtypes or human β-amyloid isoforms, antisense oligonucleotides targeting human tau mRNA subtypes or human β-amyloid isoforms, LNA oligonucleotides targeting human tau mRNA subtypes or human β-amyloid isoforms, CRISPRn-based therapeutic agents targeting human MAPT or human APP loci, CRISPRi-based therapeutic agents targeting human MAPT or human APP loci, allogeneic human MSCs, SNK01 (autologous natural killer cells), allogeneic adipose MSC-exosomes, CA-AC-02 (placental MSCs), HUVEC-derived MSCs (NEUROSTEM), and AstroStem (autologous adipose-derived MSCs). In some embodiments, the HCDR1 sequence contains SEQ ID NO: 2, the HCDR2 sequence contains SEQ ID NO: 11, the HCDR3 sequence contains SEQ ID NO: 19, the LCDR1 sequence contains SEQ ID NO: 25, the LCDR2 sequence contains SEQ ID NO: 33, and the LCDR3 sequence contains SEQ ID NO: 38. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 1, the HCDR2 sequence contains SEQ ID NO: 10, the HCDR3 sequence contains SEQ ID NO: 18, the LCDR1 sequence contains SEQ ID NO: 24, the LCDR2 sequence contains SEQ ID NO: 32, and the LCDR3 sequence contains SEQ ID NO: 37. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 2, the HCDR2 sequence contains SEQ ID NO: 11, the HCDR3 sequence contains SEQ ID NO: 19, the LCDR1 sequence contains SEQ ID NO: 26, the LCDR2 sequence contains SEQ ID NO: 34, and the LCDR3 sequence contains SEQ ID NO: 39. In some implementations, the HCDR1 sequence contains SEQ ID NO:3, the HCDR2 sequence contains SEQ ID NO:12, the HCDR3 sequence contains SEQ ID NO:18, the LCDR1 sequence contains SEQ ID NO:27, the LCDR2 sequence contains SEQ ID NO:32, and the LCDR3 sequence contains SEQ ID NO:40.In some embodiments, the HCDR1 sequence contains SEQ ID NO: 4, the HCDR2 sequence contains SEQ ID NO: 11, the HCDR3 sequence contains SEQ ID NO: 20, the LCDR1 sequence contains SEQ ID NO: 28, the LCDR2 sequence contains SEQ ID NO: 35, and the LCDR3 sequence contains SEQ ID NO: 41. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 5, the HCDR2 sequence contains SEQ ID NO: 13, the HCDR3 sequence contains SEQ ID NO: 21, the LCDR1 sequence contains SEQ ID NO: 29, the LCDR2 sequence contains SEQ ID NO: 33, and the LCDR3 sequence contains SEQ ID NO: 42. In some embodiments, the neurodegenerative disease is Alzheimer's disease (AD). In some embodiments, the prodromal stage of AD is characterized by mild cognitive impairment (MCI). In some embodiments, the prodromal stage of AD, as determined by tau-PET, is at least characterized as Braak stage I. In some embodiments, the prodromal stage of AD is characterized by a spatial range determined by tau-PET as at least Braak stage II. In some embodiments, the method includes detecting the level of pT217 tau in the sample, wherein the detected pT217 tau level is quantified as a value higher than a standard value of pT217 tau levels derived from a plurality of reference samples taken from healthy individuals not suspected of having AD. In some embodiments, the subject meets the inclusion criteria for initiating treatment, and wherein the inclusion criteria include detecting the level of pT217 tau in a sample collected prior to d) the initiation of treatment. In some embodiments, the subject is at least 60 years old. In some embodiments, the subject is between 60 and 85 years old at d) the initiation of treatment. In some embodiments, the selected therapeutic agent is doneemab. In some embodiments, the selected therapeutic agent is lencanemab. In some embodiments, the selected therapeutic agent is remenetatumab. In some embodiments, the selected therapeutic agent is aducamab. In some embodiments, c) determining the early prognosis includes determining the likelihood of AD progression to Alzheimer's disease in the subject based at least in part on the detection in a). In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microbodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or endoantibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites selected from: pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites at pT217-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a phosphorylated tau polypeptide contained at sites pT217-tau and pT231-tau.In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, depending on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of approximately 700-1400 mg.In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administering the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses comprises a dose of approximately 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration comprises intravenous administration of the therapeutic agent. In some embodiments, systemic administration comprises subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration comprises oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0008] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of a small molecule therapeutic agent targeting tau listed in Table 10, wherein the subject is selected based on a criterion that detects a level of pT217 tau in a sample from the subject that is higher than the pT217 tau levels from a plurality of reference samples, and wherein the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting tau bioactivity. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO:44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microantibodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0009] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an antibody therapeutic agent targeting tau listed in Table 10, wherein the subject is selected based on a criterion that detects a level of pT217 tau in a sample from the subject that is higher than the pT217 tau levels from a plurality of reference samples, and wherein the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting tau bioactivity. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO:44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microantibodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0010] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of a small molecule therapeutic agent targeting β-amyloid protein listed in Table 10, wherein the subject is selected based on a criterion that detects a level of pT217 tau in a sample from the subject that is higher than the pT217 tau levels from a plurality of reference samples, and wherein the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting the biological activity of β-amyloid protein. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microantibodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0011] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an antibody therapeutic agent targeting β-amyloid protein listed in Table 10, wherein the subject is selected based on a criterion that detects a pT217 tau level in a sample from the subject that is higher than the pT217 tau levels from a plurality of reference samples, and wherein the pT217 tau level predicts a positive therapeutic response in the subject to treatment targeting β-amyloid protein bioactivity. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microantibodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0012] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of a cholinesterase inhibitor listed in Table 10, wherein the subject is selected based on a criterion that detects a pT217 tau level in a sample from the subject that is higher than the pT217 tau levels from a plurality of reference samples, and wherein the pT217 tau level predicts a positive therapeutic response in the subject to treatment targeting cholinesterase inhibition. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO:44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microantibodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0013] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an NMDA receptor antagonist therapeutic agent listed in Table 10, wherein the subject is selected based on a criterion that detects a pT217 tau level in a sample from the subject that is higher than the pT217 tau levels from a plurality of reference samples, and wherein the pT217 tau level predicts a positive therapeutic response in the subject to treatment targeting and inhibiting NMDA receptor function. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microantibodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0014] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an acetylcholinesterase and butyrylcholinesterase inhibitor listed in Table 10, wherein the subject is selected based on a criterion that the level of pT217 tau in a sample from the subject is higher than the pT217 tau levels from a plurality of reference samples, and wherein the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting the inhibition of cholinesterase and butyrylcholinesterase function. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, bivalent antibody, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibody, microantibody, microantibody, TriBi microantibody, scFv-CH3 KIH, Fab-scFv-FcKIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibody. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0015] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an NMDA receptor antagonist therapeutic agent listed in Table 10 and a cholinesterase inhibitor therapeutic agent listed in Table 10, wherein the subject is selected based on a criterion that detects a pT217 tau level in a sample from the subject that is higher than the pT217 tau levels from a plurality of reference samples, and wherein the pT217 tau level predicts a positive therapeutic response in the subject to treatments targeting and inhibiting NMDA receptor function. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, bivalent antibody, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibody, microantibody, microantibody, TriBi microantibody, scFv-CH3KIH, Fab-scFv-FcKIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibody. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0016] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an antibody therapeutic agent targeting β-amyloid peptides listed in Table 10, wherein the subject is selected based on a criterion that detects a level of pT217 tau in a sample from the subject that is higher than the pT217 tau levels from a plurality of reference samples, and wherein the level of pT217 tau predicts a positive therapeutic response in the subject to treatment of both soluble and insoluble forms of the β-amyloid peptide aggregation. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, bivalent antibody, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibody, microantibody, microantibody, TriBi microantibody, scFv-CH3 KIH, Fab-scFv-FcKIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibody. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0017] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an antibody therapeutic agent targeting β-amyloid peptides listed in Table 10, wherein the subject is selected based on a criterion that detects a level of pT217 tau in a sample from the subject that is higher than the pT217 tau levels from a plurality of reference samples, and wherein the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting the removal of aggregates of soluble and insoluble forms of β-amyloid peptides. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, bivalent antibody, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibody, microantibody, microantibody, TriBi microantibody, scFv-CH3 KIH, Fab-scFv-FcKIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibody. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0018] In some aspects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: administering to the subject a therapeutically effective amount of an antisense therapy targeting huntingtin protein (HTT) listed in Table 10, wherein the subject is selected based on a criterion that detects a level of pT217 tau in a sample from the subject that is higher than the pT217 tau levels from a plurality of reference samples, and wherein the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting HHT mRNA. In some embodiments, the level of pT217 tau in the sample is detected using an anti-anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) domain and a variable light chain (VL) domain. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microantibodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0019] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) determining, by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with a standardized value of pT217 tau CSF levels from a plurality of reference samples, whether the subject has an elevated risk of neurodegenerative symptoms leading to pathological memory impairment and cognitive decline compared to a reference subject, and whether the subject is suitable for treatment with a small molecule tau inhibitor, wherein the detection comprises immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises a sequence selected from SEQ ID NO: 10-17. (a) The LCDR1 sequence selected from SEQ ID NO: 34-31, the LCDR2 sequence selected from SEQ ID NO: 32-36, and the LCDR3 sequence selected from SEQ ID NO: 37-43; and (b) the subject is treated by administering a therapeutically effective amount of a small molecule tau inhibitor listed in Table 10. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with the sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with the sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microbodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or endoantibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites selected from: pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites at pT217-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a phosphorylated tau polypeptide comprising sites pT217-tau and pT231-tau. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tauinopathy (PART), argyrophilic granuloma (AGD), glial tauinopathy (GGT), vacuole tauinopathy, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease of the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually.In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of a neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of a neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject via intravenous administration at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject via intravenous administration at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of approximately 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration comprises intravenous administration of the therapeutic agent. In some embodiments, systemic administration comprises subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration comprises oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0020] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) determining, by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with a standardized value of pT217 tau CSF levels from a plurality of reference samples, whether the subject has an elevated risk of neurodegenerative symptoms leading to pathological memory impairment and cognitive decline compared to a reference subject, and whether the subject is suitable for treatment with an anti-tau antibody, wherein the detection comprises immunoassay of the sample using an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises a sequence selected from SEQ ID NO: 10-17. (a) The LCDR1 sequence selected from SEQ ID NO: 34-31, the LCDR2 sequence selected from SEQ ID NO: 32-36, and the LCDR3 sequence selected from SEQ ID NO: 37-43; and (b) the subject is treated by administering a therapeutically effective amount of the anti-tau antibody listed in Table 10. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with the sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with the sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microbodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or endoantibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease of the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually.In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of a neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of a neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject via intravenous administration at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject via intravenous administration at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of approximately 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration comprises intravenous administration of the therapeutic agent. In some embodiments, systemic administration comprises subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration comprises oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0021] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) determining, by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with a standardized value of pT217 tau CSF levels from a plurality of reference samples, whether the subject has an elevated risk of neurodegenerative symptoms leading to pathological memory impairment and cognitive decline, and whether the subject is suitable for treatment with an anti-Aβ antibody, wherein the detection comprises immunoassay of the sample using an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises a sequence selected from SEQ ID NO: 10-17. (a) The LCDR1 sequence selected from SEQ ID NO: 34-31, the LCDR2 sequence selected from SEQ ID NO: 32-36, and the LCDR3 sequence selected from SEQ ID NO: 37-43; and (b) the subject is treated by administering a therapeutically effective amount of the anti-Aβ antibody listed in Table 10. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with the sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with the sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microbodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or endoantibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease of the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually.In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of a neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of a neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject via intravenous administration at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject via intravenous administration at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of approximately 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration comprises intravenous administration of the therapeutic agent. In some embodiments, systemic administration comprises subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration comprises oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0022] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) determining, by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with a standardized value of pT217 tau CSF levels from a plurality of reference samples, whether the subject has an elevated risk of neurodegenerative symptoms leading to pathological memory impairment and cognitive decline, and whether the subject is suitable for treatment with a small molecule β-amyloid peptide inhibitor, wherein the detection comprises immunoassay of the sample using an antibody or an antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises a sequence selected from SEQ ID NO: 10-17. (a) The LCDR1 sequence selected from SEQ ID NO: 34-31, the LCDR2 sequence selected from SEQ ID NO: 32-36, and the LCDR3 sequence selected from SEQ ID NO: 37-43; and (b) the subject is treated by administering a therapeutically effective amount of a small molecule β-amyloid peptide inhibitor listed in Table 10. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with the sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with the sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microbodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or endoantibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites selected from: pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites at pT217-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a phosphorylated tau polypeptide comprising sites pT217-tau and pT231-tau. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tauinopathy (PART), argyrophilic granuloma (AGD), glial tauinopathy (GGT), vacuole tauinopathy, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease of the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually.In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of a neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of a neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject via intravenous administration at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject via intravenous administration at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of approximately 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration comprises intravenous administration of the therapeutic agent. In some embodiments, systemic administration comprises subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration comprises oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0023] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) receiving data obtained by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with standardized values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection comprises immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR2 sequence selected from SEQ ID NO: 18-23. (a) LCDR3 sequence of 37-43; (b) analyzing the likelihood of a clinical diagnosis of neurodegenerative disease of the subject based at least in part on the receipt; (c) providing an early prognosis of neurodegenerative disease of the subject based at least in part on the analysis, wherein the early prognosis is earlier than the provision of a diagnosis of the prodromal stage of neurodegenerative disease of the subject; and (d) initiating treatment comprising administration of a formulation containing a therapeutic agent, wherein the decision to initiate treatment is based at least in part on the provision, wherein the therapeutic agent is selected from: ABvac40LY3002813, AADvac-1, ACI-35, AAV-Htert, ACU193, ASN51, ACI-242, AD-35, etc. Ducatumab, AGB101, AL002, Allogestrinone, APH-1105, Azaginsta (COR388), AVP-786, AXS-05, Baricitinib, Bereninaxab, BCG, BEIY2153, BPN14770, Bromocriptine, Lichenstatin 1, BXCL-501, Bracamexine (ANAVEX2-73), Bavizumab, BIIB092 (BMS-986168, IPN007, Gonadumab), BIIB080 / IONIS-MAPTRx, BIIB076, BPDO-1603, BMS-984923, BDPP (Bioactive Dietary Polyphenols), Iripiparazole, Caffeine, CAD1063, Kanamumab, Contraloid acetate, COR588, CORT108297, CNP520 (AMG520), C2N-8E12 (ABBV-8E12), Crizotinib, CST-2032, Curcumin, CY6463, Dabigatran, DAOIB, Dapagliflozin, Daratumumab, Dasatinib, Deferiprone, Donepezil (LY3002813), Donepezil ( Aricept, Drocannabinol, Dutanumab, Erdrinib (JNJ-40346527), Efavirenz, Emtricitabine, Empagliflozin, Elenbesta (E2609), E2814, Edonapeptide (T-817mA), Elayta (CT1812), ExPlas, Ediprom, Fosgonimeton (ATH01017), Galantamine, Gantrinumab, Brain Shuttle Gantnetumab (RO7126209), GB301, Grape Seed Extract, GV1001, Guanifaxine, GV-971, Intranasal Insulin, HT-ALZ, Huperzine A, Hydralazine, IGC AD1, Eicosapentaenoic Acid Ethyl Eicosapentaenoic Acid (IPE), JNJ-63733657, KHK 66401, Lu AF87908, LuAF20513, Lamivudine (3TC), Labestat, Lenalidomide, Levetiracetam, L-Serine, Lupron, Remenetatumab (LY3372993), LY3372689, LMTX, LY3303560 (Zegertnetumab), Lencanemab (BAN2401), Losartan, LX1001, MEDI 1814, Memantine, Metformin, MK-1942, MIB-626, Montelukast, MW 150, Neuramod (VX-745), Cannabinol, NE3107, Nicotinamide, Nicotine, NNI-362, Nilotinib BE, Succinyl-O-Acridine, Obitrapi, Omega-3 (DHA+EPA), Perindopril, Pebinetrazol (VX15), Boxifen, Prazosin, Ponaizumab, Protolin, PQ912, PNT001, PU-AD, Quercetin, Rapamycin, REM0046127, RG7345 (RO6926496), Ribavirin, RG6100 RO7105705 (MTAU9937A, RG6100, Cirenafil), Disalicylates, Saxaglastine, Cirenafil, Sanicacip, Smegglutide, SHR-1707, Simulfil (PTI-125), Sodium Mannoside, Solatumab, Squalinositol, Sovastatin (PMZ-1620), Suvorexin, T3D-959, TB006, Telmisartan, Trehalose, Tdap vaccine, THC-free CBD oil, Thiorazine (TEP), Traluzole (BHV4157), TPI2871, Tricaprylate (AC-1202), TRx0237, UB-311, UCB0107, valiltramiprosate (ALZ-801), valacyclovir, varoglutamstat(PQ912), VGH-AD1, Vorinostat, VT301, XPro1595, Xanamem, Yangxue Qingnao Wan, antisense RNA targeting human tau mRNA subtypes or human β-amyloid isoforms, siRNA targeting human tau mRNA subtypes or human β-amyloid isoforms, antisense oligonucleotides targeting human tau mRNA subtypes or human β-amyloid isoforms, LNA oligonucleotides targeting human tau mRNA subtypes or human β-amyloid isoforms, CRISPRn-based therapeutic agents targeting human MAPT or human APP loci, CRISPRi-based therapeutic agents targeting human MAPT or human APP loci, allogeneic human MSCs, SNK01 (autologous natural killer cells), allogeneic adipose MSCs-exosomes, CA-AC-02 (placental MSCs), HUVEC-derived MSCs (NEUROSTEM), and AstroStem (autologous adipose-derived MSCs). In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microbodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or endoantibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0024] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) receiving data obtained by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with standardized values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection comprises immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR2 sequence selected from SEQ ID NO: 18-23. (a) the LCDR3 sequence of SEQ ID NO: 37-43; (b) analyzing the likelihood of a clinical diagnosis of the neurodegenerative disease of the subject, at least in part based on the receipt; (c) providing an early prognosis of the neurodegenerative disease of the subject, at least in part based on the analysis, wherein the early prognosis is earlier than the provision of a diagnosis of the prodromal stage of the neurodegenerative disease of the subject; and (d) initiating treatment comprising administration of a formulation containing a therapeutic agent, wherein the decision to initiate treatment is at least in part based on the provision, wherein the therapeutic agent is selected from the tau inhibitors listed in Table 10. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, bivalent antibody, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibody, microantibody, microantibody, TriBi microantibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibody.In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites selected from: pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at site pT217-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at sites pT217-tau and pT231-tau. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tauinopathy (PART), argyrophilic granuloma (AGD), glial tauinopathy (GGT), vacuole tauinopathy, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved.In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, depending on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses comprises a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration comprises intravenous administration of the therapeutic agent. In some embodiments, systemic administration comprises subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration comprises oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63.In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 64 and LC containing the sequence of SEQ ID NO: 65.

[0025] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) receiving data obtained by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with a standardized value of pT217 tau CSF levels derived from a plurality of reference samples, wherein the detection comprises immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR2 sequence selected from SEQ ID NO: 18-23. (a) the LCDR3 sequence of SEQ ID NO: 37-43; (b) analyzing the likelihood of a clinical diagnosis of the neurodegenerative disease of the subject based at least in part on the receipt; (c) providing an early prognosis of the neurodegenerative disease of the subject based at least in part on the analysis, wherein the early prognosis is earlier than the provision of a diagnosis of the prodromal stage of the neurodegenerative disease of the subject; and (d) initiating treatment comprising administration of a formulation containing a therapeutic agent, wherein the decision to initiate treatment is based at least in part on the provision, wherein the therapeutic agent is selected from the inhibitors of β-amyloid peptides listed in Table 10. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, bivalent antibody, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibody, microantibody, microantibody, TriBi microantibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibody.In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites selected from: pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at site pT217-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at sites pT217-tau and pT231-tau. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tauinopathy (PART), argyrophilic granuloma (AGD), glial tauinopathy (GGT), vacuole tauinopathy, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved.In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, depending on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses comprises a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration comprises intravenous administration of the therapeutic agent. In some embodiments, systemic administration comprises subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration comprises oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63.In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 64 and LC containing the sequence of SEQ ID NO: 65.

[0026] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) receiving data obtained by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with standardized values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection comprises immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR2 sequence selected from SEQ ID NO: 18-23. (a) the LCDR3 sequence of SEQ ID NO: 37-43; (b) analyzing the likelihood of a clinical diagnosis of the neurodegenerative disease of the subject based at least in part on the receipt; (c) providing an early prognosis of the neurodegenerative disease of the subject based at least in part on the analysis, wherein the early prognosis is earlier than the provision of a diagnosis of the prodromal stage of the neurodegenerative disease of the subject; and (d) initiating treatment comprising administration of a formulation containing a therapeutic agent, wherein the decision to initiate treatment is based at least in part on the provision, wherein the therapeutic agent is selected from the cholinesterase inhibitors listed in Table 10. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, bivalent antibody, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibody, microantibody, microantibody, TriBi microantibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibody.In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites selected from: pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at site pT217-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at sites pT217-tau and pT231-tau. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tauinopathy (PART), argyrophilic granuloma (AGD), glial tauinopathy (GGT), vacuole tauinopathy, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved.In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, depending on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses comprises a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration comprises intravenous administration of the therapeutic agent. In some embodiments, systemic administration comprises subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration comprises oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63.In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 64 and LC containing the sequence of SEQ ID NO: 65.

[0027] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) receiving data obtained by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with standardized values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection comprises immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR2 sequence selected from SEQ ID NO: 18-23. (a) the LCDR3 sequence of SEQ ID NO: 37-43; (b) analyzing the likelihood of a clinical diagnosis of neurodegenerative disease of the subject based at least in part on the receipt; (c) providing an early prognosis of neurodegenerative disease of the subject based at least in part on the analysis, wherein the early prognosis is earlier than the provision of a diagnosis of the prodromal stage of neurodegenerative disease of the subject; and (d) initiating treatment comprising administration of a formulation containing a therapeutic agent, wherein the decision to initiate treatment is based at least in part on the provision, wherein the therapeutic agent is selected from NMDA receptor antagonists listed in Table 10. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, bivalent antibody, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibody, microantibody, microantibody, TriBi microantibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibody.In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites selected from: pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a phosphorylated tau polypeptide (p-Tau 217-tau protein) at site pT217-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a phosphorylated tau polypeptide at sites pT217-tau and pT231-tau. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved.In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, depending on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses comprises a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63.In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 64 and LC containing the sequence of SEQ ID NO: 65.

[0028] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) receiving data obtained by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with standardized values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection comprises immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR2 sequence selected from SEQ ID NO: 18-23. (a) the LCDR3 sequence of SEQ ID NO: 37-43; (b) analyzing the likelihood of a clinical diagnosis of the neurodegenerative disease of the subject based at least in part on the receipt; (c) providing an early prognosis of the neurodegenerative disease of the subject based at least in part on the analysis, wherein the early prognosis is earlier than the provision of a diagnosis of the prodromal stage of the neurodegenerative disease of the subject; and (d) initiating treatment comprising administration of a formulation containing a therapeutic agent, wherein the decision to initiate treatment is based at least in part on the provision, wherein the therapeutic agent is selected from the acetylcholinesterase and butyrylcholinesterase inhibitors listed in Table 10. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, bivalent antibody, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibody, microantibody, microantibody, TriBi microantibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibody.In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites selected from: pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at site pT217-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at sites pT217-tau and pT231-tau. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tauinopathy (PART), argyrophilic granuloma (AGD), glial tauinopathy (GGT), vacuole tauinopathy, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved.In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, depending on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses comprises a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63.In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 64 and LC containing the sequence of SEQ ID NO: 65.

[0029] In some respects, this document describes a method for treating a neurodegenerative disease in a subject, the method comprising: (a) receiving data obtained by detecting the level of pT217 tau in a sample from the subject and correlating the level of pT217 tau in the sample with standardized values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection comprises immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment thereof comprising i) a heavy chain comprising a variable heavy chain (VH) domain and ii) a light chain comprising a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR2 sequence selected from SEQ ID NO: 18-23. (a) the LCDR3 sequence of SEQ ID NO: 37-43; (b) analyzing the likelihood of a clinical diagnosis of neurodegenerative disease of the subject based at least in part on the receipt; (c) providing an early prognosis of neurodegenerative disease of the subject based at least in part on the analysis, wherein the early prognosis is earlier than the provision of a diagnosis of the prodromal stage of neurodegenerative disease of the subject; and (d) initiating treatment comprising administration of a formulation containing two or more therapeutic agents, wherein the decision to initiate treatment is based at least in part on the provision, wherein the two or more therapeutic agents are selected from NMDA receptor antagonists and cholinesterase inhibitors listed in Table 10. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, bivalent antibody, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibody, microantibody, microantibody, TriBi microantibody, scFv-CH3 KIH, Fab-scFv-FcKIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibody.In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated sites selected from: pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at site pT217-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at sites pT217-tau and pT231-tau. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tauinopathy (PART), argyrophilic granuloma (AGD), glial tauinopathy (GGT), vacuole tauinopathy, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved.In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease. In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having a neurodegenerative disease. In some embodiments, the plurality of samples from reference subjects are taken from individuals in the early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, depending on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses comprises a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 55 and LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 57 and LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63.In some embodiments, the anti-tau antibody comprises HC containing the sequence of SEQ ID NO: 64 and LC containing the sequence of SEQ ID NO: 65.

[0030] As described herein, in some embodiments of the method, detecting the level of pT217 tau in a sample from the object comprises immunoassay of the sample using an anti-tau antibody or an antigen-binding fragment thereof, the anti-tau antibody or antigen-binding fragment thereof comprising i) a heavy chain containing a variable heavy chain (VH) domain and ii) a light chain containing a variable light chain (VL) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NO: 1-9, an HCDR2 sequence selected from SEQ ID NO: 10-17, and an HCDR3 sequence selected from SEQ ID NO: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NO: 24-31, an LCDR2 sequence selected from SEQ ID NO: 32-36, and an LCDR3 sequence selected from SEQ ID NO: 37-43. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 2, the HCDR2 sequence contains SEQ ID NO: 11, the HCDR3 sequence contains SEQ ID NO: 19, the LCDR1 sequence contains SEQ ID NO: 25, the LCDR2 sequence contains SEQ ID NO: 33, and the LCDR3 sequence contains SEQ ID NO: 38. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 1, the HCDR2 sequence contains SEQ ID NO: 10, the HCDR3 sequence contains SEQ ID NO: 18, the LCDR1 sequence contains SEQ ID NO: 24, the LCDR2 sequence contains SEQ ID NO: 32, and the LCDR3 sequence contains SEQ ID NO: 37. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 2, the HCDR2 sequence contains SEQ ID NO: 11, the HCDR3 sequence contains SEQ ID NO: 19, the LCDR1 sequence contains SEQ ID NO: 26, the LCDR2 sequence contains SEQ ID NO: 34, and the LCDR3 sequence contains SEQ ID NO: 39. In some implementations, the HCDR1 sequence contains SEQ ID NO: 3, the HCDR2 sequence contains SEQ ID NO: 12, the HCDR3 sequence contains SEQ ID NO: 18, the LCDR1 sequence contains SEQ ID NO: 27, the LCDR2 sequence contains SEQ ID NO: 32, and the LCDR3 sequence contains SEQ ID NO: 40.In some embodiments, the HCDR1 sequence contains SEQ ID NO: 4, the HCDR2 sequence contains SEQ ID NO: 11, the HCDR3 sequence contains SEQ ID NO: 20, the LCDR1 sequence contains SEQ ID NO: 28, the LCDR2 sequence contains SEQ ID NO: 35, and the LCDR3 sequence contains SEQ ID NO: 41. In some embodiments, the HCDR1 sequence contains SEQ ID NO: 5, the HCDR2 sequence contains SEQ ID NO: 13, the HCDR3 sequence contains SEQ ID NO: 21, the LCDR1 sequence contains SEQ ID NO: 29, the LCDR2 sequence contains SEQ ID NO: 33, and the LCDR3 sequence contains SEQ ID NO: 42. In some embodiments, the VH domain has at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NO: 44-48. In some embodiments, the VL domain has at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NO: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobodies, BiTE, bivalent antibodies, DART, TandAb, scDiabody, scDiabody-CH3, trivalent antibodies, microantibodies, microantibodies, TriBi microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, bivalent antibody-Fc, tandem scFv-Fc, or internal antibodies. In some embodiments, the anti-tau antibody has an isotype selected from: IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of the tau polypeptide. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the pT217-tau protein. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to the cis conformation of the pT217-tau protein.In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at a site selected from: pT181-tau, pT212-tau, phosphorylated serine (pS) 214-tau, pT217-tau, pT220-tau, and pT231-tau. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylated tau at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylated tau at both the pT217-tau and pT231-tau sites. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobe degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lytico-Bodig disease, tangles-dominant dementia, meningioma, primary age-related tau disease (PART), argyrophilic granuloma (AGD), glioblastoma (GGT), vacuoletous tau disease, tuberous sclerosis, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis, and muscular atrophy. Amyotrophic lateral sclerosis (ALS), myotonic dystrophy, globus pallidus-pons-substantia nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxing dementia, Down syndrome, Gerstmann-Straussler-Schenk disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, tangled dementia, Hallewarden-Schpatrick disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, Friedrich's ataxia, Wernicke-Korsakov syndrome, prions, vascular dementia, Alzheimer's disease-associated dementia, Huntington's disease (HD), or transgenic-induced tau proteinosis. In some embodiments, the sample is selected from cerebrospinal fluid (CSF) samples, plasma samples, blood samples, or serum samples. In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, one or more symptoms of the neurodegenerative disease of the subject are improved. In some embodiments, the progression of one or more symptoms of the neurodegenerative disease in the subject is slowed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, intrathecally, intracerebrally, subcutaneously, orally, nasally, topically, orally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, intrathecal delivery, intracisional delivery, intraspinal delivery, subpial delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of the neurodegenerative disease. In some embodiments, the subject is in the prodromal stage of the neurodegenerative disease.In some embodiments, the plurality of reference samples are taken from healthy individuals not suspected of having neurodegenerative diseases. In some embodiments, the plurality of samples from reference subjects are taken from individuals in an early stage of suspected neurodegenerative disease. In some embodiments, the therapeutic agent is administered at a dose of about 0.1-100 mg / kg body weight, based on the subject's weight. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 200-1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously at a dose of about 700-1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen comprising administration of the therapeutic agent approximately every 4 weeks (q4w). In some embodiments, the first three doses administered to the subject comprise a dose of about 700 mg of the therapeutic agent. In some embodiments, the doses administered to the subject after the first three doses comprise a dose of about 1400 mg of the therapeutic agent. In some embodiments, the therapeutic agent is administered systemically. In some embodiments, systemic administration includes intravenous administration of the therapeutic agent. In some embodiments, systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 55 and an LC containing the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 57 and an LC containing the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 60 and an LC containing the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 62 and an LC containing the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody comprises an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65. Incorporation

[0031] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is expressly and individually indicated to be incorporated by reference. Where a publication, patent, or patent application incorporated by reference contradicts the disclosure contained in this specification, this specification is intended to supersede and / or give precedence to any such contradictory material. Attached Figure Description

[0032] The various aspects of this disclosure are set forth in the appended claims. A better understanding of the features and advantages of this disclosure will be obtained by referring to the following detailed description and the accompanying drawings, which illustrate the illustrative aspects utilizing the principles of this disclosure.

[0033] Figure 1 An outline of the single-molecule array (Simoa®) method used in this paper for the determination of the tau antibody described herein is presented. After adding the substrate to the sample (sandwich ELISA on beads, 1.1), the sample is added to a Simoa® disk (1.2). The beads are given time to settle into the microarray wells on the disk (one bead per well) (1.3). Excess beads are then removed using sealing oil for imaging (1.4). Beads with the sandwich complex (positive beads) will fluoresce through the substrate and be visible during imaging; beads without the sandwich complex (negative beads) will still be visible in the imaging but will not fluoresce (1.5). The percentage of positive beads is converted to an AEB (average enzyme / bead) value.

[0034] Figure 2A-2D Data for antibodies 1, 2, 3, 4, 5, and 6 in the Simoa® assay are presented. Figure 2A Data from a two-step protocol assay were depicted, in which all capture antibodies were tested against the Tau-12 detector. Figure 2B Data from a two-step assay are depicted, in which all capture antibodies were tested against the HT7-BT2 detector (which detects Tau in the middle domain region). Figure 2C Data from a 3-step protocol assay were depicted, in which all capture antibodies were tested against the Tau-12 detector. Figure 2D Data from a 3-step protocol assay were depicted, in which all capture antibodies were tested against the HT7-BT2 detector.

[0035] Figure 3 ELISA data for different monoclonal antibodies with varying peptide concentrations were presented.

[0036] Figure 4 The graph depicts the indirect ELISA assay and the ELISA data for the assay of the antibody binding to the pTau-217 peptide.

[0037] Figure 5 A graph depicting the signal / noise (S / N) analysis of ELISA assays of antibody 2 bound to pTau-217 peptide in 120 clinical samples derived from plasma and a graph depicting the coefficient of variation (CV%) of ELISA assays of antibody 2 bound to pTau-217 peptide in 120 clinical samples derived from plasma.

[0038] Figure 6 A calibration curve (Cal curve) of Simoa®-based pTau-217 assay using antibody 2 was plotted for a group (plate) of clinical samples (plates) of specified QTx derived from cerebrospinal fluid (68 CSF samples) and plasma (120 plasma samples).

[0039] Figure 7 The results of Simoa®-based pTau assay-217 using antibody 2 in matched samples derived from plasma (Y-axis) or CSF (X-axis) from individual samples are plotted, along with statistical analysis of the relevant results for individuals with non-Alzheimer's disease clinical diagnoses, indeterminate diagnoses, or Alzheimer's disease clinical diagnoses.

[0040] Figure 8 A graph depicting the results of Simoa®-based pTau assay-217 using antibody 2 / sample versus the results of Simoa®-based pTau assay-181 using antibody 2 / sample is presented, along with a statistical analysis of the relevant results.

[0041] Figure 9 A graph depicts the results of the Simoa®-based pTau assay-217 using antibody 2 / sample versus the results of the Simoa®-based Tau assay using Innotest pTau 181 antibody / sample, along with a statistical analysis of the relevant results.

[0042] Figure 10 The results of Simoa®-based pTau assays using antibody 2 as the capture antibody, antibody ADx p204 as the detection antibody, and peptide as the calibrator are plotted, along with a statistical analysis of the results.

[0043] Figure 11 A graph depicts the results of the Simoa®-based pTau assay-217, which grouped samples from individuals clinically diagnosed with Alzheimer's disease and samples from control individuals derived from CSF or plasma.

[0044] Figure 12A graph depicts the results of the Simoa®-based pTau assay-217 using antibody 2 against plasma samples of different concentrations of EDTA, and a graph listing the coefficient of variation for each sample concentration to illustrate the accuracy of the assay.

[0045] Figure 13 The results of the Simoa®-based pTau assay-217 using antibody 2 are plotted as coefficient of variation (CV%) relative to the measured concentration.

[0046] Figure 14 A graph depicting the results of the Simoa®-based pTau assay-217 using antibody 2, and a statistical analysis of parallelism to determine whether real samples containing high concentrations of endogenous analyte after dilution would provide a similar level of detection in the standard curve.

[0047] Figure 15 The results of the Simoa®-based pTau assay-217 using antibody 2 are plotted, and statistical analysis of linearity is performed to determine whether sample matrices spiked with analytes above the upper limit of detection can still provide reliable quantification after dilution within the standard curve range of the four sample buffer spike peaks.

[0048] Figure 16 The results of the Simoa®-based pTau assay-217 using antibody 2 are plotted, and statistical analysis of linearity is performed to determine whether sample matrices spiked with analytes above the detection limit can still provide reliable quantification after dilution within the standard curve range of three samples plus calibration samples.

[0049] Figure 17 A graph depicts the results of Simoa®-based pTau assay-217 using antibody 2 in clinical validation in a memory clinical cohort, and a graph of receiver operating characteristic (ROC) analysis plotting the sensitivity of the pTau-217 assay.

[0050] Figure 18 A graph depicts the results of the Simoa®-based pTau assay-217 using antibody 2 against groups of individuals with Alzheimer's disease and those with AD.

[0051] Figure 19 A graph depicting the results of the Simoa®-based pTau assay-181 using antibodies from Quanterix® against groups of controls and individuals with Alzheimer's disease is presented, along with a chart showing sample stratification.

[0052] Figure 20A graph depicting the results of the Simoa®-based pTau assay-217 using antibody 2 and the Simoa®-based pTau assay-181 using an antibody from Quanterix® shows the accuracy plot with the calculated coefficient of variation.

[0053] Figure 21 The graphs depict the clinical performance of various Simoa®-based pTau assays, comparing sensitivity and specificity, and the charts present statistical analyses of the results.

[0054] Figure 22 A schematic diagram of Tau, indicating the relative positions of various protein domains and the positions of threonine residues, is shown, which can be used to determine phosphorylation status using the methods disclosed herein.

[0055] Figure 23 A graph depicts the reactivity of Tau fragments with unphosphorylated T217 (Bio-pt654) and full-length Tau (Tau441) in indirect ELISA with various antibodies.

[0056] Figure 24 A graph depicting the reactivity of Tau fragments with phosphorylated T181 (Bio-pt126) and phosphorylated T231 (Bio-pt146) in indirect ELISA with various antibodies is presented.

[0057] Figure 25 The graph depicts the assays using p-Tau 217 monoclonal antibody as a capture tool for various synthetic peptides, and the results of this assay using antibody 2 as a capture tool.

[0058] Figure 26 This study describes the use of various Tau antibodies in the analysis of protein blots from brain lysate samples from AD patients or controls. Detailed Implementation

[0059] Neurodegenerative diseases, such as Alzheimer's disease, are complex conditions, and effective treatment requires accurate diagnosis and treatment selection. This article describes improved compositions and methods for identifying subjects as having or at risk of developing neurodegenerative diseases, such as Alzheimer's disease, characterized by the accumulation of β-amyloid peptides in the brain or the deposition of abnormally phosphorylated tau, or both. Compositions and methods for selecting subjects for treatment of neurodegenerative diseases, and / or for treating neurodegenerative diseases, are also provided, based at least in part on the results of tests measuring the level of abnormally phosphorylated tau in samples obtained from the subject (e.g., blood, cerebrospinal fluid). As will be further explained below, the inventors of this disclosure have discovered that aberrantly phosphorylated tau is a useful biomarker for the diagnosis and disease progression in tau protein diseases such as Alzheimer's disease, and have developed antibody reagents for measuring the level of aberrantly phosphorylated tau (e.g., p-Tau 217) in samples of subjects (e.g., plasma or CSF samples), as provided in International Application No. PCT / US2022 / 042963, which is incorporated herein by reference in its entirety.

[0060] In a secondary analysis of patients with early symptomatic Alzheimer's disease receiving donepemab in the TRAILBLAZER-ALZ randomized clinical trial (NCT03367403), the authors found that plasma biomarkers (including p-Tau 217) were significantly lower after donepemab treatment compared to placebo, as early as 12 weeks after treatment initiation, and persisted until week 76 of the study. (Pontecorvo MJ et al.) Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial JAMA Neurol. Dec 1, 2022;79(12):1250-1259. In this study, the authors reported a significant correlation between plasma p-Tau 217 levels and percentage changes in amyloid plaque levels, as measured by amyloid PET imaging, thus supporting the potential therapeutic efficacy of inhibitors of β-amyloid peptides (e.g., donepemumab, lencanemumab, lemminetamab, aducamab, etc.) for the treatment of early-onset symptomatic Alzheimer's disease.

[0061] Based on the discovery that abnormal phosphorylated tau levels (e.g., p-Tau 217) can be used as a biomarker for diagnosis and disease progression in tau protein diseases, and the discovery by Pontecorvo MJ et al. that p-Tau 217 can be used as a biomarker for outcomes in patients with positive early symptomatic Alzheimer's disease treated with donepemab, this disclosure provides compositions and methods for selecting subjects treated with therapeutic agents (e.g., provided in Table 10 and elsewhere herein) to treat neurodegenerative diseases (e.g., donepemab, lencanemab, remenetamarab, aducamab, etc.) with antibody agents specific to phosphorylated tau protein (e.g., p-Tau 217).

[0062] Tau is an important microtubule-associated protein, highly expressed in CNS neurons and playing a crucial role in normal cellular physiology. Tau has also been found to be dysregulated in Alzheimer's disease and other tau protein disorders. Six isoforms of the tau protein are generated through alternative splicing... TAU Gene generation. The various allotypes differ from one another in the presence or absence of two N-terminal inserts and a repeating sequence called R2. All six protein allotypes of Tau are highly soluble under normal and healthy cellular conditions and are generally regulated by phosphorylation and dephosphorylation. Tau has been shown to interact with microtubules and promote microtubule assembly. In neurons, tau promotes the formation and stabilization of axonal microtubules. Tau plays an additional role in driving neurite growth. Impaired interaction between Tau and microtubules may be an important component of the pathology, development, and progression of tau protein diseases. Hyperphosphorylation of Tau is a hallmark feature of Alzheimer's disease and other tau protein diseases, and the degree of hyperphosphorylation is often associated with disease progression. Hyperphosphorylation of Tau protein may lead to the self-assembly of insoluble tangles of paired helical and straight filaments of tau. These insoluble tangle aggregates, called neurofibrillary tangles (NFTs), contain hyperphosphorylated tau and are considered pathological markers of tau protein diseases.

[0063] Phosphorylated tau (pTau), total tau, and Aβ were detected in cerebrospinal fluid (CSF) and / or blood, respectively. 42CSF pTau is an individual biomarker for Alzheimer's disease and several other related tau protein disorders. Compared to age- and sex-matched controls, CSF pTau was increased in both the prodromal and dementia stages in individuals later diagnosed with Alzheimer's disease. CSF pTau levels showed a strong correlation with the degree of cognitive impairment in individuals with Alzheimer's disease. In fact, CSF pTau levels can be used with a certain degree of precision as a biomarker to predict progression from cognitively unimpaired to mild cognitive impairment (MCI) and then to Alzheimer's dementia. CSF pTau has been shown to be significantly increased in samples from individuals with preclinical Alzheimer's disease, even in relatively early stages, in terms of its utility as a biomarker predicting the progression of Alzheimer's disease. Changes in pTau phosphorylation have been demonstrated in both preclinical sporadic cases of Alzheimer's disease and in the early stages of autosomal dominant Alzheimer's disease. When measured within the same individual, pTau, total tau, and Aβ... 42 Blood levels of these biomarkers are typically lower than CSF levels, and if blood levels of these biomarkers can be measured with sufficient specificity and accuracy, they can be used as informative biomarkers for Alzheimer's disease and other related tau protein disorders.

[0064] Several phosphorylation sites of hyperphosphorylated tau leading to aggregation into NFTs have been identified. In the longest tau isoform, 79 potential serine or threonine phosphorylation sites are present, and at least 30 of these sites have been identified as phosphorylating in NFT aggregates. A common site used to determine the phosphorylation status of tau molecules is threonine-181. CSF fluid contains a range of tau fragments of varying abundance. Tau fragments from the N-terminal and middle regions of tau peptides are much more abundant in CSF samples than C-terminal tau fragments. Plasma samples from individuals also contain tau peptides and tau peptide fragments, but they tend to be present at lower concentrations than in matched CSF samples. The ability to detect tau phosphorylation at specific amino acid residues associated with disease pathology and progression is a key component of diagnosis, disease staging, and an indicator of the therapeutic efficacy of Alzheimer's disease and other tau protein diseases. Detecting and measuring pTau levels at specific disease-related residues in plasma samples will greatly contribute to the development of more sensitive and refined diagnostic, prognostic, and disease analyses for individuals who may be at risk of developing Alzheimer's disease or other tau protein disorders, or who are in their early stages. Tau phosphorylation at threonine 217 (pTau 217) is one such residue of particular interest in the development of novel biomarkers and diagnostic assays. Changes in pTau biomarker concentrations in CSF and plasma are thought to precede measurable behavioral or cognitive changes in Alzheimer's disease and other tau protein disorders. Developing new assays to enable the continuous detection of specific points and degrees of tau phosphorylation at certain residues will undoubtedly aid in clinically relevant medical diagnostic and treatment decisions. Comparing the results of new assays with those of existing assays can also yield further medically informative determinations. Results of plasma-based tau biomarker assays can be compared with matched CSF samples (detecting CSF pTau or CSF-soluble Aβ) and with positron emission tomography (PET) scans that detect the extent and location of Aβ aggregates, serving as indicators of their practicality, particularly for analysis in preclinical or early disease stages.

[0065] There remains a need to prevent the progression of neurodegenerative diseases (including various taupathies), and to effectively treat them. Currently, there are limited options (and limited chances of success) to try treating patients with taupathies using existing disease-modifying therapies. Current challenges in treating taupathies include the lack of ability to diagnose symptoms at early time points before significant neurodegeneration. Another major obstacle is the lack of effective therapies that can alter, slow, stop, or repair the progressive pathogenesis of taupathies.

[0066] Tau antibody This document provides antibodies that bind to tau. In some cases, the tau-binding antibodies are monoclonal antibodies. In some aspects, this document discloses an anti-tau antibody. In some cases, the anti-tau antibody specifically binds to mammalian tau. In some cases, the anti-tau antibody specifically binds to human tau. In some cases, the anti-tau antibody specifically binds to the N-terminal portion of tau. In some cases, the anti-tau antibody specifically binds to the N-terminal portion of human tau. In some cases, the anti-tau antibody specifically binds to the portion of tau containing the protein domain P2. In some cases, the anti-tau antibody specifically binds to the portion of human tau containing the protein domain P2. In some cases, the anti-tau antibody specifically binds to the portion of tau containing the protein domain P1. In some cases, the anti-tau antibody specifically binds to the portion of human tau containing the protein domain P1. In some cases, the anti-tau antibody specifically binds to the portions of tau containing both protein domains P1 and P2. In some cases, the anti-tau antibody binds specifically to portions of human tau containing protein domains P1 and P2.

[0067] In some embodiments, the anti-tau antibody comprises i) a heavy chain containing a variable heavy chain (VH) domain and ii) a light chain containing a variable light chain (VL) domain. In some embodiments, the VH domain comprises a heavy chain CDR1 (HCDR1) sequence containing sequences selected from SEQ ID NO: 1-9, a heavy chain CDR2 (HCDR2) sequence containing sequences selected from SEQ ID NO: 10-17, and a heavy chain CDR3 (HCDR3) sequence containing sequences selected from SEQ ID NO: 18-23. In some embodiments, the VL domain comprises a light chain CDR1 (LCDR1) sequence containing sequences selected from SEQ ID NO: 24-31, a light chain CDR2 (LCDR2) sequence containing sequences selected from SEQ ID NO: 32-36, and a light chain CDR3 (LCDR3) sequence containing sequences selected from SEQ ID NO: 37-43.

[0068] In some implementations, the VH region of the anti-tau antibody contains HCDR1, HCDR2 and HCDR3 sequences selected from Table 1.

[0069] Table 1. Amino acid sequence of HCDR

[0070] In some embodiments, the VH region contains the HCDR1 sequence containing SEQ ID NO: 1; the HCDR2 sequence containing SEQ ID NO: 10; and the HCDR3 sequence containing SEQ ID NO: 18. In some embodiments, the VH region contains the HCDR1 sequence containing SEQ ID NO: 2; the HCDR2 sequence containing SEQ ID NO: 11; and the HCDR3 sequence containing SEQ ID NO: 19. In some embodiments, the VH region contains the HCDR1 sequence containing SEQ ID NO: 3; the HCDR2 sequence containing SEQ ID NO: 12; and the HCDR3 sequence containing SEQ ID NO: 18. In some embodiments, the VH region contains the HCDR1 sequence containing SEQ ID NO: 4; the HCDR2 sequence containing SEQ ID NO: 11; and the HCDR3 sequence containing SEQ ID NO: 20. In some embodiments, the VH region contains the HCDR1 sequence of SEQ ID NO: 5; the HCDR2 sequence of SEQ ID NO: 13; and the HCDR3 sequence of SEQ ID NO: 21. In some embodiments, the VH region contains the HCDR1 sequence of SEQ ID NO: 6; the HCDR2 sequence of SEQ ID NO: 14; and the HCDR3 sequence of SEQ ID NO: 22. In some embodiments, the VH region contains the HCDR1 sequence of SEQ ID NO: 7; the HCDR2 sequence of SEQ ID NO: 15; and the HCDR3 sequence of SEQ ID NO: 19. In some embodiments, the VH region contains the HCDR1 sequence of SEQ ID NO: 8; the HCDR2 sequence of SEQ ID NO: 16; and the HCDR3 sequence of SEQ ID NO: 19. In some implementations, the VH region contains the HCDR1 sequence containing SEQ ID NO: 9; the HCDR2 sequence containing SEQ ID NO: 17; and the HCDR3 sequence containing SEQ ID NO: 23.

[0071] In some implementations, the VL region of the anti-tau antibody contains sequences selected from LCDR1, LCDR2, and LCDR3 in Table 2.

[0072] Table 2. LCDR amino acid sequence

[0073] In some embodiments, the VL region comprises the LCDR1 sequence containing SEQ ID NO: 24; the LCDR2 sequence containing SEQ ID NO: 32; and the LCDR3 sequence containing SEQ ID NO: 37. In some embodiments, the VL region comprises the LCDR1 sequence containing SEQ ID NO: 25; the LCDR2 sequence containing SEQ ID NO: 33; and the LCDR3 sequence containing SEQ ID NO: 38. In some embodiments, the VL region comprises the LCDR1 sequence containing SEQ ID NO: 26; the LCDR2 sequence containing SEQ ID NO: 34; and the LCDR3 sequence containing SEQ ID NO: 39. In some embodiments, the VL region comprises the LCDR1 sequence containing SEQ ID NO: 27; the LCDR2 sequence containing SEQ ID NO: 32; and the LCDR3 sequence containing SEQ ID NO: 40. In some embodiments, the VL region comprises the LCDR1 sequence containing SEQ ID NO: 28; the LCDR2 sequence containing SEQ ID NO: 35; and the LCDR3 sequence containing SEQ ID NO: 41. In some embodiments, the VL region comprises the LCDR1 sequence containing SEQ ID NO: 29; the LCDR2 sequence containing SEQ ID NO: 33; and the LCDR3 sequence containing SEQ ID NO: 42. In some embodiments, the VL region comprises the LCDR1 sequence containing SEQ ID NO: 30; the LCDR2 sequence containing RAS; and the LCDR3 sequence containing SEQ ID NO: 38. In some embodiments, the VL region comprises the LCDR1 sequence containing SEQ ID NO: 31; the LCDR2 sequence containing SEQ ID NO: 36; and the LCDR3 sequence containing SEQ ID NO: 44.

[0074] In some embodiments, the anti-tau antibody is its antigen-binding fragment. In some embodiments, the anti-tau antibody is a chimeric antibody or its antigen-binding fragment. In some embodiments, the anti-tau antibody includes IgG-scFv, nanobodies, microbodies, microantibodies, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, Fab', F(ab')2, F(ab')3, F(ab')2-scFv2, scFv, scFv-KIH, Fab-scFv-Fc, or endoantibodies. In some embodiments, the anti-tau antibody includes bispecific antibodies. In some embodiments, the anti-tau antibody includes multispecific antibodies. In some embodiments, the anti-tau antibody is an IgG1 antibody. In some embodiments, the anti-tau antibody is an IgG2 antibody. In some embodiments, the anti-tau antibody is an IgG4 antibody. In some embodiments, the anti-tau antibody comprises a light chain, wherein the light chain is a κ chain.

[0075] In some embodiments, the anti-tau antibody specifically binds to the tau protein. In some embodiments, the anti-tau antibody specifically binds to the N-terminal region of the tau protein. In some embodiments, the anti-tau antibody specifically binds to the cis conformation of the tau protein. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any of positions 1-441. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any of positions 152-400. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any of positions 198-275. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any of positions 244-369. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any of positions 152-275. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any of positions 152-244. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any of positions 181, 217, and 231. In some embodiments, the anti-tau antibody specifically binds to the tau protein at position 181. In some embodiments, the anti-tau antibody specifically binds to the tau protein at position 217. In some embodiments, the anti-tau antibody specifically binds to the tau protein at position 231.

[0076] In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at any of positions 1-441. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at any of positions 1-441, wherein any combination of the following residues is phosphorylated: Y18, S46, S68, T69, T71, S113, T123, T153, T175, T181, S184, S185, S191, Y197, S198, S199. S208, S210, T212, S214, T217, T220, T231, S235, S237, S238, S258, S262, S289, S356, Y394, S396, S400, T403, S404, S409, S412, S413, S416, S422, T427, S433 or S435. In some embodiments, the anti-tau antibody specifically binds to one or any combination of phosphorylated serine, threonine, or tyrosine residues within the tau protein, wherein one or any combination of phosphorylated serine, threonine, or tyrosine residues is selected from Y18, S46, S68, T69, T71, S113, T123, T153, T175, T181, S184, S185, S191, Y1 97, S198, S199, S208, S210, T212, S214, T217, T220, T231, S235, S237, S238, S258, S262, S289, S356, Y394, S396, S400, T403, S404, S409, S412, S413, S416, S422, T427, S433, and S435. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at any of positions 152-400. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at any of positions 198-275. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at any of positions 244-369. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at any of positions 152-275. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at any of positions 152-244. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at any of positions 181, 217, and 231. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein when any combination of T181, T217, and T231 is phosphorylated.In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at position 181. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein when T181 is phosphorylated. In some embodiments, the anti-tau antibody specifically binds to phosphorylated residue T181 in tau protein. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at position 217. In some embodiments, the anti-tau antibody specifically binds to phosphorylated residue T217 in tau protein. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein when T217 is phosphorylated. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein at position 231. In some embodiments, the anti-tau antibody specifically binds to phosphorylated residue T231 in tau protein. In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein when T231 is phosphorylated. In some embodiments, the phosphorylated tau protein is human tau protein. The amino acid residue numbering system for tau residues refers to their position in the full-length 441 amino acid variant of human microtubule-associated protein tau (MAPT; NBCI gene ID: 4137; exemplary protein sequence - NBCI entry: 7SP1_A).

[0077] In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to about 3 nM for human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 300 pM for human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 500 pM for human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 800 pM for human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 600 pM for human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 900 pM for human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 400 pM to 1 nM for human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 1.5 nM for human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 2 nM for human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 600 pM to 3 nM for human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to about 3 nM for human tau.

[0078] In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 300 pM for phosphorylated human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 500 pM for phosphorylated human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 800 pM for phosphorylated human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 600 pM for phosphorylated human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 900 pM for phosphorylated human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 400 pM to 1 nM for phosphorylated human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 1.5 nM for phosphorylated human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 2 nM for phosphorylated human tau. In some embodiments, the anti-tau antibody has a binding affinity of about 600 pM to 3 nM for phosphorylated human tau.

[0079] In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 300 pM for threonine-phosphorylated tau 181 (ptau 181). In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 500 pM for ptau 181. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 800 pM for ptau 181. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 600 pM for ptau 181. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 900 pM for ptau 181. In some embodiments, the anti-tau antibody has a binding affinity of about 400 pM to 1 nM for ptau 181. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 1.5 nM for ptau 181. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 2 nM for ptau 181. In some embodiments, the anti-tau antibody has a binding affinity of about 600 pM to 3 nM for ptau 181.

[0080] In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 300 pM for threonine-phosphorylated tau 212 (ptau 212). In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 500 pM for ptau 212. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 800 pM for ptau 212. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 600 pM for ptau 212. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 900 pM for ptau 212. In some embodiments, the anti-tau antibody has a binding affinity of about 400 pM to 1 nM for ptau 212. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 1.5 nM for ptau 212. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 2 nM for ptau 212. In some embodiments, the anti-tau antibody has a binding affinity of about 600 pM to 3 nM for ptau 212.

[0081] In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 300 pM for serine phosphorylated tau 214 (ptau 214). In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 500 pM for ptau 214. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 800 pM for ptau 214. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 600 pM for ptau 214. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 900 pM for ptau 214. In some embodiments, the anti-tau antibody has a binding affinity of about 400 pM to 1 nM for ptau 214. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 1.5 nM for ptau 214. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 2 nM for ptau 214. In some embodiments, the anti-tau antibody has a binding affinity of about 600 pM to 3 nM for ptau 214.

[0082] In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 300 pM for threonine-phosphorylated tau 217 (ptau 217). In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 500 pM for ptau 217. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 800 pM for ptau 217. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 600 pM for ptau 217. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 900 pM for ptau 217. In some embodiments, the anti-tau antibody has a binding affinity of about 400 pM to 1 nM for ptau 217. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 1.5 nM for ptau 217. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 2 nM for ptau 217. In some embodiments, the anti-tau antibody has a binding affinity of about 600 pM to 3 nM for ptau 217.

[0083] In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 300 pM for threonine-phosphorylated tau 220 (ptau 220). In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 500 pM for ptau 220. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 800 pM for ptau 220. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 600 pM for ptau 220. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 900 pM for ptau 220. In some embodiments, the anti-tau antibody has a binding affinity of about 400 pM to 1 nM for ptau 220. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 1.5 nM for ptau 220. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 2 nM for ptau 220. In some embodiments, the anti-tau antibody has a binding affinity of about 600 pM to 3 nM for ptau 220.

[0084] In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 300 pM for threonine-phosphorylated tau 231 (ptau 231). In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 500 pM for ptau 231. In some embodiments, the anti-tau antibody has a binding affinity of about 100 pM to 800 pM for ptau 231. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 600 pM for ptau 231. In some embodiments, the anti-tau antibody has a binding affinity of about 300 pM to 900 pM for ptau 231. In some embodiments, the anti-tau antibody has a binding affinity of about 400 pM to 1 nM for ptau 231. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 1.5 nM for ptau 231. In some embodiments, the anti-tau antibody has a binding affinity of about 500 pM to 2 nM for ptau 231. In some embodiments, the anti-tau antibody has a binding affinity of about 600 pM to 3 nM for ptau 231.

[0085] This article describes antibodies that include any of the sequences shown in Table 3 or Table 4.

[0086] Table 3. Variable structural domains of heavy chains

[0087] Table 4. Variable domains in light chains

[0088] In some embodiments, the variable domain (VH) of the heavy chain region comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 91% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 92% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 93% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 94% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of any one of SEQ ID NO: 44-48.

[0089] In some embodiments, the VH comprises an amino acid sequence of at least 50 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 60 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 70 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 80 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 90 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 100 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 105 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 110 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 115 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 120 consecutive amino acid residues of any one of SEQ ID NO: 44-48.

[0090] In some embodiments, the VH comprises an amino acid sequence of at least 50 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 80% sequence identity with the at least 50 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 60 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 80% sequence identity with the at least 60 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 70 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 80% sequence identity with the at least 70 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 80% sequence identity with the at least 80 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 80% sequence identity with the at least 90 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 80% sequence identity with the at least 100 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 80% sequence identity with the at least 105 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 110 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 80% sequence identity with the at least 110 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 115 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 80% sequence identity with the at least 115 consecutive amino acid residues from any one of SEQ ID NO: 44-48.In some embodiments, the VH comprises an amino acid sequence of at least 120 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 80% sequence identity with at least 120 consecutive amino acid residues of any one of SEQ ID NO: 44-48.

[0091] In some embodiments, the VH comprises an amino acid sequence of at least 50 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 90% sequence identity with at least 50 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 60 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 90% sequence identity with at least 60 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 70 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 90% sequence identity with at least 70 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 90% sequence identity with the at least 80 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 90% sequence identity with the at least 90 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 90% sequence identity with the at least 100 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 90% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 110 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 90% sequence identity with at least 110 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 115 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 90% sequence identity with at least 115 consecutive amino acid residues from any one of SEQ ID NO: 44-48.In some embodiments, the VH comprises an amino acid sequence of at least 120 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 90% sequence identity with at least 120 consecutive amino acid residues of any one of SEQ ID NO: 44-48.

[0092] In some embodiments, the VH comprises an amino acid sequence of at least 50 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 95% sequence identity with at least 50 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 60 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 95% sequence identity with at least 60 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 70 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 95% sequence identity with at least 70 consecutive amino acid residues of any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 95% sequence identity with at least 80 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 95% sequence identity with at least 90 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 95% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 95% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 110 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 95% sequence identity with at least 110 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 115 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 95% sequence identity with at least 115 consecutive amino acid residues from any one of SEQ ID NO: 44-48.In some embodiments, the VH comprises an amino acid sequence of at least 120 consecutive amino acid residues of any one of SEQ ID NO: 44-48, and has at least 95% sequence identity with at least 120 consecutive amino acid residues of any one of SEQ ID NO: 44-48.

[0093] In some embodiments, the VH comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 99% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 99% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 110 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 99% sequence identity with at least 110 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 115 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 99% sequence identity with at least 115 consecutive amino acid residues from any one of SEQ ID NO: 44-48. In some embodiments, the VH comprises an amino acid sequence of at least 120 consecutive amino acid residues from any one of SEQ ID NO: 44-48, and has at least 99% sequence identity with at least 120 consecutive amino acid residues from any one of SEQ ID NO: 44-48.

[0094] In some embodiments, the light chain variable domain (VL) comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 91% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 92% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 93% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 94% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of any one of SEQ ID NO: 49-54.

[0095] In some embodiments, the VL comprises an amino acid sequence of at least 50 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 60 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 70 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 80 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 90 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 100 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 105 consecutive amino acid residues of any one of SEQ ID NO: 49-54.

[0096] In some embodiments, the VL comprises an amino acid sequence of at least 50 consecutive amino acid residues of any one of SEQ ID NO: 49-54, and has at least 80% sequence identity with at least 50 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 60 consecutive amino acid residues of any one of SEQ ID NO: 49-54, and has at least 80% sequence identity with at least 60 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 70 consecutive amino acid residues of any one of SEQ ID NO: 49-54, and has at least 80% sequence identity with at least 70 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 80% sequence identity with at least 80 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 80% sequence identity with at least 90 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 80% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 105 consecutive amino acid residues of any one of SEQ ID NO: 49-54, and has at least 80% sequence identity with at least 105 consecutive amino acid residues of any one of SEQ ID NO: 49-54.

[0097] In some embodiments, the VL comprises an amino acid sequence of at least 50 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 90% sequence identity with at least 50 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 60 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 90% sequence identity with at least 60 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 70 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 90% sequence identity with at least 70 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 90% sequence identity with at least 80 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 90% sequence identity with at least 90 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 90% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 105 consecutive amino acid residues of any one of SEQ ID NO: 49-54, and has at least 90% sequence identity with at least 105 consecutive amino acid residues of any one of SEQ ID NO: 49-54.

[0098] In some embodiments, the VL comprises an amino acid sequence of at least 50 consecutive amino acid residues of any one of SEQ ID NO: 49-54, and has at least 95% sequence identity with at least 50 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 60 consecutive amino acid residues of any one of SEQ ID NO: 49-54, and has at least 95% sequence identity with at least 60 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 70 consecutive amino acid residues of any one of SEQ ID NO: 49-54, and has at least 95% sequence identity with at least 70 consecutive amino acid residues of any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 95% sequence identity with at least 80 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 95% sequence identity with at least 90 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 95% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 95% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 99% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NO: 49-54. In some embodiments, the VL comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NO: 49-54, and has at least 99% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NO: 49-54.

[0099] In some embodiments, the VH comprises an amino acid sequence having at least 70% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 70% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 80% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 80% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 85% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 85% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 90% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 90% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 91% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 91% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 92% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 92% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 93% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 93% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 94% sequence identity with the amino acid sequence of any one of SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 94% sequence identity with the amino acid sequence of any one of SEQ ID NO: 49-54.In some embodiments, the VH comprises an amino acid sequence having at least 95% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 95% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 96% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 96% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 97% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 97% sequence identity with any one of the amino acid sequences according to SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 98% sequence identity with any of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 98% sequence identity with any of the amino acid sequences according to SEQ ID NO: 49-54. In some embodiments, the VH comprises an amino acid sequence having at least 99% sequence identity with any of the amino acid sequences according to SEQ ID NO: 44-48; and the VL comprises an amino acid sequence having at least 99% sequence identity with any of the amino acid sequences according to SEQ ID NO: 49-54.

[0100] In some embodiments, the VH comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence according to SEQ ID NO: 35. In some embodiments, the VH comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, the VH comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, the VH comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, the VH comprises an amino acid sequence having at least 91% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 91% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, the VH comprises an amino acid sequence having at least 92% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 92% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, the VH comprises an amino acid sequence having at least 93% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 93% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, the VH comprises an amino acid sequence having at least 94% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 94% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, the VH comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 49.In some embodiments, the VH comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, the VH comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, the VH comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, the VH comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and the VL comprises an amino acid sequence having at least 99% sequence identity with the amino acid sequence according to SEQ ID NO: 49.

[0101] In some embodiments, the VH comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 70% sequence identity with the amino acid sequence according to SEQ ID NO: 50. In some embodiments, the VH comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 50. In some embodiments, the VH comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 50. In some embodiments, the VH comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 50. In some embodiments, the VH comprises an amino acid sequence having at least 91% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 91% sequence identity with the amino acid sequence according to SEQ ID NO: 50. In some embodiments, the VH comprises an amino acid sequence having at least 92% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 92% sequence identity with the amino acid sequence according to SEQ ID NO: 50. In some embodiments, the VH comprises an amino acid sequence having at least 93% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 93% sequence identity with the amino acid sequence according to SEQ ID NO: 50. In some embodiments, the VH comprises an amino acid sequence having at least 94% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 94% sequence identity with the amino acid sequence according to SEQ ID NO: 50. In some embodiments, the VH comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 50.In some embodiments, the VH comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 50. In some embodiments, the VH comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 45; and the VL comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 50. In some embodiments, the VH comprises an amino acid sequence having at least 98% sequence identity with the amino acid sequence a...

Claims

1. Use of an inhibitor of β-amyloid (Aβ) plaques in the preparation of a medicament for treating Alzheimer's disease in a subject, the subject being identified as having Aβ plaques associated with mild cognitive impairment or dementia or preclinical Alzheimer's disease based at least in part on the detection of a pTau217 level higher than a standard value of pTau217 from a reference sample obtained from a non-Alzheimer's disease individual by analysis of a biological fluid sample obtained from the subject using an anti-pTau217 antibody, wherein the anti-pTau217 antibody comprises: a) A heavy chain containing a variable heavy chain (VH) domain, wherein the VH domain comprises an HCDR1 sequence containing SEQ ID NO: 2, an HCDR2 sequence containing SEQ ID NO: 11, and an HCDR3 sequence containing SEQ ID NO: 19; and b) A light chain containing a variable light chain (VL) domain, wherein the VL domain contains an LCDR1 sequence containing SEQ ID NO: 25, an LCDR2 sequence containing SEQ ID NO: 33, and an LCDR3 sequence containing SEQ ID NO:

38.

2. The use according to claim 1, wherein the analysis of the biological fluid sample comprises performing an immunoassay using the anti-pTau217 antibody.

3. The use according to claim 2, wherein the immunoassay comprises digital immunoassay.

4. The use according to claim 3, wherein the immunoassay comprises a single-molecule array (SIMOA).

5. The use according to claim 2, wherein the immunoassay includes enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), fluorescence immunoassay (FIA), chemiluminescent immunoassay (CLIA), electrochemiluminescent immunoassay, or counting immunoassay (CIA).

6. The use according to claim 1, wherein the VH comprises a sequence having at least 90% sequence identity with SEQ ID NO: 45 and the VL comprises a sequence having at least 90% sequence identity with SEQ ID NO:

50.

7. The use according to claim 1, wherein the heavy chain comprises a sequence having at least 90% sequence identity with SEQ ID NO: 57 and the light chain comprises a sequence having at least 90% sequence identity with SEQ ID NO:

58.

8. The use according to claim 1, wherein the anti-tau antibody or its antigen-binding fragment comprises Fab, F(ab')2, Fab', Fv, sFv, scFv, sdAb, sdFv or nanobodies.

9. The use according to claim 1, wherein the inhibitor of β-amyloid (Aβ) plaque comprises ABvac40, ABBV-916, ACU193, AD-35, aduhelm®, APH-1105, BPN14770, bapilizumab, BMS-984923, contraloid acetate, CNP520 (AMG520), cresolumab, donepezil (LY3002813), donepezil (Aricept), elembestat (E2609), gantenatumab, Brain Shutle gantenatumab (RO7126209), GV-971, HT-ALZ, KHK 66401, labestat, lencanemab (BAN2401) (Leqembi®), Lu AF20513, MEDI 1814, Ponozumab, Remenetamarab (LY3372993), Boxifen, Ristimin, SHR-1707, Simulfil (PTI-125), Sodium Mannoside, Sorapizumab, Squalinosin, UB-311, Valiltramiprosate (ALZ-801), Varoglutamstat (PQ912), Verositol (MK-8931), VGH-AD1, Antisense RNA against human β-amyloid isoform, siRNA against human β-amyloid isoform, Antisense oligonucleotide against human β-amyloid isoform, LNA oligonucleotide against human β-amyloid isoform, CRISPRn-based therapeutic agents targeting the human APP locus, or CRISPRi-based therapeutic agents targeting the human APP locus.

10. The use according to claim 1, wherein the inhibitor of β-amyloid (Aβ) plaques includes aducalumab, donepemumab, lencanemumab, lemminetatumab, gantenemumab, or Brain Shutle gantenemumab.

11. The use according to claim 1, wherein the biological fluid sample is a cerebrospinal fluid (CSF) sample, a plasma sample, a blood sample, or a serum sample.

12. The use according to claim 1, wherein the drug is formulated as an inhibitor of the β-amyloid (Aβ) plaque for intravenous, intramuscular, intrathecal, intracerebral, subcutaneous, oral, nasal, topical, oral, or sublingual administration.

13. The use according to claim 1, wherein the drug is formulated for administration of the β-amyloid (Aβ) plaque inhibitor at a dose of about 0.1-100 mg / kg of the subject's body weight.

14. The use according to claim 1, wherein the drug is formulated for application as an inhibitor of the β-amyloid (Aβ) plaque at approximately once every 1 week, every 2 weeks, every 4 weeks, every 2 months, or every 6 months.

15. The use according to claim 1, wherein the object is Braak stage I or Braak stage II of Alzheimer's disease.

16. Use of an inhibitor of β-amyloid (Aβ) plaques in the preparation of a medicament for treating a subject with Alzheimer's disease, the subject being classified, at least in part, as having mild cognitive impairment or dementia or preclinical Alzheimer's disease, based on a level of pTau217 detected by analysis of biological fluid samples obtained from the subject using an anti-pTau217 antibody that is higher than a standard value of pTau217 derived from reference samples obtained from non-Alzheimer's individuals, wherein the level of pTau217 distinguishes Alzheimer's samples from non-Alzheimer's samples by an area under the curve of at least 0.85, as calculated by receiver operating characteristic analysis.

17. The use according to claim 16, wherein the level of pTau217 distinguishes Alzheimer's disease samples from non-Alzheimer's disease samples with a sensitivity of at least about 85%.

18. The use according to claim 16, wherein the level of pTau217 distinguishes Alzheimer's disease samples from non-Alzheimer's disease samples with at least about 85% specificity.

19. The use according to claim 16, wherein the level of pTau217 distinguishes Alzheimer's disease samples from non-Alzheimer's disease samples with a positive predictive value (PPV) of at least about 70%.

20. The use according to claim 16, wherein the level of pTau217 distinguishes Alzheimer's disease samples from non-Alzheimer's disease samples with a negative predictive value (PPV) of at least about 70%.

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