Methods for diagnosing and treating neurodegenerative disorders

Abstract

Compositions and methods relating to improved assays for demonstrating and providing treatment for neurodegenerative diseases are provided herein. Compositions and methods relating to improved antibodies for assays, including immunoassays used for diagnosing and providing treatment for Alzheimer's disease, are further provided herein. Kits of parts containing pharmaceutical compositions together with instructions for use are further provided. For convenience, the kits of parts, together with instructions for use, may contain predetermined amounts of reagents.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the benefits 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]

[0002] background The discovery of biomarkers and screening techniques for Alzheimer's disease (AD) and other tauopathies is an ongoing area of ​​development. These tools can be applied to screen populations to determine which non-dementia individuals are at highest risk of developing AD dementia, and also to assess disease progression in patients. Amyloid beta-42 (Aβ 42 Proteins reflecting AD pathology, including neurofilamentous light chains and various tau isoforms, have been detected by various means. Abnormal or excessive phosphorylation of tau is associated with the conversion of pathologically normal tau molecules into paired helical filament (PHF) tau and neurofibrillary tangles (NFTs), which exhibit various taupathological pathologies. Inclusion by referencing the sequence list

[0003] This application is filed together with an electronically formatted sequence listing. The sequence listing is provided as a file named 58484-707_601_SL.xml, created on March 15, 2024, and is 106,132 bytes in size. The information in the electronically formatted sequence listing is incorporated entirely by reference. [Overview of the project] [Problems that the invention aims to solve]

[0004] Abstract In one embodiment, a method for treating a neurodegenerative disease in a subject, wherein the neurodegenerative disease is characterized by the accumulation of amyloid-β (Aβ) peptide in the subject's brain, and the method comprises the step of administering to the subject a therapeutic agent for treatment of the neurodegenerative disease, comprising (i) an inhibitor of Aβ peptide or a modified form of Aβ peptide, or (ii) an inhibitor of phosphorylated tau protein, wherein the subject is identified for treatment based on the measured level of p-tau 217 in a sample obtained from the subject, which exceeds the measured level of p-tau 217 in a sample having standard values ​​of phosphorylated tau 217 levels derived from multiple reference samples from a reference subject that does not have a neurodegenerative disease, and this method predicts that the subject has abnormal tau protein deposition in the brain with a sensitivity higher than or equal to about 85%. In some embodiments, p-tau 217 is measured in the sample by a method comprising the step of performing an immunoassay on 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, which is a liquid sample. In some embodiments, the digital immunoassay is a single-molecule array (SIMOA). In some embodiments, the immunoassay includes enzyme-linked immunoassay (ELISA), radioimmunoassay (RIA), fluorescence immunoassay (FIA), chemiluminescence 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 NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 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 NOs: 24-31, an LCDR2 sequence selected from SEQ ID NOs: 32-36, and an LCDR3 sequence selected from SEQ ID NOs: 37-43.In some embodiments, the HCDR1 sequence includes sequence number 2, the HCDR2 sequence includes sequence number 11, and the HCDR3 sequence includes sequence number 19; the LCDR1 sequence includes sequence number 25, the LCDR2 sequence includes sequence number 33, and the LCDR3 sequence includes sequence number 38. In some embodiments, the HCDR1 sequence includes sequence number 1, the HCDR2 sequence includes sequence number 10, and the HCDR3 sequence includes sequence number 18; the LCDR1 sequence includes sequence number 24, the LCDR2 sequence includes sequence number 32, and the LCDR3 sequence includes sequence number 37. In some embodiments, the HCDR1 sequence includes sequence number 2, the HCDR2 sequence includes sequence number 11, and the HCDR3 sequence includes sequence number 19; the LCDR1 sequence includes sequence number 26, the LCDR2 sequence includes sequence number 34, and the LCDR3 sequence includes sequence number 39. In some embodiments, the HCDR1 sequence includes SEQ ID NO: 3, the HCDR2 sequence includes SEQ ID NO: 12, and the HCDR3 sequence includes SEQ ID NO: 18; the LCDR1 sequence includes SEQ ID NO: 27, the LCDR2 sequence includes SEQ ID NO: 32, and the LCDR3 sequence includes SEQ ID NO: 40. In some embodiments, the HCDR1 sequence includes SEQ ID NO: 4, the HCDR2 sequence includes SEQ ID NO: 11, and the HCDR3 sequence includes SEQ ID NO: 20; the LCDR1 sequence includes SEQ ID NO: 28, the LCDR2 sequence includes SEQ ID NO: 35, and the LCDR3 sequence includes SEQ ID NO: 41. In some embodiments, the HCDR1 sequence includes SEQ ID NO: 5, the HCDR2 sequence includes SEQ ID NO: 13, and the HCDR3 sequence includes SEQ ID NO: 21; the LCDR1 sequence includes SEQ ID NO: 29, the LCDR2 sequence includes SEQ ID NO: 33, and the LCDR3 sequence includes SEQ ID NO: 42. In some embodiments, the anti-tau antibody includes a heavy chain (HC) sequence including SEQ ID NO: 57 and a light chain (LC) sequence including SEQ ID NO: 58. In some embodiments, the anti-tau antibody includes an HC sequence including SEQ ID NO: 57 and an LC sequence including SEQ ID NO: 59. In some embodiments, the anti-tau antibody comprises an HC sequence containing SEQ ID NO: 60 and an LC sequence containing 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 includes an HC sequence containing SEQ ID NO: 55 and an LC sequence containing SEQ ID NO: 56. In some embodiments, the anti-tau antibody includes a variable weight (VH) domain containing 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 NOs: 44-48. In some embodiments, the anti-tau antibody includes a variable light (VL) domain containing 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 NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 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 that includes phosphorylation at a site selected from the group consisting of pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau.In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, the subject has or is suspected of having Alzheimer's disease (AD). In some embodiments, AD causes, is associated with, or presents a tauopathy in the subject. In some embodiments, the tauopathy includes secondary tauopathy including neurofibrillary tangle (NTF) pathology in the subject's brain, and the tauopathy is secondary to amyloid-beta plaques in the subject's brain. In some embodiments, the method according to claim 30, wherein AD includes variant AD selected from the group consisting of early-onset Alzheimer's disease, late-onset Alzheimer's disease, familial Alzheimer's disease (FAD), mixed dementia including Alzheimer's disease and vascular dementia, logopenic aphasia, posterior cortical atrophy, frontotemporal Alzheimer's disease, and Alzheimer's disease combined with corticobasal syndrome (AD-CBS). In some embodiments, tauopathy includes hyperphosphorylated tau, misfolded tau, oligomeric tau, tau aggregated paired helical filaments (PFH), neurofibrillary tangles (NFTs), or any combination thereof. In some embodiments, the subject is a human being 60 years of age or older.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningioaniomatosis, primary age-related tauopathy (PART), argyrophilic granule disease (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, and myotonic tauopathy. This includes tonic dystrophy, pallid-pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. In some embodiments, the neurodegenerative disease is Alzheimer's disease. In some embodiments, the prodromal stage of Alzheimer's disease is characterized by mild cognitive impairment (MCI). In some embodiments, the prodromal stage of Alzheimer's disease is characterized as Braak stage I, at least according to the degree of spatial determination by tau-PET. In some embodiments, the prodromal stage of Alzheimer's disease is characterized as Braak stage II, at least according to the degree of spatial determination by tau-PET. In some embodiments, the neurodegenerative disease is a tauopathy, which includes hyperphosphorylated tau, misfolded tau, oligomeric tau, tau aggregated paired helical filaments (PFHs), neurofibrillary tangles (NFTs), or any combination thereof.In some embodiments, inhibitors of Aβ peptides or modified forms of Aβ peptides include ABvac40, ABBV-916, ACU193, AD-35, aducanumab (Aduhelm®), APH-1105, BPN14770, bapineuzumab, BMS-984923, contraloid acetate, CNP520 (AMG520), crenezumab, donanemab (LY3002813), donepezil (Aricept), elenbecestat (E2609), gantenerumab, brain shuttle gantenerumab (RO7126209), GV-971, HT-ALZ, KHK 66401, lanabesestat, lecanemab (BAN2401) (Leqembi®), Lu This includes AF20513, MEDI 1814, ponezumab, remternetsug (LY3372993), rivastigmine, SHR-1707, symphyllam (PTI-125), oligomannate sodium, solanezumab, scyllo-inositol, UB-311, valyltramiprosate (ALZ-801), baloglutamstat (PQ912), verbecestat (MK-8931), VGH-AD1, antisense RNA directed to human amyloid beta isoforms, siRNA directed to human amyloid beta isoforms, antisense oligonucleotides directed to human amyloid beta isoforms, LNA oligonucleotides directed to human amyloid beta isoforms, and CRISPRn-based or CRISPRi-based therapeutics targeting the human APP locus. Some implementations. In some embodiments, the inhibitor of Aβ peptide or a modified form of Aβ peptide includes donanemab. In some embodiments, the inhibitor of Aβ peptide or a modified form of Aβ peptide includes lecanemab. In some embodiments, the inhibitor of Aβ peptide or a modified form of Aβ peptide includes remternetsug. In some embodiments, the inhibitor of Aβ peptide or a modified form of Aβ peptide includes aducanumab. In some embodiments, the inhibitor of Aβ peptide or a modified form of Aβ peptide is selected from Table 10. In some embodiments, the inhibitor of phosphorylated tau protein includes inhibitors of 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 sensitivity is higher than or equal to about 90%. In some embodiments, the sensitivity is higher 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 with an area under the curve (AUC) higher than or equal to about 0.85. In some embodiments, the AUC is higher than or equal to about 0.90. In some embodiments, the measured level of p-tau-217 predicts that the subject has abnormal tau protein deposition in the brain with a specificity higher than or equal to about 81%. In some embodiments, the specificity is higher than or equal to about 85%. In some embodiments, the measured level of p-tau-217 predicts that the subject has abnormal tau protein deposition in the brain with a positive predictive value (PPV) higher than or equal to about 51%. In some embodiments, the PPV is higher than or equal to about 70%. In some embodiments, the measured level of p-tau-217 predicts that the subject has abnormal tau protein deposition in the brain with a negative predictive value (NPV) higher than or equal to about 51%. In some embodiments, the NPV is higher 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 therapeutic agent with a specificity of about 70% or higher. In some embodiments, the measured level of p-tau 217 predicts that the subject will exhibit a positive therapeutic response to the therapeutic agent with a sensitivity of about 70% or higher. In some embodiments, the measured level of p-tau 217 predicts that the subject will exhibit a positive therapeutic response to the therapeutic agent with a PPV of about 70% or higher. In some embodiments, the measured level of p-tau 217 predicts that the subject will exhibit a positive therapeutic response to the therapeutic agent with an NPV of about 70% or higher. In some embodiments, the measured level of p-tau 217 predicts that the subject will exhibit a positive therapeutic response to the therapeutic agent with an AUC of about 0.70 or higher. 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, at least in part, a step of determining the likelihood of a clinical diagnosis of neurodegenerative disease in the subject based on the measured level of p-tau-217 in the sample. In some embodiments, the method includes, at least in part, a step of establishing an early prognosis diagnosis of neurodegenerative disease in the subject based on the measured level of p-tau-217 in the sample, the early prognosis diagnosis preceding a step of providing a diagnosis of a prodromal stage of neurodegenerative disease in the subject. In some embodiments, the neurodegenerative disease is Alzheimer's disease, and the step of establishing an early prognosis diagnosis of Alzheimer's disease includes, at least in part, a step of establishing the likelihood of Alzheimer's disease progressing to Alzheimer's dementia in the subject based on the measured level of p-tau-217 in the sample. In some embodiments, the method includes, at least in part, a step of identifying an increased risk of pathological memory impairment and cognitive decline in the subject based on the measured level of p-tau-217 in the sample. In some embodiments, the method includes a step of reversing one or more symptoms of neurodegenerative disease in the subject.In some embodiments, the method includes a step of delaying the progression of one or more symptoms of a neurodegenerative disease in the subject. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of a neurogenesis disease. In some embodiments, the subject is in the prodromal stage of a neurogenesis disease. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered in a dosage of approximately 10 mg / kg body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes a step of administering the therapeutic agent once every approximately two weeks (q2week). In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes a step of administering the therapeutic agent once every approximately four weeks (q4week). In some embodiments, the therapeutic agent is administered to the subject in multiple doses, the first three doses of which are administered to the subject in amounts containing approximately 700 mg per dose. In some embodiments, the doses of which are administered to the subject after the first three doses are in amounts containing approximately 1400 mg per dose. In some embodiments, the administration step is systemic administration. In some embodiments, systemic administration includes intravenous administration. In some embodiments, systemic administration includes subcutaneous administration. In some embodiments, systemic administration includes oral administration.In some embodiments, the method includes a) a step of 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) a step of administering another dose of the therapeutic agent to the subject.

[0005] In one embodiment, a kit for selecting subjects for the treatment of neurodegenerative diseases, a)i) a heavy chain comprising a variable heavy chain (VH) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 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 NOs: 24-31, an LCDR2 sequence selected from SEQ ID NOs: 32-36, and an LCDR3 sequence selected from SEQ ID NOs: 37-43;ii) a heavy chain (HC) sequence comprising any one of SEQ ID NOs: 57, 60, 62, 64, or 55; and a light chain (LC) sequence comprising any one of SEQ ID NOs: 58, 59, 63, 65, or 56; or sequence number a) an anti-tau antibody or its antigen-binding fragment comprising a variable weight (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 sequence numbers 44-48; and a variable light (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 sequence numbers 49-54; b) instructions for analyzing a sample obtained from a subject using the anti-tau antibody or its antigen-binding fragment in an immunoassay; c) instructions for treating neurodegenerative diseases in a subject with a therapeutic agent comprising (i) an inhibitor of Aβ peptide or a modified form of Aβ peptide, or (ii) an inhibitor of phosphorylated tau protein; and d) a kit comprising the therapeutic agent as appropriate. In some embodiments, the kit comprises the therapeutic agent. In some embodiments, the kit comprises one or more immunoassay components, the immunoassay including single-molecule arrays (SIMOA), enzyme-linked immunoassays (ELISA), radioimmunoassays (RIA), fluorescence immunoassays (FIA), chemiluminescent immunoassays (CLIA), or counting immunoassays (CIA).In some embodiments, the kit includes a system for performing an immunoassay, the immunoassay including single-molecule array (SIMOA), enzyme-linked immunoassay (ELISA), radioimmunoassay (RIA), fluorescence immunoassay (FIA), chemiluminescence immunoassay (CLIA), or counting immunoassay (CIA). In some embodiments, the anti-tau antibody or its antigen-binding fragment includes a heavy chain comprising a variable heavy chain (VH) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23; and a light chain comprising a variable light chain (VL) domain, wherein the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs: 24-31, an LCDR2 sequence selected from SEQ ID NOs: 32-36, and an LCDR3 sequence selected from SEQ ID NOs: 37-43. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises a heavy chain (HC) sequence containing one of sequence numbers 57, 60, 62, 64, or 55; and a light chain (LC) sequence containing one of sequence numbers 58, 59, 63, 65, or 56. In some embodiments, the anti-tau antibody or its antigen-binding fragment comprises a variable heavy (VH) domain containing a sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from sequence numbers 44-48; and a variable light (VL) domain containing a sequence having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from sequence numbers 49-54.In some embodiments, the inhibitors of the therapeutic agent include ABvac40, ABBV-916, ACU193, AD-35, aducanumab (Aduhelm®), APH-1105, BPN14770, bapineuzumab, BMS-984923, contraloid acetate, CNP520 (AMG520), crenezumab, donanemab (LY3002813), donepezil (Aricept), elenbecestat (E2609), gantenerumab, brain shuttle gantenerumab (RO7126209), GV-971, HT-ALZ, KHK 66401, lanabesestat, lecanemab (BAN2401) (Leqembi®), Lu AF20513, MEDI The present invention includes 1814, ponezumab, remternetsug (LY3372993), rivastigmine, SHR-1707, simfilam (PTI-125), oligomannate sodium, solanezumab, scyllo-inositol, UB-311, valyltramiprosate (ALZ-801), baloglutamstat (PQ912), verbecestat (MK-8931), VGH-AD1, antisense RNA directed to human amyloid beta isoforms, siRNA directed to human amyloid beta isoforms, antisense oligonucleotides directed to human amyloid beta isoforms, LNA oligonucleotides directed to human amyloid beta isoforms, and CRISPRn-based or CRISPRi-based therapeutics targeting the human APP locus. In some embodiments, the therapeutic agent includes donanemab. In some embodiments, the therapeutic agent comprises recanemab. In some embodiments, the therapeutic agent comprises remternetsug. In some embodiments, the therapeutic agent comprises aducanumab. 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 of 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 instructions for analyzing the sample further include standard values ​​of p-tau 217 levels derived from multiple reference samples from a reference subject without neurodegenerative disease.

[0006] In a particular embodiment, a method for treating neurodegenerative disease in a subject, the method comprising: (a) detecting the level of pT217 tau in a sample derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises performing an immunoassay on the sample using an anti-tau antibody or its antigen-binding fragment 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 is SEQ ID NO: 1~ (b) a step in which the detection step includes an HCDR1 sequence selected from 9, an HCDR2 sequence selected from sequence numbers 10-17, and an HCDR3 sequence selected from sequence numbers 18-23, and the VL domain includes an LCDR1 sequence selected from sequence numbers 24-31, an LCDR2 sequence selected from sequence numbers 32-36, and an LCDR3 sequence selected from sequence numbers 37-43; (c) a step in which, at least in part, based on the detection step, the possibility of a clinical diagnosis of neurodegenerative disease in the subject; (d) a step in which, at least in part, based on the determination step, (d) a step of establishing an early prognosis for neurodegenerative disease, wherein the early prognosis precedes a step of providing a diagnosis of a prodromal stage of neurodegenerative disease in the subject; and (f) a step of initiating treatment, wherein the decision to initiate the initiation step is, at least in part, based on the establishing step, the therapeutic agent being ABvac40, LY3002813, AADvac-1, ACI-35, AAV-Htert, ACU193, ASN51, ACI-242, AD-35, aducanumab, AGB101, AL002, alloprene Gunanolone, APH-1105, Atuzaginstat (COR388), AVP-786, AXS-05, Baricitinib, Bepranemab, BCG vaccine, BEIY2153, BPN14770, Bromocriptine, Briostatin 1, BXCL-501, Brarcamecin (ANAVEX2-73), Bapineuzumab, BIIB092 (BMS-986168, IPN007, Goslanemab), BIIB080 / IONIS-MAPTRx, BIIB076, BPDO-1603, BMS-984923, BDPP (Bioactive Food Polyphenol Preparation),Brexpiprazole, caffeine, CAD 1063, canakinumab, contraloid acetate, COR588, CORT108297, CNP520 (AMG520), C2N-8E12 (ABBV-8E12), crenezumab, CST-2032, curcumin, CY6463, dabigatran, DAOIB, dapagliflozin, daratumumab, dasatinib, deferipron, donanemab (LY3002813), donepezil (Aricept), dronabinol, dutanumab, edicotinib (JNJ-40346527), E Favirenz, emtricitabine, empagliflozin, elenbecestat (E2609), E2814, ednerpic (T-817mA), elayta (CT1812), ExPlas, escitalopram, phosgonimeton (ATH01017), galantamine, gantenerumab, brain shuttle gantenerumab (RO7126209), GB301, grape seed extract, GV1001, guanfacine, GV-971, intranasal insulin, HT-ALZ, huperzine A, hydralazine, IGC AD1, Ethyl Icosapentate (IPE), JNJ-63733657, KHK 66401, Lu AF87908, Lu AF20513, Lamivudine (3TC), Lanabesestat, Lenalidomide, Levetiracetam, L-Serine, Leupron, Remternetsug (LY3372993), LY3372689, LMTX, LY3303560 (Zagotenemab), Lecanemab (BAN2401), Losartan, LX1001, MEDI 1814, Memantine, Metformin, MK-1942, MIB-626, Montelukast, MW150, Neframapimod (VX-745), Nabilon, NE3107, Nicotinamide, Nicotine, NNI-362, Nilotinib BE, Octohydro-aminoacridine succinate, Obicetrapib, Omega-3 (DHA+EPA), Perindopril, Pepinemab (VX15), Posifen, Prazosin, Ponezumab, Protolin, PQ912, PNT001, PU-AD, Quercetin, Rapamycin, REM0046127, RG7345 (RO6926496), Rivastigmine, RG6100,RO7105705 (MTAU9937A, RG6100, semolinemab), salsalat, salglamostim, semolinemab, senicapok, semaglutide, SHR-1707, symphyllam (PTI-125), sodium oligomannate, solanezumab, scyllo-inositol, buckateltide (PMZ-1620), suvorexant, T3D-959, TB006, telmisartan, trehalose, Tdap vaccine, THC-free CBD oil, thiethylperazine (TEP), troriruzole (BHV4157), TPI 2871, Tricaprylin (AC-1202), TRx0237, UB-311, UCB0107, Valyltramiprosate (ALZ-801), Valacyclovir, Baloglutamstat (PQ912), VGH-AD1, Vorinostat, VT301, XPro1595, Xanamem, Yangxue A method is disclosed herein that includes the steps of: Qingao pills; antisense RNA directed to an isoform of human tau mRNA or human amyloid beta; siRNA directed to an isoform of human tau mRNA or human amyloid beta; antisense oligonucleotides directed to an isoform of human tau mRNA or human amyloid beta; LNA oligonucleotides directed to an isoform of human tau mRNA or human amyloid beta; a CRISPRn-based therapeutic agent targeting the human MAPT or human APP locus; a CRISPRi-based therapeutic agent targeting the human MAPT or human APP locus; and a selected human MSC, SNK01 (autologous natural killer cells); allogeneic adipose-derived MSC exosomes; CA-AC-02 (placenta-derived MSC); HUVEC-derived MSC (NEUROSTEM); and AstroStem (autologous adipose-derived MSC). In some embodiments, the HCDR1 sequence includes sequence number 2, the HCDR2 sequence includes sequence number 11, the HCDR3 sequence includes sequence number 19, the LCDR1 sequence includes sequence number 25, the LCDR2 sequence includes sequence number 33, and the LCDR3 sequence includes sequence number 38. In some embodiments, the HCDR1 sequence includes sequence number 1, the HCDR2 sequence includes sequence number 10,The HCDR3 sequence includes sequence number 18, the LCDR1 sequence includes sequence number 24, the LCDR2 sequence includes sequence number 32, and the LCDR3 sequence includes sequence number 37. In some embodiments, the HCDR1 sequence includes sequence number 2, the HCDR2 sequence includes sequence number 11, the HCDR3 sequence includes sequence number 19, the LCDR1 sequence includes sequence number 26, the LCDR2 sequence includes sequence number 34, and the LCDR3 sequence includes sequence number 39. In some embodiments, the HCDR1 sequence includes sequence number 3, the HCDR2 sequence includes sequence number 12, the HCDR3 sequence includes sequence number 18, the LCDR1 sequence includes sequence number 27, the LCDR2 sequence includes sequence number 32, and the LCDR3 sequence includes sequence number 40. In some embodiments, the HCDR1 sequence includes sequence number 4, the HCDR2 sequence includes sequence number 11, the HCDR3 sequence includes sequence number 20, the LCDR1 sequence includes sequence number 28, the LCDR2 sequence includes sequence number 35, and the LCDR3 sequence includes sequence number 41. In some embodiments, the HCDR1 sequence includes SEQ ID NO: 5, the HCDR2 sequence includes SEQ ID NO: 13, the HCDR3 sequence includes SEQ ID NO: 21, the LCDR1 sequence includes SEQ ID NO: 29, the LCDR2 sequence includes SEQ ID NO: 33, and the LCDR3 sequence includes 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 is characterized by Braak stage I, at least, by the degree of spatial determination on tau-PET. In some embodiments, the prodromal stage of AD is characterized by Braak stage II, at least, by the degree of spatial determination on tau-PET. In some embodiments, the method includes the step of detecting the level of pT217 tau in a sample, the detected level of pT217 tau is quantified as being above the standard value of pT217 tau levels derived from multiple reference samples, the multiple reference samples are obtained from healthy individuals not suspected of having AD. In some embodiments, the subject meets inclusion criteria for initiating treatment, and the inclusion criteria include d) detecting the level of pT217 tau in the sample, obtained prior to the step of initiating treatment. In some embodiments, the subject,The subject is at least 60 years old. In some embodiments, the subject is between 60 and 85 years old at step d) initiating treatment. In some embodiments, the selected therapeutic agent is donanemab. In some embodiments, the selected therapeutic agent is recanemab. In some embodiments, the selected therapeutic agent is remternetsug. In some embodiments, the selected therapeutic agent is aducanumab. In some embodiments, step c) establishing an early prognosis includes, at least in some embodiments, a step of establishing the likelihood that AD in the subject will progress to AD dementia, based on step a) detection. In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs. 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs. 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides including phosphorylation at 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 lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Ritiko-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis.In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having a neurogenic disorder. In some embodiments, multiple samples from reference subjects are obtained from individuals in an early disease stage of suspected neurogenic disorder. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every approximately 4 weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, doses administered to the subject after the first three doses include a dose of approximately 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 includes 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 includes 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 includes 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 includes 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 includes 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 includes an HC containing the sequence of SEQ ID NO: 64 and an LC containing the sequence of SEQ ID NO: 65.

[0007] In certain embodiments, a method for treating neurodegenerative disease in a subject is described herein, the method comprising the step of administering to the subject a therapeutically effective dose of a tau-targeting small molecule therapeutic agent listed in Table 10, wherein the subject is selected based on the detection of a level of pT217 tau in a subject-derived sample that exceeds a standard value of pT217 tau levels derived from a plurality of reference samples, and the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting tau biological activity. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or an antigen-binding fragment thereof includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed.In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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.

[0008] In certain embodiments, a method for treating a neurodegenerative disease in a subject is described herein, the method comprising the step of administering to the subject a therapeutically effective amount of a tau-targeting antibody therapeutic agent listed in Table 10, wherein the subject is selected based on the detection of a level of pT217 tau in a subject-derived sample that exceeds a standard value of pT217 tau levels derived from a plurality of reference samples, and the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting tau biological activity. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or an antigen-binding fragment thereof includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed.In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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 certain embodiments, a method for treating neurodegenerative disease in a subject is described herein, the method comprising the step of administering to the subject a therapeutically effective amount of a small molecule therapeutic agent targeting beta-amyloid as listed in Table 10, wherein the subject is selected based on the detection of a level of pT217 tau in a subject-derived sample that exceeds a standard value of pT217 tau levels derived from a plurality of reference samples, and the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting beta-amyloid biological activity. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or an antigen-binding fragment thereof includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed.In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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 certain embodiments, a method for treating neurodegenerative disease in a subject is described herein, the method comprising the step of administering to the subject a therapeutically effective amount of a beta-amyloid-targeting antibody therapeutic agent listed in Table 10, wherein the subject is selected based on the detection of a level of pT217 tau in a subject-derived sample that exceeds a standard value of pT217 tau levels derived from a plurality of reference samples, and the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting beta-amyloid biological activity. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or an antigen-binding fragment thereof includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed.In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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 certain embodiments, a method for treating a neurodegenerative disease in a subject is described herein, the method comprising the step of administering to the subject a therapeutically effective dose of a cholinesterase inhibitor therapeutic agent listed in Table 10, wherein the subject is selected based on the detection of a level of pT217 tau in a sample derived from the subject that exceeds a standard value of pT217 tau levels derived from a plurality of reference samples, and the level of pT217 tau predicts a positive therapeutic response in the subject to a treatment targeting cholinesterase inhibition. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or an antigen-binding fragment thereof includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed.In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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 certain embodiments, a method for treating neurodegenerative disease in a subject is described herein, the method comprising the step of administering to the subject a therapeutically effective dose of a tau-targeting NMDA receptor antagonist therapeutic agent listed in Table 10, wherein the subject is selected based on the detection of a level of pT217 tau in a subject-derived sample that exceeds a standard value of pT217 tau levels derived from a plurality of reference samples, and the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting inhibition of NMDA receptor function. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or an antigen-binding fragment thereof includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed.In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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 certain embodiments, a method for treating neurodegenerative disease in a subject is described herein, the method comprising the step of administering to the subject a therapeutically effective dose of an acetylcholinesterase and butyrylcholinesterase inhibitor listed in Table 10, wherein the subject is selected based on the detection of a level of pT217 tau in a subject-derived sample that exceeds a standard value of pT217 tau levels derived from a plurality of reference samples, and the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting inhibition of acetylcholinesterase and butyrylcholinesterase function. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or its antigen-binding fragment. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body dementia (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 neurodegenerative disease in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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 certain embodiments, a method for treating neurodegenerative disease in a subject is described herein, the method comprising the step of 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 the detection of a level of pT217 tau in a subject-derived sample that exceeds a standard value of pT217 tau levels derived from a plurality of reference samples, wherein the level of pT217 tau predicts a positive therapeutic response in the subject to inhibition of NMDA receptor function and treatment targeting inhibition of NMDA receptor function. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or an antigen-binding fragment thereof includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body dementia (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 neurodegenerative disease in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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 certain embodiments, a method for treating neurodegenerative disease in a subject is described herein, the method comprising the step of administering to the subject a therapeutically effective amount of an antibody therapeutic agent targeting an amyloid-beta peptide listed in Table 10, wherein the subject is selected based on the detection of a level of pT217 tau in a sample derived from the subject that exceeds a standard value of pT217 tau levels derived from a plurality of reference samples, and the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting aggregated soluble and insoluble forms of amyloid-beta peptide. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or an antigen-binding fragment thereof includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body dementia (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 neurodegenerative disease in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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 certain embodiments, a method for treating neurodegenerative disease in a subject is described herein, the method comprising the step of administering to the subject a therapeutically effective amount of an antibody therapeutic agent targeting amyloid-beta peptide listed in Table 10, wherein the subject is selected based on the detection of a level of pT217 tau in a sample derived from the subject that exceeds a standard value of pT217 tau levels derived from a plurality of reference samples, and the level of pT217 tau predicts a positive therapeutic response in the subject to a treatment targeting the removal of aggregated soluble and insoluble forms of amyloid-beta peptide. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or an antigen-binding fragment thereof includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigra degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body dementia (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 neurodegenerative disease in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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 certain embodiments, a method for treating a neurodegenerative disease in a subject is described herein, the method comprising the step of administering to the subject an effective dose of an antisense therapy targeting huntingtin protein (HTT) listed in Table 10, wherein the subject is selected based on the detection of a level of pT217 tau in a subject-derived sample that exceeds a standard value of pT217 tau levels from a plurality of reference samples, and the level of pT217 tau predicts a positive therapeutic response in the subject to treatment targeting HHT mRNA. In some embodiments, the detection of the level of pT217 tau in the sample is performed using an anti-tau antibody or an antigen-binding fragment thereof. In some embodiments, the anti-tau antibody or an antigen-binding fragment thereof includes a variable weight (VH) domain and a variable light (VL) domain. In some embodiments, the VH domain includes at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment contains IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed.In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 includes 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 a particular embodiment, a method for treating a neurodegenerative disease in a subject, the method comprising: (a) determining whether the subject is suitable for treatment with a small molecule tau inhibitor by detecting whether the subject has an increased risk of neurodegenerative conditions leading to pathological memory impairment and cognitive decline compared to a reference subject, and detecting the level of pT217 tau in a sample derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises an anti-tau inhibitor comprising i) a heavy chain containing a variable heavy chain (VH) domain and ii) a light chain containing a variable light chain (VL) domain. A method is described herein that includes the steps of: (b) performing an immunoassay on a sample using the body or an antigen-binding fragment thereof, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23; and the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs: 24-31, an LCDR2 sequence selected from SEQ ID NOs: 32-36, and an LCDR3 sequence selected from SEQ ID NOs: 37-43; and (b) treating the subject by administering a therapeutically effective amount of a low molecular weight tau inhibitor listed in Table 10. In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs: 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 phosphorylation at a site selected from the group consisting of 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 phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau and pT231-tau sites.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis.In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 a particular embodiment, a method for treating neurodegenerative disease in a subject, the method comprising: (a) determining whether the subject is suitable for treatment with an anti-tau antibody by detecting whether the subject has an increased risk of neurodegenerative conditions leading to pathological memory impairment and cognitive decline compared to a reference subject, and detecting the level of pT217 tau in a sample derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises an antibody comprising i) a heavy chain containing a variable heavy chain (VH) domain and ii) a light chain containing a variable light chain (VL) domain. A method is described herein that includes the steps of (b) performing an immunoassay on a sample using the antigen-binding fragment, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs: 24-31, an LCDR2 sequence selected from SEQ ID NOs: 32-36, and an LCDR3 sequence selected from SEQ ID NOs: 37-43; and (b) treating the subject by administering a therapeutically effective amount of an anti-tau antibody listed in Table 10. In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs: 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 phosphorylation at a site selected from the group consisting of 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 phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau and pT231-tau sites.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis.In some embodiments, the therapeutic agent is administered at a dosage between about 0.1 and 100 mg / kg body weight, according to the subject's weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration at a dosage between about 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration at a dosage between about 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes administering the therapeutic agent once every about 4 weeks (q4week). In some embodiments, the first 3 doses administered to the subject include a dosage of about 700 mg of the therapeutic agent. In some embodiments, the dosage administered to the subject after the first 3 doses administered includes a dosage of about 1400 mg of the therapeutic agent. In some embodiments, it is systemic administration of the therapeutic agent. In some embodiments, systemic administration includes i.v. 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 includes a HC comprising the sequence of SEQ ID NO: 55 and a LC comprising the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 57 and a LC comprising the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 57 and a LC comprising the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 60 and a LC comprising the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 62 and a LC comprising the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 64 and a LC comprising the sequence of SEQ ID NO: 65.

[0020] In a particular embodiment, a method for treating a neurodegenerative disease in a subject, the method comprising: (a) determining whether the subject is suitable for treatment with an anti-Aβ antibody by detecting whether the subject has an increased risk of neurodegenerative conditions leading to pathological memory impairment and cognitive decline compared to a reference subject, and detecting the level of pT217 tau in a sample derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises an antibody comprising i) a heavy chain containing a variable heavy chain (VH) domain and ii) a light chain containing a variable light chain (VL) domain. A method is described herein that includes the steps of: (a) performing an immunoassay on a sample using the antigen-binding fragment, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23; and the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs: 24-31, an LCDR2 sequence selected from SEQ ID NOs: 32-36, and an LCDR3 sequence selected from SEQ ID NOs: 37-43; and (b) treating the subject by administering a therapeutically effective amount of an anti-Aβ antibody listed in Table 10. In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs: 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 phosphorylation at a site selected from the group consisting of 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 phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau and pT231-tau sites.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis.In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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.

[0021] In a particular embodiment, a method for treating neurodegenerative disease in a subject, the method comprising: (a) determining whether the subject is suitable for treatment with a low molecular weight amyloid-beta peptide inhibitor by detecting whether the subject has an increased risk of neurodegenerative conditions leading to pathological memory impairment and cognitive decline compared to a reference subject, and detecting the level of pT217 tau in a sample derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises an antibody comprising i) a heavy chain containing a variable heavy chain (VH) domain and ii) a light chain containing a variable light chain (VL) domain. A method is described herein that includes the steps of: (a) performing an immunoassay on a sample using the antigen-binding fragment, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23; and the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs: 24-31, an LCDR2 sequence selected from SEQ ID NOs: 32-36, and an LCDR3 sequence selected from SEQ ID NOs: 37-43; and (b) treating the subject by administering a therapeutically effective amount of a low molecular weight amyloid-beta peptide inhibitor listed in Table 10. In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs: 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 phosphorylation at a site selected from the group consisting of 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 phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau and pT231-tau sites.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis.In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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.

[0022] In a particular embodiment, a method for treating neurodegenerative disease in a subject, the method comprising: (a) receiving data obtained by detecting the level of pT217 tau in a sample derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises performing an immunoassay on the subject using an anti-tau 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 NOs. 1-9, an HCDR2 sequence selected from SEQ ID NOs. 10-17 and an HCDR3 sequence selected from SEQ ID NOs. 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs. 24-31, an LCDR2 sequence selected from SEQ ID NOs. 32-36 and an LCDR3 sequence selected from SEQ ID NOs. 37-43; (b) at least in part, a step of analyzing the possibility of a clinical diagnosis of neurodegenerative disease in the subject based on the receiving step; (c) at least in part (d) a step of providing an early prognosis diagnosis of neurodegenerative disease in a subject based on an analysis step, wherein the early prognosis diagnosis precedes a step of providing a diagnosis of the prodromal stage of neurodegenerative disease in the subject; and (d) a step of initiating a procedure including administration of a preparation containing a therapeutic agent, wherein the decision to initiate the procedure is, at least in part, based on the step of providing, the therapeutic agent is ABvac40, LY3002813, AADvac-1, ACI-35, AAV-Htert, ACU193, ASN51, ACI-242, AD-35, Adu Kanumab, AGB101, AL002, Allopregnanolone, APH-1105, Atuzaginstat (COR388), AVP-786, AXS-05, Baricitinib, Bepranemab, BCG vaccine, BEIY2153, BPN14770, Bromocriptine, Briostatin 1, BXCL-501, Brarcamecin (ANAVEX2-73), Bapineuzumab, BIIB092 (BMS-986168, IPN007, Goslanemab), BIIB080 / IONIS-MAPTRx, BIIB076, BPDO-1603, BMS-984923,BDPP (bioactive food polyphenol preparation), brexpiprazole, caffeine, CAD 1063, canakinumab, contraloid acetate, COR588, CORT108297, CNP520 (AMG520), C2N-8E12 (ABBV-8E12), crenezumab, CST-2032, curcumin, CY6463, dabigatran, DAOIB, dapagliflozin, daratumumab, dasatinib, deferipron, donanemab (LY3002813), donepezil (Aricept), dronabinol, dutanumab, edicotinib (JNJ-40346527), F Avirenz, emtricitabine, empagliflozin, elenbecestat (E2609), E2814, ednerpic (T-817mA), elaita (CT1812), ExPlas, escitalopram, phosgonimeton (ATH01017), galantamine, gantenerumab, brain shuttle gantenerumab (RO7126209), GB301, grape seed extract, GV1001, guanfacine, GV-971, intranasal insulin, HT-ALZ, huperzine A, hydralazine, IGC AD1, Ethyl Icosapentate (IPE), JNJ-63733657, KHK 66401, Lu AF87908, Lu AF20513, Lamivudine (3TC), Lanabesestat, Lenalidomide, Levetiracetam, L-Serine, Leupron, Remternetsug (LY3372993), LY3372689, LMTX, LY3303560 (Zagotenemab), Lecanemab (BAN2401), Losartan, LX1001, MEDI 1814, Memantine, Metformin, MK-1942, MIB-626, Montelukast, MW150, Neframapimod (VX-745), Nabilon, NE3107, Nicotinamide, Nicotine, NNI-362, Nilotinib BE, Octahydro-aminoacridine succinate, Obicetrapib, Omega-3 (DHA+EPA), Perindopril, Pepinemab (VX15), Posifen, Prazosin, Ponezumab, Protolin, PQ912, PNT001, PU-AD, Quercetin, Rapamycin, REM0046127, RG7345 (RO6926496), Rivastigmine, RG6100, RO7105705 (MTAU9937A, RG6100, Semolinemab), Salsalat,Sarglamostim, semolinemab, senicapok, semaglutide, SHR-1707, Symphyllam (PTI-125), sodium oligomannate, solanezumab, scyllo-inositol, buckateltide (PMZ-1620), suvorexant, T3D-959, TB006, telmisartan, trehalose, Tdap vaccine, THC-free CBD oil, thiethylperazine (TEP), troriruzole (BHV4157), TPI 2871, Tricaprylin (AC-1202), TRx0237, UB-311, UCB0107, Valyltramiprosate (ALZ-801), Valacyclovir, Baloglutamstat (PQ912), VGH-AD1, Vorinostat, VT301, XPro1595, Xanamem, Yangxue A method is described herein that includes the step of selecting from the group consisting of Qingao pills, antisense RNA directed to an isoform of human tau mRNA or human amyloid beta, siRNA directed to an isoform of human tau mRNA or human amyloid beta, antisense oligonucleotides directed to an isoform of human tau mRNA or human amyloid beta, LNA oligonucleotides directed to an isoform of human tau mRNA or human amyloid beta, a CRISPRn-based therapeutic agent targeting the human MAPT or human APP locus, a CRISPRi-based therapeutic agent targeting the human MAPT or human APP locus, allogeneic human MSCs, SNK01 (autologous natural killer cells), allogeneic adipose-derived MSC exosomes, CA-AC-02 (placenta-derived MSCs), HUVEC-derived MSCs (NEUROSTEM), and AstroStem (autologous adipose-derived MSCs). In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 44-48. In some embodiments, the VL domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment is an IgG-scFv, nanobody, BiTE, diabody,The anti-tau antibody includes DART, TandAb, scDiabody, scDiabody-CH3, Triplebody, Mini-Antibody, Minibody, TriBiMinibody, 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, Diabody-Fc, Tandem scFv-Fc, or Intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 tau polypeptides containing phosphorylation at a site selected from the group consisting of 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 tau polypeptides containing phosphorylation at the pT217-tau site. In some embodiments, the anti-tau antibody or its antigen-binding fragment specifically binds to tau polypeptides containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism,This includes subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 neurodegenerative disease in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from reference subjects are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in a dose between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject by intravenous administration in a dose between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments,The first 3 doses administered to the subject include a dosage of about 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first 3 doses administered is about 1400 mg of the therapeutic agent. In some embodiments, it is systemic administration of the therapeutic agent. In some embodiments, the systemic administration includes i.v. administration of the therapeutic agent. In some embodiments, the systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, the systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 55 and a LC comprising the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 57 and a LC comprising the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 57 and a LC comprising the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 60 and a LC comprising the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 62 and a LC comprising the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 64 and a LC comprising the sequence of SEQ ID NO: 65. In some embodiments, the systemic administration includes subcutaneous administration of the therapeutic agent. In some embodiments, the systemic administration includes oral administration of the therapeutic agent. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 55 and a LC comprising the sequence of SEQ ID NO: 56. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 57 and a LC comprising the sequence of SEQ ID NO: 58. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 57 and a LC comprising the sequence of SEQ ID NO: 59. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 60 and a LC comprising the sequence of SEQ ID NO: 61. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 62 and a LC comprising the sequence of SEQ ID NO: 63. In some embodiments, the anti-tau antibody includes a HC comprising the sequence of SEQ ID NO: 64 and a LC comprising the sequence of SEQ ID NO: 65.

[0023] In a particular embodiment, a method for treating neurodegenerative disease in a subject, the method comprising: (a) receiving data obtained by detecting the level of pT217 tau in a sample derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises performing an immunoassay on the sample using an anti-tau antibody or an 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 NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23, and the VL domain comprises an HCDR1 sequence selected from SEQ ID NOs: 24-31 A method is described herein that includes the steps of: (b) a step of including an LCDR1 sequence, an LCDR2 sequence selected from SEQ ID NOs. 32-36, and an LCDR3 sequence selected from SEQ ID NOs. 37-43; (c) a step of analyzing the possibility of a clinical diagnosis of neurodegenerative disease in a subject based on at least part of the receiving step; (d) a step of providing an early prognostic diagnosis of neurodegenerative disease in a subject based on the analyzing step, wherein the early prognostic diagnosis precedes a step of providing a diagnosis of a prodromal stage of neurodegenerative disease in a subject; and (d) a step of initiating a treatment comprising the administration of a formulation containing a therapeutic agent, wherein the determination of the initiating step is, at least part of the providing step, based on the providing step, the therapeutic agent is selected from tau inhibitors listed in Table 10. In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs. 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 a sequence selected from sequence numbers 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 phosphorylation at a site selected from the group consisting of 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 phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau and pT231-tau sites.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis.In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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 a particular embodiment, 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 derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau CSF levels derived from a plurality of reference samples, wherein the detection step comprises performing an immunoassay on the sample using an anti-tau antibody or an 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 NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23, and the VL domain comprises an LC sequence selected from SEQ ID NOs: 24-31 A method is described herein that includes the steps of: (b) a step of including a DR1 sequence, an LCDR2 sequence selected from SEQ ID NOs. 32-36, and an LCDR3 sequence selected from SEQ ID NOs. 37-43; (c) a step of analyzing the possibility of a clinical diagnosis of neurodegenerative disease in a subject based on at least part of the receiving step; (d) a step of providing an early prognostic diagnosis of neurodegenerative disease in a subject based on the analyzing step, wherein the early prognostic diagnosis precedes a step of providing a diagnosis of a prodromal stage of neurodegenerative disease in a subject; and (d) a step of initiating a treatment comprising the administration of a formulation containing a therapeutic agent, wherein the determination of the initiating step is, at least part of the providing step, based on the providing step, the therapeutic agent is selected from an amyloid-beta peptide inhibitor listed in Table 10. In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs. 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 a sequence selected from sequence numbers 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 phosphorylation at a site selected from the group consisting of 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 phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau and pT231-tau sites.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis.In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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.

[0025] In a particular embodiment, 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 derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises performing an immunoassay on the sample using an anti-tau 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 NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23, and the VL domain comprises an L sequence selected from SEQ ID NOs: 24-31 A method is described herein that includes the steps of: (b) a step of including a CDR1 sequence, an LCDR2 sequence selected from SEQ ID NOs. 32-36, and an LCDR3 sequence selected from SEQ ID NOs. 37-43; (c) a step of analyzing the possibility of a clinical diagnosis of neurodegenerative disease in a subject based on at least part of the receiving step; (d) a step of providing an early prognostic diagnosis of neurodegenerative disease in a subject based on the analyzing step, wherein the early prognostic diagnosis precedes a step of providing a diagnosis of a prodromal stage of neurodegenerative disease in a subject; and (d) a step of initiating a treatment comprising the administration of a formulation containing a therapeutic agent, wherein the determination of the initiating step is, at least part of the providing step, based on the providing step, the therapeutic agent is selected from cholinesterase inhibitors listed in Table 10. In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs. 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 a sequence selected from sequence numbers 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 phosphorylation at a site selected from the group consisting of 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 phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau and pT231-tau sites.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis.In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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.

[0026] In a particular embodiment, 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 derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises performing an immunoassay on the sample using an anti-tau antibody or an 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 NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23, and the VL domain comprises an LC sequence selected from SEQ ID NOs: 24-31 A method is described herein that includes the steps of: (b) a step of including a DR1 sequence, an LCDR2 sequence selected from SEQ ID NOs. 32-36, and an LCDR3 sequence selected from SEQ ID NOs. 37-43; (c) a step of analyzing the possibility of a clinical diagnosis of neurodegenerative disease in a subject based on at least part of the receiving step; (d) a step of providing an early prognostic diagnosis of neurodegenerative disease in a subject based on the analyzing step, wherein the early prognostic diagnosis precedes a step of providing a diagnosis of a prodromal stage of neurodegenerative disease in a subject; and (d) a step of initiating a procedure comprising administering a formulation containing a therapeutic agent, wherein the determination of the initiating step is, at least part of the providing step, based on the providing step, the therapeutic agent is selected from NMDA receptor antagonists listed in Table 10. In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from SEQ ID NOs. 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 a sequence selected from sequence numbers 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 phosphorylation at a site selected from the group consisting of 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 phosphorylation at a site of pT217-tau (p-tau217-tau protein). In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau and pT231-tau sites.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis.In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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.

[0027] In a particular embodiment, 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 derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises performing an immunoassay on the sample using an anti-tau antibody or an 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 NOs. 1-9, an HCDR2 sequence selected from SEQ ID NOs. 10-17, and an HCDR3 sequence selected from SEQ ID NOs. 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs. 24-31, sequence number A method is described herein that includes the steps of: (b) a step of including an LCDR2 sequence selected from sequence numbers 32-36 and an LCDR3 sequence selected from sequence numbers 37-43; (c) a step of at least in part of receiving, analyzing the possibility of a clinical diagnosis of neurodegenerative disease in a subject based on the receiving step; (d) a step of at least in part of analyzing, providing an early prognostic diagnosis of neurodegenerative disease in a subject, wherein the early prognostic diagnosis precedes a step of providing a diagnosis of a prodromal stage of neurodegenerative disease in a subject; and (d) a step of initiating a treatment, comprising administering a formulation containing a therapeutic agent, wherein the determination of the initiating step is at least in part of providing, based on the providing step, the therapeutic agent is selected from acetylcholinesterase and butyrylcholinesterase inhibitors listed in Table 10. In some embodiments, the VH domain contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from sequence numbers 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 a sequence selected from sequence numbers 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 phosphorylation at a site selected from the group consisting of 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 phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau and pT231-tau sites.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis.In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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.

[0028] In a particular embodiment, a method for treating neurodegenerative disease in a subject, the method comprising: (a) receiving data obtained by detecting the level of pT217 tau in a sample derived from the subject; and correlating the level of pT217 tau in the sample with standard values ​​of pT217 tau levels derived from a plurality of reference samples, wherein the detection step comprises performing an immunoassay on the sample using an anti-tau antibody or an 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 NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs: 24-31, and an LCDR1 sequence selected from SEQ ID NOs: 32-36 A method is described herein that includes the steps of: (b) a step of including an LCDR2 sequence and an LCDR3 sequence selected from SEQ ID NOs: 37-43; (c) a step of at least in part of receiving a sequence, based on the receiving step, analyzing the possibility of a clinical diagnosis of neurodegenerative disease in the subject; (d) a step of at least in part of analyzing a sequence, providing an early prognostic diagnosis of neurodegenerative disease in the subject, wherein the early prognostic diagnosis precedes a step of providing a diagnosis of a prodromal stage of neurodegenerative disease in the subject; and (d) a step of initiating a treatment comprising the administration of a formulation comprising two or more therapeutic agents, wherein the determination of the initiating step is at least in part based on the providing step, and 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 contains at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with a sequence selected from SEQ ID NOs: 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 a sequence selected from sequence numbers 49-54.In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 phosphorylation at a site selected from the group consisting of 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 phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau and pT231-tau sites.In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of neurogenesis. In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis.In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every four weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, the dose administered to the subject after the first three doses includes a dose of approximately 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.

[0029] In certain embodiments of the method, the detection of pT217 tau levels in a sample derived from a subject comprises the step of performing an immunoassay on the sample using an anti-tau antibody or its antigen-binding fragment 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 NOs: 1-9, an HCDR2 sequence selected from SEQ ID NOs: 10-17, and an HCDR3 sequence selected from SEQ ID NOs: 18-23, and the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs: 24-31, an LCDR2 sequence selected from SEQ ID NOs: 32-36, and an LCDR3 sequence selected from SEQ ID NOs: 37-43. In some embodiments, the HCDR1 sequence includes sequence number 1, the HCDR2 sequence includes sequence number 10, the HCDR3 sequence includes sequence number 18, the LCDR1 sequence includes sequence number 24, the LCDR2 sequence includes sequence number 32, and the LCDR3 sequence includes sequence number 37. In some embodiments, the HCDR1 sequence includes sequence number 2, the HCDR2 sequence includes sequence number 11, the HCDR3 sequence includes sequence number 19, the LCDR1 sequence includes sequence number 26, the LCDR2 sequence includes sequence number 34, and the LCDR3 sequence includes sequence number 39. In some embodiments, the HCDR1 sequence includes sequence number 3, the HCDR2 sequence includes sequence number 12, the HCDR3 sequence includes sequence number 18, the LCDR1 sequence includes sequence number 27, the LCDR2 sequence includes sequence number 32, and the LCDR3 sequence includes sequence number 40. In some embodiments, the HCDR1 sequence includes sequence number 4, the HCDR2 sequence includes sequence number 11, the HCDR3 sequence includes sequence number 20, the LCDR1 sequence includes sequence number 28, the LCDR2 sequence includes sequence number 35, and the LCDR3 sequence includes sequence number 41.In some embodiments, the HCDR1 sequence includes sequence number 5, the HCDR2 sequence includes sequence number 13, the HCDR3 sequence includes sequence number 21, the LCDR1 sequence includes sequence number 29, the LCDR2 sequence includes sequence number 33, and the LCDR3 sequence includes sequence number 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 sequence numbers 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 sequence numbers 49-54. In some embodiments, the anti-tau antibody or its antigen-binding fragment includes IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody. In some embodiments, the anti-tau antibody has an isotype selected from the group consisting of 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 that includes phosphorylation at a site selected from the group consisting of pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau.In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylation at the pT217-tau site. In some embodiments, an anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylation at the pT217-tau and pT231-tau sites. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Liticor-Bodig disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, This includes Pallid-Pont-nigronitus degeneration, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy. 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 in the subject are reversed. In some embodiments, the progression of one or more symptoms of a neurodegenerative disease in the subject is delayed. In some embodiments, the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually. In some embodiments, the therapeutic agent is administered directly to the subject's CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, intracisional delivery, intraspinal delivery, subpia delivery, or intraventricular delivery. In some embodiments, the subject is in the preclinical stage of a neurogenesis disorder.In some embodiments, the subject is in the prodromal stage of neurogenesis. In some embodiments, multiple reference samples are obtained from healthy individuals not suspected of having neurogenesis. In some embodiments, multiple samples from the reference subject are obtained from individuals in the early disease stage of suspected neurogenesis. In some embodiments, the therapeutic agent is administered in doses between approximately 0.1 and 100 mg / kg of body weight, according to the subject's body weight. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 200 and 1500 mg. In some embodiments, the therapeutic agent is administered to the subject intravenously in doses between approximately 700 and 1400 mg. In some embodiments, the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every approximately 4 weeks (q4week). In some embodiments, the first three doses administered to the subject include a dose of approximately 700 mg of the therapeutic agent. In some embodiments, doses administered to the subject after the first three doses include a dose of approximately 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. Embedding by reference

[0030] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent that each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference. To the extent that the publications and patents or patent applications incorporated by reference are in conflict with the disclosures contained herein, this application is intended to supersede and / or take precedence over any such conflicting material.

[0031] Various aspects of this disclosure are described in particular by the appended claims. A better understanding of the features and merits of this disclosure is obtained from the following detailed description of exemplary aspects in which the principles of this disclosure are used, and from reference to the appended drawings below. [Brief explanation of the drawing]

[0032] [Figure 1] Figure 1 shows the schema of the single-molecule array (Simoa®) used herein to assay the tau antibody described herein. After adding the substrate to the sample (sandwich ELISA on beads, 1.1), the sample is added to the Simoa® disk (1.2). The beads are given time to precipitate in the microarray wells on the disk (one bead per well) (1.3). Excess beads are then removed using sealing oil to enable imaging (1.4). Beads with a sandwich complex (positive beads) fluoresce with the substrate and are clearly visible during imaging; beads without a sandwich complex (negative) are still clearly visible during imaging but do not fluoresce (1.5). The percentage of positive beads is converted to an AEB (mean enzyme / bead) value.

[0033] [Figure 2-1]Figures 2A-2D show data for antibody 1, antibody 2, antibody 3, antibody 4, antibody 5, and antibody 6 in the Simoa® assay. Figure 2A shows data from a 2-step protocol assay in which all capture antibodies were tested against the tau-12 detector. Figure 2B shows data from a 2-step protocol assay in which all capture antibodies were tested against the HT7-BT2 detector (which detects tau in the central domain region). Figure 2C shows data from a 3-step protocol assay in which all capture antibodies were tested against the tau-12 detector. Figure 2D shows data from a 3-step protocol assay in which all capture antibodies were tested against the HT7-BT2 detector. [Figure 2-2] Same as above.

[0034] [Figure 3] Figure 3 shows ELISA data for different monoclonal antibodies against varying peptide concentrations.

[0035] [Figure 4] Figure 4 shows a diagram of an indirect ELISA assay and a graph of ELISA data for assaying antibody binding to the p-tau-217 peptide.

[0036] [Figure 5] Figure 5 shows graphs of the signal / noise (S / N) analysis of ELISA assays for antibody-2 binding to p-tau-217 peptide for 120 clinic samples derived from plasma, and graphs of the coefficient of variation (CV%) for ELISA assays for antibody-2 binding to p-tau-217 peptide for 120 clinic samples derived from plasma.

[0037] [Figure 6]Figure 6 shows a graph of the calibration curve (Cal curve) for the Simoa®-based p-tau-217 assay using antibody 2, compared to the assay using ADx p204 antibody, for groups (plates) indicated by QTx, of clinical samples derived from cerebrospinal fluid (68 CSF samples) and clinical samples derived from plasma (120 plasma samples).

[0038] [Figure 7] Figure 7 shows a graph of Simoa®-based p-tau assay-217 results using antibody 2 in individuals with a clinical diagnosis of either non-Alzheimer's disease, an unconfirmed diagnosis, or Alzheimer's disease, and a statistical analysis of correlation results in matched samples from individuals, using either plasma (Y axis) or CSF (X axis).

[0039] [Figure 8] Figure 8 shows graphs comparing the results of the Simoa®-based p-tau assay-217 using antibody 2 versus the results of the Simoa®-based p-tau assay-181 using antibody 2 for each sample, as well as a statistical analysis of the correlation results.

[0040] [Figure 9] Figure 9 shows graphs of the results of the Simoa®-based p-tau assay-217 using antibody 2 versus the results of the Simoa®-based tau assay using Innotest p-tau 181 antibody for each sample, as well as a statistical analysis of the correlation results.

[0041] [Figure 10] Figure 10 shows graphs of Simoa®-based p-tau assay results using antibody 2 as the capture antibody, antibody ADx p204 as the detector antibody, and peptide as the calibrator, as well as a statistical analysis of the correlation results.

[0042] [Figure 11]Figure 11 shows a graph of Simoa®-based p-tau assay-217 results using antibody 2, grouping together samples from individuals with a clinical diagnosis of Alzheimer's disease and control individuals, either derived from CSF or plasma.

[0043] [Figure 12] Figure 12 shows graphs of the results of the Simoa®-based p-tau assay-217 using antibody 2 for EDTA plasma samples of various concentrations, and a chart listing the coefficients of variation for each sample concentration to indicate the accuracy of the assay.

[0044] [Figure 13] Figure 13 shows a graph of the results of the Simoa®-based p-tau assay-217 using antibody 2, graphed as coefficient of variation (CV%) versus measured concentration.

[0045] [Figure 14] Figure 14 shows a graph of Simoa®-based p-tau assay-217 results using antibody 2, and a statistical analysis of parallelism, determining whether actual samples containing high endogenous analyte concentrations provide a similar degree of detection on the standard curve after dilution.

[0046] [Figure 15] Figure 15 shows graphs of Simoa®-based p-tau assay-217 results using antibody 2, and a statistical analysis of linearity, determining whether a sample matrix spiked with detection analytes exceeding the detection limit still provides reliable quantification within the standard curve range after dilution for four sample plus buffer spikes.

[0047] [Figure 16]Figure 16 shows graphs of Simoa®-based p-tau assay-217 results using antibody 2, and a statistical analysis of linearity, determining whether a sample matrix spiked with analytes above the detection limit still provides reliable quantification within the standard curve range after dilution for three samples plus a calibration sample.

[0048] [Figure 17] Figure 17 shows graphs of the Simoa®-based p-tau assay-217 results using antibody 2 in the clinical validation of the memory loss clinic cohort, and graphs of receiver operating characteristic (ROC) analysis graphed against p-tau-217 assay sensitivity.

[0049] [Figure 18] Figure 18 shows a graph of the results of the Simoa®-based p-tau assay-217 using antibody 2 against control and AD dementia individuals.

[0050] [Figure 19] Figure 19 shows graphs of Simoa®-based p-tau assay-181 results using antibodies from Quanterix®, and a chart of sample stratification, for control and AD dementia individuals.

[0051] [Figure 20] Figure 20 shows graphs of the results for Simoa®-based p-tau assay-217 using antibody 2 and Simoa®-based p-tau assay-181 using antibody from Quanterix®, with calculated coefficients of variation.

[0052] [Figure 21] Figure 21 shows graphs of the clinical performance of various p-tau Simoa®-based assays comparing sensitivity and specificity, as well as charts including statistical analysis of the results.

[0053] [Figure 22] Figure 22 shows a schematic diagram of tau, illustrating the relative positions of various protein domains and the positions of threonine residues that can be assayed for phosphorylation status using the methods disclosed herein.

[0054] [Figure 23] Figure 23 shows graphs of the reactivity of various antibodies to tau fragments using indirect ELISA with unphosphorylated T217 (Bio-pt654) and full-length tau (tau441).

[0055] [Figure 24] Figure 24 shows graphs of the reactivity to tau fragments using phosphorylated T181 (Bio-pt126) and phosphorylated T231 (Bio-pt146) in indirect ELISA for various antibodies.

[0056] [Figure 25] Figure 25 shows a diagram of an assay utilizing p-tau 217 monoclonal antibody as a capture tool for various synthetic peptides, and a graph of the results for the same assay using antibody 2 as the capture tool.

[0057] [Figure 26] Figure 26 shows Western blot analysis using various tau antibodies on brain lysate samples from AD patients or controls. [Modes for carrying out the invention]

[0058] Detailed explanation Neurodegenerative diseases such as Alzheimer's disease are complex conditions, and effective treatment requires accurate diagnosis and treatment selection. Improved compositions and methods for identifying subjects as having, or at risk of developing, a neurodegenerative disease such as Alzheimer's disease, which can be characterized by the accumulation of amyloid-beta peptide in the brain, or the deposition of abnormal phosphorylated tau, or both, are described herein. In at least part, compositions and methods are also provided for selecting subjects for treatment of neurodegenerative diseases and / or treating them based on the results of tests measuring abnormal phosphorylated tau levels in samples obtained from the subjects (e.g., blood, cerebrospinal fluid). As further described below, the inventors of this disclosure have found that abnormal phosphorylated tau is useful as a biomarker for the diagnosis and progression of tauopathy, such as Alzheimer's disease, and that antibody reagents have been developed to measure abnormal phosphorylated tau levels (e.g., p-tau-217) in a sample of interest (e.g., plasma or CSF sample).

[0059] In a secondary analysis of patients with early symptomatic Alzheimer's disease receiving donanemab in the TRAILBLAZER-ALZ randomized clinical trial (NCT03367403), the authors found that plasma biomarkers (including p-tau 217) were significantly reduced after donanemab treatment compared to placebo, starting approximately 12 weeks after the initiation of treatment, and this reduction 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. 2022 Dec 1;79(12):1250-1259. In this study, the authors found that plasma p-tau 217 levels were significantly correlated with the percentage change in amyloid plaque levels as measured by amyloid PET imaging, thus supporting the possibility that amyloid-β peptide inhibitors (e.g., donanemab, lecanemab, remternetsug, aducanumab, etc.) may be therapeutically effective in treating early symptomatic Alzheimer's disease.

[0060] Building upon the finding that abnormal phosphorylated tau levels (e.g., p-tau-217) can be used as a biomarker for diagnosis and disease progression in tauopathy, and the findings by Pontecorvo MJ, et al. that p-tau-217 can be used as a biomarker for positive early symptomatic Alzheimer's disease patient outcomes in patients treated with donanemab, this disclosure provides compositions and methods for selecting subjects for treatment with therapeutic agents (e.g., provided in Table 10 and elsewhere herein) (e.g., donanemab, lecanemab, remternetsug, aducanumab, etc.) for the treatment of neurodegenerative diseases, using antibody reagents specific to phosphorylated tau protein (e.g., p-tau-217).

[0061] Tau is an important microtubule-associated protein that is abundantly expressed in CNS neurons and plays a crucial role in normal cell physiology. Tau has also been found to be dysregulated in Alzheimer's disease and other tauopathies. Six isoforms of the tau protein are generated from the tau gene by alternative splicing. These isoforms differ from each other in the presence or absence of two N-terminal insertions and one repeat called R2. All six tau protein isoforms are highly soluble under normal and healthy cell conditions and are typically regulated by phosphorylation and dephosphorylation. Tau has been demonstrated to interact with microtubules and promote microtubule assembly. In neurons, tau promotes the formation and stabilization of axonal microtubules. Tau has a further role in driving neurite outgrowth. The impaired interaction between tau and microtubules may be a key component in the pathology, onset, and progression of tauopathies. Tau hyperphosphorylation is a hallmark feature of Alzheimer's disease and other tauopathies, and the degree of hyperphosphorylation often correlates with disease progression. Hyperphosphorylation of the tau protein can lead to the self-assembly of insoluble tangles of tau's paired helical and straight filaments. These insoluble aggregates of tangles, called neurofibrillary tangles (NFTs), are composed of hyperphosphorylated tau and are considered a pathological marker of tauopathies.

[0062] Phosphoricated tau (p-tau), total tau, and Aβ are detected in cerebrospinal fluid (CSF) and / or blood, respectively. 42CSF p-tau is an individual biomarker for Alzheimer's disease and several other related tauopathies. CSF p-tau is elevated in individuals later confirmed to have Alzheimer's disease in both the prodromal and dementia stages, compared to age- and sex-matched controls. CSF p-tau levels show a strong correlation with the degree of cognitive impairment in individuals with Alzheimer's disease. In fact, CSF p-tau levels can be used with some accuracy as a biomarker to predict progression from cognitively impaired to mild cognitive impairment (MCI) and then to Alzheimer's disease. Regarding its usefulness as a biomarker to predict even relatively early stages of Alzheimer's disease progression, CSF p-tau has been shown to be significantly increased in samples from individuals with preclinical Alzheimer's disease. Changes in the degree of p-tau phosphorylation have been demonstrated in both preclinical sporadic cases of Alzheimer's disease and early stages of autosomal dominant Alzheimer's disease. p-tau, total tau, and Aβ 42 The blood levels of these biomarkers are generally lower than CSF levels when assayed within the same individual, and if the blood levels of these biomarkers can be assayed with sufficient specificity and precision, they can be used as informative biomarkers for Alzheimer's disease and other related tauopathies.

[0063] Several phosphorylation sites contributing to hyperphosphorylated tau that aggregates into NFTs have been identified. The longest tau isoforms contain 79 potential serine or threonine phosphorylation sites, of which at least 30 have been identified as phosphorylated in NFT aggregates. A common site used to assay tau molecules for phosphorylation status is threonine-181. CSF solutions contain arrays of tau fragments in varying abundances. Tau fragments from the N-terminal and mid-regions of tau polypeptides are considerably more abundant in CSF samples than C-terminal tau fragments. Plasma samples derived from individuals also contain tau polypeptides and tau polypeptide fragments, although these 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 crucial component as a metric for diagnosis, disease staging, and measuring the effectiveness of treatments for Alzheimer's disease and other tauopathy. The detection and measurement of p-tau levels at specific disease-associated residues in plasma samples will be a significant asset in developing more sensitive and precisely engineered diagnoses, prognoses, and disease analyses for individuals at risk of developing Alzheimer's disease or other tauopathies, or those in the early stages of Alzheimer's disease or other tauopathies. Phosphorylation of tau at threonine 217 (p-tau 217) is one such residue that is particularly targeted in the development of novel biomarkers and diagnostic assays. Changes in p-tau biomarker concentrations in CSF and plasma are thought to precede measurable behavioral or cognitive changes in Alzheimer's disease and other tauopathies. The development of novel assays that allow for a specific range of points and degrees of tau phosphorylation at a particular residue will undoubtedly be useful in clinically relevant medical diagnostic and treatment decisions. Comparison of results from novel assays with results from existing assays can also lead to further medically informative decisions.Results from plasma-based tau biomarker assays can be compared to matched CSF samples (detecting CSF p-tau or CSF-soluble Aβ) and also to positron emission tomography (PET) scans that detect the degree and location of Aβ aggregates, particularly as a benchmark for their usefulness in preclinical or early disease stage analysis.

[0064] The need remains to prevent, slow the progression of, and effectively treat neurodegenerative disorders, which include various tauopathies. Currently, there are limited options, with limited opportunities for success, to attempt to treat patients with tauopathies using existing pathomodulatory therapies. Current challenges in treating tauopathies include the lack of ability to diagnose the condition at an early stage before significant neurodegeneration occurs. Another significant obstacle is the lack of effective therapies that can alter, delay, halt, or correct the pathology that causes the progression of tauopathies. Tau antibody

[0065] Antibodies that bind to tau are provided herein. In some examples, the antibodies that bind to tau are monoclonal antibodies. In certain embodiments, anti-tau antibodies are disclosed herein. In some examples, the anti-tau antibodies bind specifically to mammalian tau. In some examples, the anti-tau antibodies bind specifically to human tau. In some examples, the anti-tau antibodies bind specifically to the N-terminal portion of tau. In some examples, the anti-tau antibodies bind specifically to the N-terminal portion of human tau. In some examples, the anti-tau antibodies bind specifically to a portion of tau containing protein domain P2. In some examples, the anti-tau antibodies bind specifically to a portion of human tau containing protein domain P2. In some examples, the anti-tau antibodies bind specifically to a portion of tau containing protein domain P1. In some examples, the anti-tau antibodies bind specifically to a portion of human tau containing protein domain P1. In some examples, the anti-tau antibodies bind specifically to a portion of tau containing protein domains P1 and P2. In some examples, the anti-tau antibodies bind specifically to a portion of human tau containing protein domains P1 and P2.

[0066] 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 a sequence selected from SEQ ID NOs: 1 to 9, a heavy chain CDR2 (HCDR2) sequence containing a sequence selected from SEQ ID NOs: 10 to 17, and a heavy chain CDR3 (HCDR3) sequence containing a sequence selected from SEQ ID NOs: 18 to 23. In some embodiments, the VL domain comprises a light chain CDR1 (LCDR1) sequence containing a sequence selected from SEQ ID NOs: 24 to 31, a light chain CDR2 (LCDR2) sequence containing a sequence selected from SEQ ID NOs: 32 to 36, and a light chain CDR3 (LCDR3) sequence containing a sequence selected from SEQ ID NOs: 37 to 43.

[0067] In some embodiments, the VH region of the anti-tau antibody includes HCDR1, HCDR2, and HCDR3 sequences selected from Table 1. [Table 1-1] [Table 1-2]

[0068] In some embodiments, the VH region includes an HCDR1 sequence containing sequence number 1; an HCDR2 sequence containing sequence number 10; and an HCDR3 sequence containing sequence number 18. In some embodiments, the VH region includes an HCDR1 sequence containing sequence number 2; an HCDR2 sequence containing sequence number 11; and an HCDR3 sequence containing sequence number 19. In some embodiments, the VH region includes an HCDR1 sequence containing sequence number 3; an HCDR2 sequence containing sequence number 12; and an HCDR3 sequence containing sequence number 18. In some embodiments, the VH region includes an HCDR1 sequence containing sequence number 4; an HCDR2 sequence containing sequence number 11; and an HCDR3 sequence containing sequence number 20. In some embodiments, the VH region includes an HCDR1 sequence containing sequence number 5; an HCDR2 sequence containing sequence number 13; and an HCDR3 sequence containing sequence number 21. In some embodiments, the VH region includes an HCDR1 sequence containing sequence number 6; an HCDR2 sequence containing sequence number 14; and an HCDR3 sequence containing sequence number 22. In some embodiments, the VH region includes an HCDR1 sequence containing sequence number 7; an HCDR2 sequence containing sequence number 15; and an HCDR3 sequence containing sequence number 19. In some embodiments, the VH region includes an HCDR1 sequence containing sequence number 8; an HCDR2 sequence containing sequence number 16; and an HCDR3 sequence containing sequence number 19. In some embodiments, the VH region includes an HCDR1 sequence containing sequence number 9; an HCDR2 sequence containing sequence number 17; and an HCDR3 sequence containing sequence number 23.

[0069] In some embodiments, the VL region of the anti-tau antibody includes LCDR1, LCDR2, and LCDR3 sequences selected from Table 2. [Table 2-1] [Table 2-2]

[0070] In some embodiments, the VL region includes an LCDR1 sequence containing sequence number 24; an LCDR2 sequence containing sequence number 32; and an LCDR3 sequence containing sequence number 37. In some embodiments, the VL region includes an LCDR1 sequence containing sequence number 25; an LCDR2 sequence containing sequence number 33; and an LCDR3 sequence containing sequence number 38. In some embodiments, the VL region includes an LCDR1 sequence containing sequence number 26; an LCDR2 sequence containing sequence number 34; and an LCDR3 sequence containing sequence number 39. In some embodiments, the VL region includes an LCDR1 sequence containing sequence number 27; an LCDR2 sequence containing sequence number 32; and an LCDR3 sequence containing sequence number 40. In some embodiments, the VL region includes an LCDR1 sequence containing sequence number 28; an LCDR2 sequence containing sequence number 35; and an LCDR3 sequence containing sequence number 41. In some embodiments, the VL region includes an LCDR1 sequence containing sequence number 29; an LCDR2 sequence containing sequence number 33; and an LCDR3 sequence containing sequence number 42. In some embodiments, the VL region includes an LCDR1 sequence containing sequence number 30; an LCDR2 sequence containing RAS; and an LCDR3 sequence containing sequence number 38. In some embodiments, the VL region includes an LCDR1 sequence containing sequence number 31; an LCDR2 sequence containing sequence number 36; and an LCDR3 sequence containing sequence number 44.

[0071] 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, nanobody, mini-antibody, minibody, 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 intrabody. In some embodiments, the anti-tau antibody includes a bispecific antibody. In some embodiments, the anti-tau antibody includes a polyspecific antibody. 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 includes a light chain, which is a kappa chain.

[0072] 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-concept of the tau protein. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any one of positions 1 to 441. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any one of positions 152 to 400. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any one of positions 198 to 275. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any one of positions 244 to 369. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any one of positions 152 to 275. In some embodiments, the anti-tau antibody specifically binds to the tau protein at any one of positions 152 to 244. In some embodiments, the anti-tau antibody specifically binds to the tau protein at one of the following positions: 181, 217, or 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.

[0073] In some embodiments, the anti-tau antibody specifically binds to phosphorylated tau protein. In some embodiments, the anti-tau antibody specifically binds to tau protein phosphorylated at any one of positions 1 to 441. In some embodiments, the anti-tau antibody specifically binds to tau protein phosphorylated at any one of positions 1 to 441, and any combination of the following residues is phosphorylated: Y18, S46, S68, T69, T71, S113, T123, T153, T175, T181, S184, S185, S191, Y197, S 198, 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, and one or any combination of phosphorylated serine, threonine, or tyrosine residues is Y18, S46, S68, T69, T71, S113, T123, T153, T175, T181, S184, S Selected from 185, 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, and S435. In some embodiments, the anti-tau antibody specifically binds to a tau protein phosphorylated at any one of positions 152 to 400. In some embodiments, the anti-tau antibody specifically binds to a tau protein phosphorylated at any one of positions 198 to 275. In some embodiments, the anti-tau antibody specifically binds to a tau protein phosphorylated at any one of positions 244-369. In some embodiments, the anti-tau antibody specifically binds to a tau protein phosphorylated at any one of positions 152-275.In some embodiments, the anti-tau antibody specifically binds to tau protein phosphorylated at any one of positions 152-244. In some embodiments, the anti-tau antibody specifically binds to tau protein phosphorylated at any one of positions 181, 217, or 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 tau protein phosphorylated 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 the phosphorylated residue T181 in the tau protein. In some embodiments, the anti-tau antibody specifically binds to tau protein phosphorylated at position 217. In some embodiments, the anti-tau antibody specifically binds to the phosphorylated residue T217 in the 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 tau protein phosphorylated at position 231. In some embodiments, the anti-tau antibody specifically binds to the phosphorylated residue T231 in the 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 points to the positions of the full-length 441 amino acid isoforms of human microtubule-associated protein tau (MAPT; NBCI gene ID: 4137; exemplary protein sequence - NBCI entry: 7SP1_A).

[0074] In some embodiments, the anti-tau antibody has a binding affinity to human tau of approximately 100 pM to approximately 3 nM. In some embodiments, the anti-tau antibody has a binding affinity to human tau of approximately 100 pM to approximately 300 pM. In some embodiments, the anti-tau antibody has a binding affinity to human tau of approximately 100 pM to approximately 500 pM. In some embodiments, the anti-tau antibody has a binding affinity to human tau of approximately 100 pM to approximately 800 pM. In some embodiments, the anti-tau antibody has a binding affinity to human tau of approximately 300 pM to approximately 600 pM. In some embodiments, the anti-tau antibody has a binding affinity to human tau of approximately 300 pM to approximately 900 pM. In some embodiments, the anti-tau antibody has a binding affinity to human tau of approximately 400 pM to approximately 1 nM. In some embodiments, the anti-tau antibody has a binding affinity to human tau of approximately 500 pM to approximately 1.5 nM. In some embodiments, the anti-tau antibody has a binding affinity for human tau of approximately 500 pM to 2 nM. In some embodiments, the anti-tau antibody has a binding affinity for human tau of approximately 600 pM to 3 nM. In some embodiments, the anti-tau antibody has a binding affinity for human tau of approximately 100 pM to approximately 3 nM.

[0075] In some embodiments, the anti-tau antibody has a binding affinity to phosphorylated human tau of approximately 100 pM to 300 pM. In some embodiments, the anti-tau antibody has a binding affinity to phosphorylated human tau of approximately 100 pM to 500 pM. In some embodiments, the anti-tau antibody has a binding affinity to phosphorylated human tau of approximately 100 pM to 800 pM. In some embodiments, the anti-tau antibody has a binding affinity to phosphorylated human tau of approximately 300 pM to 600 pM. In some embodiments, the anti-tau antibody has a binding affinity to phosphorylated human tau of approximately 300 pM to 900 pM. In some embodiments, the anti-tau antibody has a binding affinity to phosphorylated human tau of approximately 400 pM to 1 nM. In some embodiments, the anti-tau antibody has a binding affinity to phosphorylated human tau of approximately 500 pM to 1.5 nM. In some embodiments, the anti-tau antibody has a binding affinity of approximately 500 pM to 2 nM for phosphorylated human tau. In some embodiments, the anti-tau antibody has a binding affinity of approximately 600 pM to 3 nM for phosphorylated human tau.

[0076] In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 300 pM for threonine-phosphorylated tau 181 (p-tau 181). In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 500 pM for p-tau 181. In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 800 pM for p-tau 181. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 600 pM for p-tau 181. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 900 pM for p-tau 181. In some embodiments, the anti-tau antibody has a binding affinity of approximately 400 pM to 1 nM for p-tau 181. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-181 of approximately 500 pM to 1.5 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-181 of approximately 500 pM to 2 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-181 of approximately 600 pM to 3 nM.

[0077] In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 300 pM for threonine-phosphorylated tau-212 (p-tau-212). In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 500 pM for p-tau-212. In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 800 pM for p-tau-212. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 600 pM for p-tau-212. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 900 pM for p-tau-212. In some embodiments, the anti-tau antibody has a binding affinity of approximately 400 pM to 1 nM for p-tau-212. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-212 of approximately 500 pM to 1.5 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-212 of approximately 500 pM to 2 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-212 of approximately 600 pM to 3 nM.

[0078] In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 300 pM for serine-phosphorylated tau-214 (p-tau-214). In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 500 pM for p-tau-214. In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 800 pM for p-tau-214. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 600 pM for p-tau-214. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 900 pM for p-tau-214. In some embodiments, the anti-tau antibody has a binding affinity of approximately 400 pM to 1 nM for p-tau-214. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-214 of approximately 500 pM to 1.5 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-214 of approximately 500 pM to 2 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-214 of approximately 600 pM to 3 nM.

[0079] In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 300 pM for threonine-phosphorylated tau-217 (p-tau-217). In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 500 pM for p-tau-217. In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 800 pM for p-tau-217. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 600 pM for p-tau-217. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 900 pM for p-tau-217. In some embodiments, the anti-tau antibody has a binding affinity of approximately 400 pM to 1 nM for p-tau-217. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-217 of approximately 500 pM to 1.5 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-217 of approximately 500 pM to 2 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-217 of approximately 600 pM to 3 nM.

[0080] In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 300 pM for threonine-phosphorylated tau-220 (p-tau-220). In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 500 pM for p-tau-220. In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 800 pM for p-tau-220. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 600 pM for p-tau-220. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 900 pM for p-tau-220. In some embodiments, the anti-tau antibody has a binding affinity of approximately 400 pM to 1 nM for p-tau-220. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-220 of approximately 500 pM to 1.5 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-220 of approximately 500 pM to 2 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-220 of approximately 600 pM to 3 nM.

[0081] In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 300 pM for threonine-phosphorylated tau 231 (p-tau 231). In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 500 pM for p-tau 231. In some embodiments, the anti-tau antibody has a binding affinity of approximately 100 pM to 800 pM for p-tau 231. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 600 pM for p-tau 231. In some embodiments, the anti-tau antibody has a binding affinity of approximately 300 pM to 900 pM for p-tau 231. In some embodiments, the anti-tau antibody has a binding affinity of approximately 400 pM to 1 nM for p-tau 231. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-231 of approximately 500 pM to 1.5 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-231 of approximately 500 pM to 2 nM. In some embodiments, the anti-tau antibody has a binding affinity for p-tau-231 of approximately 600 pM to 3 nM.

[0082] Antibodies containing any sequence shown in Table 3 or Table 4 are described herein. [Table 3] [Table 4-1] [Table 4-2]

[0083] In some embodiments, the heavy chain region (VH) of the variable domain includes an amino acid sequence having at least 70% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 80% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 85% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 90% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 91% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 92% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 93% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 94% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 95% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 96% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 97% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 98% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence having at least 99% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence following any one of SEQ ID NOs: 44-48.

[0084] In some embodiments, VH includes an amino acid sequence of at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence of at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence of at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence of at least 110 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence of at least 115 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH includes an amino acid sequence of at least 120 consecutive amino acid residues from any one of SEQ ID NOs: 44-48.

[0085] In some embodiments, VH comprises an amino acid sequence of at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 80% sequence identity with at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 80% sequence identity with at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 80% sequence identity with at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 80% sequence identity with at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 80% sequence identity with at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 80% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 80% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 110 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 80% sequence identity with at least 110 consecutive amino acid residues from any one of SEQ ID NOs: 44-48.In some embodiments, VH comprises an amino acid sequence of at least 115 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 80% sequence identity with at least 115 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 120 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 80% sequence identity with at least 120 consecutive amino acid residues from any one of SEQ ID NOs: 44-48.

[0086] In some embodiments, VH comprises an amino acid sequence of at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 90% sequence identity with at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 90% sequence identity with at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 90% sequence identity with at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 90% sequence identity with at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NOs. 44-48 and has at least 90% sequence identity with at least 90 consecutive amino acid residues from any one of SEQ ID NOs. 44-48. In some embodiments, VH comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NOs. 44-48 and has at least 90% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NOs. 44-48. In some embodiments, VH comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NOs. 44-48 and has at least 90% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NOs. 44-48. In some embodiments, VH comprises an amino acid sequence of at least 110 consecutive amino acid residues from any one of SEQ ID NOs. 44-48 and has at least 90% sequence identity with at least 110 consecutive amino acid residues from any one of SEQ ID NOs. 44-48.In some embodiments, VH comprises an amino acid sequence of at least 115 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 90% sequence identity with at least 115 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 120 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 90% sequence identity with at least 120 consecutive amino acid residues from any one of SEQ ID NOs: 44-48.

[0087] In some embodiments, VH comprises an amino acid sequence of at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 95% sequence identity with at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 95% sequence identity with at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 95% sequence identity with at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 95% sequence identity with at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 95% sequence identity with at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 95% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 95% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 110 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 95% sequence identity with at least 110 consecutive amino acid residues from any one of SEQ ID NOs: 44-48.In some embodiments, VH comprises an amino acid sequence of at least 115 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 95% sequence identity with at least 115 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 120 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 95% sequence identity with at least 120 consecutive amino acid residues from any one of SEQ ID NOs: 44-48.

[0088] In some embodiments, VH comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 99% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 99% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 110 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 99% sequence identity with at least 110 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 115 consecutive amino acid residues from any one of SEQ ID NOs: 44-48 and has at least 99% sequence identity with at least 115 consecutive amino acid residues from any one of SEQ ID NOs: 44-48. In some embodiments, VH comprises an amino acid sequence of at least 120 consecutive amino acid residues from any one of SEQ ID NOs: 44-48, and has at least 99% sequence identity with at least 120 consecutive amino acid residues from any one of SEQ ID NOs: 44-48.

[0089] In some embodiments, the light chain region (VL) of the variable domain includes an amino acid sequence having at least 70% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, the VL includes an amino acid sequence having at least 80% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, the VL includes an amino acid sequence having at least 85% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, the VL includes an amino acid sequence having at least 90% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, the VL includes an amino acid sequence having at least 91% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, the VL includes an amino acid sequence having at least 92% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, the VL includes an amino acid sequence having at least 93% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence having at least 94% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence having at least 95% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence having at least 96% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence having at least 97% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence having at least 98% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence having at least 99% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence following any one of SEQ ID NOs: 49-54.

[0090] In some embodiments, VL includes an amino acid sequence of at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 49-54.

[0091] In some embodiments, VL includes an amino acid sequence of at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 80% sequence identity with at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 80% sequence identity with at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 80% sequence identity with at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 80% sequence identity with at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 80% sequence identity with at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 80% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 80% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 49-54.

[0092] In some embodiments, VL includes an amino acid sequence of at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 90% sequence identity with at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 90% sequence identity with at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 90% sequence identity with at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 90% sequence identity with at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL comprises an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 90% sequence identity with at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL comprises an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 90% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 90% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 49-54.

[0093] In some embodiments, VL includes an amino acid sequence of at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 95% sequence identity with at least 50 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 95% sequence identity with at least 60 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 95% sequence identity with at least 70 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 95% sequence identity with at least 80 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 95% sequence identity with at least 90 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 95% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 95% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 49-54. In some embodiments, VL includes an amino acid sequence of at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 49-54 and has at least 99% sequence identity with at least 100 consecutive amino acid residues from any one of SEQ ID NOs: 49-54.In some embodiments, VL comprises an amino acid sequence of at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 49 to 54, and has at least 99% sequence identity with at least 105 consecutive amino acid residues from any one of SEQ ID NOs: 49 to 54.

[0094] In some embodiments, VH includes an amino acid sequence having at least 70% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 70% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 80% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 80% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 85% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 85% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 90% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 90% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 91% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 91% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 92% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 92% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 93% sequence identity with an amino acid sequence following any one of sequence numbers 44 to 48, and VL includes an amino acid sequence having at least 93% sequence identity with an amino acid sequence following any one of sequence numbers 49 to 54.In some embodiments, VH includes an amino acid sequence having at least 94% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 94% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 95% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 95% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 96% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 96% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 97% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 97% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 98% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 98% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54. In some embodiments, VH includes an amino acid sequence having at least 99% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 44-48, and VL includes an amino acid sequence having at least 99% sequence identity with an amino acid sequence following any one of SEQ ID NOs: 49-54.

[0095] In some embodiments, VH includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 70% sequence identity with the amino acid sequence according to SEQ ID NO: 35. In some embodiments, VH includes an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 80% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, VH includes an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 85% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, VH includes an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 90% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, VH includes an amino acid sequence having at least 91% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 91% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, VH includes an amino acid sequence having at least 92% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 92% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, VH includes an amino acid sequence having at least 93% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 93% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, VH includes an amino acid sequence having at least 94% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 94% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, VH includes an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 44; and VL includes an amino acid sequence having at least 95% sequence identity with the amino acid sequence according to SEQ ID NO: 49.In some embodiments, VH includes an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 96% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, VH includes an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 97% sequence identity with the amino acid sequence according to SEQ ID NO: 49. In some embodiments, VH includes an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to SEQ ID NO: 44; VL includes an amino acid sequence having at least 98% sequence identity with the amino acid sequence according to ...

Claims

1. A method for treating a neurodegenerative disease in a subject, wherein the neurodegenerative disease is characterized by the accumulation of amyloid-beta (Aβ) peptide in the brain of the subject, and the method comprises the step of administering to the subject, for treatment of the neurodegenerative disease, a therapeutic agent comprising (i) an inhibitor of the Aβ peptide or a modified form thereof, or (ii) an inhibitor of phosphorylated tau protein, wherein the subject is identified for treatment based on the measured level of p-tau 217 in a sample obtained from the subject, which is higher than the measured level of p-tau 217 in a sample having standard values ​​of phosphorylated tau 217 levels derived from a plurality of reference samples from a reference subject that does not have the neurodegenerative disease, and this predicts that the subject has abnormal tau protein deposition in the brain with a sensitivity of more than or equal to about 85%.

2. The method according to claim 1, wherein the p-tau 217 is measured in the sample by a method comprising the step of performing an immunoassay on the sample using an anti-tau antibody or an antigen-binding fragment thereof.

3. The method according to claim 2, wherein the immunoassay is a digital immunoassay configured to measure the p-tau 217 in a sample which is a liquid sample.

4. The method according to claim 3, wherein the digital immunoassay is a single-molecule array (SIMOA).

5. The method according to claim 2, wherein the immunoassay comprises an enzyme-conjugated immunoassay (ELISA), a radioimmunoassay (RIA), a fluorescent immunoassay (FIA), a chemiluminescent immunoassay (CLIA), or a counting immunoassay (CIA).

6. The anti-tau antibody or the antigen-binding fragment thereof a. A heavy chain comprising a variable heavy chain (VH) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NOs: 1 to 9, an HCDR2 sequence selected from SEQ ID NOs: 10 to 17, and an HCDR3 sequence selected from SEQ ID NOs: 18 to 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 NOs: 24-31, an LCDR2 sequence selected from SEQ ID NOs: 32-36, and an LCDR3 sequence selected from SEQ ID NOs: 37-43. The method according to claim 2, including the method described in claim 2.

7. a. The HCDR1 sequence includes sequence number 2, the HCDR2 sequence includes sequence number 11, and the HCDR3 sequence includes sequence number 19; b. The LCDR1 sequence includes sequence number 25, the LCDR2 sequence includes sequence number 33, and the LCDR3 sequence includes sequence number 38. The method according to claim 6.

8. a. The HCDR1 sequence includes sequence number 1, the HCDR2 sequence includes sequence number 10, and the HCDR3 sequence includes sequence number 18; b. The LCDR1 sequence includes sequence number 24, the LCDR2 sequence includes sequence number 32, and the LCDR3 sequence includes sequence number 37. The method according to claim 6.

9. a. The HCDR1 sequence includes sequence number 2, the HCDR2 sequence includes sequence number 11, and the HCDR3 sequence includes sequence number 19; b. The LCDR1 sequence includes sequence number 26, the LCDR2 sequence includes sequence number 34, and the LCDR3 sequence includes sequence number 39. The method according to claim 6.

10. a. The HCDR1 sequence includes sequence number 3, the HCDR2 sequence includes sequence number 12, and the HCDR3 sequence includes sequence number 18; b. The LCDR1 sequence includes sequence number 27, the LCDR2 sequence includes sequence number 32, and the LCDR3 sequence includes sequence number 40. The method according to claim 6.

11. a. The HCDR1 sequence includes sequence number 4, the HCDR2 sequence includes sequence number 11, and the HCDR3 sequence includes sequence number 20; b. The LCDR1 sequence includes sequence number 28, the LCDR2 sequence includes sequence number 35, and the LCDR3 sequence includes sequence number 41. The method according to claim 6.

12. a. The HCDR1 sequence includes sequence number 5, the HCDR2 sequence includes sequence number 13, and the HCDR3 sequence includes sequence number 21; b. The LCDR1 sequence includes sequence number 29, the LCDR2 sequence includes sequence number 33, and the LCDR3 sequence includes sequence number 42. The method according to claim 6.

13. The method according to claim 1, wherein the anti-tau antibody comprises a heavy chain (HC) sequence including SEQ ID NO: 57 and a light chain (LC) sequence including SEQ ID NO:

58.

14. The method according to claim 1, wherein the anti-tau antibody comprises an HC sequence including SEQ ID NO: 57 and an LC sequence including SEQ ID NO:

59.

15. The method according to claim 1, wherein the anti-tau antibody comprises an HC sequence including SEQ ID NO: 60 and an LC sequence including SEQ ID NO:

61.

16. The method according to claim 1, wherein the anti-tau antibody comprises an HC sequence including SEQ ID NO: 62 and an LC sequence including SEQ ID NO:

63.

17. The method according to claim 1, wherein the anti-tau antibody comprises an HC sequence including SEQ ID NO: 64 and an LC sequence including SEQ ID NO:

65.

18. The method according to claim 1, wherein the anti-tau antibody comprises an HC sequence including SEQ ID NO: 55 and an LC sequence including SEQ ID NO:

56.

19. The method according to claim 1, wherein the anti-tau antibody comprises a variable weight (VH) domain containing 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 NOs: 44 to 48.

20. The method according to claim 1, wherein the anti-tau antibody comprises a variable light (VL) domain having at least 80%, at least 85%, at least 90%, or at least 95% sequence identity with a sequence selected from SEQ ID NOs: 49 to 54.

21. The method according to claim 1, wherein the anti-tau antibody or its antigen-binding fragment comprises IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scdiabody, scdiabody-CH3, triplebody, mini-antibody, minibody, TriBi minibody, 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, diabody-Fc, tandem scFv-Fc, or intrabody.

22. The method according to claim 1, wherein the anti-tau antibody has an isotype selected from the group consisting of IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM.

23. The method according to claim 1, wherein the anti-tau antibody or its antigen-binding fragment specifically binds to an epitope in the N-terminal region of a tau polypeptide.

24. The method according to claim 1, wherein the anti-tau antibody or its antigen-binding fragment specifically binds to the p-tau 217-tau protein.

25. The method according to claim 1, wherein the anti-tau antibody or its antigen-binding fragment specifically binds to the cis-conformation of the p-tau 217-tau protein.

26. The method according to claim 1, wherein the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at a site selected from the group consisting of pT181-tau, pT212-tau, phosphorylated serine (pS)214-tau, pT217-tau, pT220-tau, and pT231-tau.

27. The method according to claim 1, wherein the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide that includes phosphorylation at the pT217-tau site.

28. The method according to claim 1, wherein the anti-tau antibody or its antigen-binding fragment specifically binds to a tau polypeptide containing phosphorylation at the pT217-tau and pT231-tau sites.

29. The method according to claim 1, wherein the subject has or is suspected of having Alzheimer's disease (AD).

30. The method according to claim 29, wherein the AD causes, is associated with, or presents tauopathy in the subject.

31. The method according to claim 30, wherein the tauopathy includes a secondary tauopathy comprising neurofibrillary tangle (NTF) pathology in the brain of the subject, and the tauopathy is secondary to amyloid-beta plaques in the brain of the subject.

32. The method according to claim 30, wherein AD comprises a variant AD selected from the group consisting of early-onset Alzheimer's disease, late-onset Alzheimer's disease, familial Alzheimer's disease (FAD), mixed dementia including Alzheimer's disease and vascular dementia, logopenic aphasia, posterior cortical atrophy, frontotemporal Alzheimer's disease, and Alzheimer's disease combined with corticobasal syndrome (AD-CBS).

33. The method according to claim 30, wherein the tauopathy comprises hyperphosphorylated tau, misfolded tau, oligomeric tau, tau aggregated paired helical filaments (PFH), neurofibrillary tangles (NFT), or any combination thereof.

34. The method according to claim 1, wherein the subject is a human being 60 years of age or older.

35. The aforementioned neurodegenerative diseases include Alzheimer's disease, Pick's disease, Niemann-Pick disease type C, frontotemporal dementia (FTD), frontotemporal lobar degeneration, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Litikordeg disease, neurofibrillary tangle-dominant senile dementia, meningiomatosis, primary age-related tauopathy (PART), argyrophilic granulopathy (AGD), glial tauopathy (GGT), vacuolar tauopathy, tuberous sclerosis, post-encephalitis parkinsonism, subacute sclerosing panencephalitis, amyotrophic lateral sclerosis, myotonic dystrophy, and pallid-pont-nisnios. The method according to claim 1, comprising degenerative diseases, Parkinson's disease, Creutzfeldt-Jakob disease, boxer's dementia, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, diffuse neurofibrillary tangles with calcification, neurofibrillary tangle-type senile dementia, Haller-Holden-Spats disease, mild cognitive impairment (MCI), Lewy body disease (LBD), amyotrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, Wernicke-Korsakoff syndrome, prion diseases, vascular dementia, Alzheimer's-related dementia, Huntington's disease (HD), or transgene-induced tauopathy.

36. The method according to claim 1, wherein the neurodegenerative disease is Alzheimer's disease.

37. The method according to claim 36, wherein the prodromal stage of Alzheimer's disease is characterized by mild cognitive impairment (MCI).

38. The method according to claim 36, wherein the prodromal stage of Alzheimer's disease is characterized as at least as Braak stage I, based on the degree of spatial determination by tau-PET.

39. The method according to claim 36, wherein the prodromal stage of Alzheimer's disease is characterized as at least as Braak stage II based on the degree of spatial determination by tau-PET.

40. The method according to claim 1, wherein the neurodegenerative disease is a tauopathy comprising hyperphosphorylated tau, misfolded tau, oligomeric tau, tau aggregated paired helical filaments (PFH), neurofibrillary tangles (NFT), or any combination thereof.

41. The inhibitors of the Aβ peptide or the modified forms of the Aβ peptide include ABvac40, ABBV-916, ACU193, AD-35, aducanumab (Aduhelm®), APH-1105, BPN14770, bapineuzumab, BMS-984923, contraloid acetate, CNP520 (AMG520), crenezumab, donanemab (LY3002813), donepezil (Aricept), elenbecestat (E2609), gantenerumab, brain shuttle gantenerumab (RO7126209), GV-971, HT-ALZ, and KHK. 66401, Ranabesestat, Lecanemab (BAN2401) (Leqembi®), Lu AF20513, MEDI The method according to claim 1, comprising 1814, ponezumab, remternetsug (LY3372993), rivastigmine, SHR-1707, symphyllam (PTI-125), oligomannate sodium, solanezumab, scyllo-inositol, UB-311, valyltramiprosate (ALZ-801), baloglutamstat (PQ912), verbecestat (MK-8931), VGH-AD1, antisense RNA directed to human amyloid beta isoforms, siRNA directed to human amyloid beta isoforms, antisense oligonucleotides directed to human amyloid beta isoforms, LNA oligonucleotides directed to human amyloid beta isoforms, a CRISPRn-based therapeutic agent targeting the human APP locus, or a CRISPRi-based therapeutic agent targeting the human APP locus.

42. The method according to claim 1, wherein the inhibitor of the Aβ peptide or the modified form of the Aβ peptide comprises donanemab.

43. The method according to claim 1, wherein the inhibitor of the Aβ peptide or the modified form of the Aβ peptide comprises lecanemab.

44. The method according to claim 1, wherein the inhibitor of the Aβ peptide or the modified form of the Aβ peptide comprises remternetsug.

45. The method according to claim 1, wherein the inhibitor of the Aβ peptide or the modified form of the Aβ peptide comprises aducanumab.

46. The method according to claim 1, wherein the inhibitor of the Aβ peptide or the modified form of the Aβ peptide is selected from Table 10.

47. The method according to claim 1, wherein the inhibitor of the phosphorylated tau protein includes p-tau 217 or a modified form of p-tau 217, p-tau 181, p-tau 212, p-tau 220, p-tau 231, or an inhibitor of phosphorylated serine (pS) 214-tau.

48. The method according to claim 47, wherein the inhibitor of the phosphorylated tau protein includes an inhibitor of p-tau 217.

49. The method according to claim 1, wherein the sensitivity is higher than or equal to about 90%.

50. The method according to claim 1, wherein the sensitivity is higher than or equal to about 92%.

51. The method according to claim 1, wherein the measured level of p-tau 217 predicts that the subject has the abnormal tau protein deposition in the brain with an area under the curve (AUC) higher than or equal to about 0.

85.

52. The method according to claim 51, wherein the AUC is higher than or equal to about 0.

90.

53. The method according to claim 1, wherein the measured level of p-tau 217 predicts that the subject has the abnormal tau protein deposition in the brain with a specificity of more than or equal to about 81%.

54. The method according to claim 53, wherein the specificity is higher than or equal to about 85%.

55. The method according to claim 1, wherein the measured level of p-tau 217 predicts that the subject has the abnormal tau protein deposition in the brain with a positive predictive value (PPV) higher than or equal to about 51%.

56. The method according to claim 55, wherein the PPV is higher than or equal to about 70%.

57. The method according to claim 1, wherein the measured level of p-tau 217 predicts that the subject has the abnormal tau protein deposition in the brain with a negative predictive value (NPV) higher than or equal to about 51%.

58. The method according to claim 57, wherein the NPV is higher than or equal to about 70%.

59. The method according to claim 1, wherein the measured level of p-tau 217 predicts that the subject will exhibit a positive therapeutic response to the therapeutic agent with a specificity of more than or equal to about 70%.

60. The method according to claim 1, wherein the measured level of p-tau 217 predicts that the subject will exhibit a positive therapeutic response to the therapeutic agent with a sensitivity of more than or equal to about 70%.

61. The method according to claim 1, wherein the measured level of p-tau 217 predicts that the subject will exhibit a positive therapeutic response to the therapeutic agent at a PPV higher than or equal to about 70%.

62. The method according to claim 1, wherein the measured level of p-tau 217 predicts that the subject will exhibit a positive therapeutic response to the therapeutic agent at an NPV higher than or equal to about 70%.

63. The method according to claim 1, wherein the measured level of p-tau 217 predicts that the subject will exhibit a positive therapeutic response to the therapeutic agent at an AUC higher than or equal to about 0.

70.

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

65. The method according to claim 1, wherein the sample is a plasma sample.

66. The method according to claim 1, further comprising the step of determining the likelihood of a clinical diagnosis of the neurodegenerative disease in the subject based on the measured level of p-tau 217 in the sample, at least in part.

67. The method according to claim 1, further comprising, at least in part, a step of establishing an early prognosis of the neurodegenerative disease in the subject based on the measured level of p-tau 217 in the sample, wherein the early prognosis precedes a step of providing a diagnosis of a precursor stage of the neurodegenerative disease in the subject.

68. The method according to claim 67, wherein the neurodegenerative disease is Alzheimer's disease, and the step of demonstrating the early prognosis of Alzheimer's disease includes, at least in part, the step of demonstrating the possibility that the Alzheimer's disease in the subject will progress to Alzheimer's dementia based on the measured level of p-tau 217 in the sample.

69. The method according to claim 1, further comprising, in at least in part, the step of identifying, based on the measured level of p-tau 217 in the sample, an increased risk that the neurodegenerative disease leads to pathological memory impairment and cognitive decline in the subject.

70. The method according to claim 1, further comprising the step of restoring one or more symptoms of the neurodegenerative disease in the subject.

71. The method according to claim 1, further comprising the step of delaying the progression of one or more symptoms of the neurodegenerative disease in the subject.

72. The method according to claim 1, wherein the therapeutic agent is administered intravenously, intramuscularly, subarachnoidally, intracerebrally, subcutaneously, orally, nasally, topically, buccally, or sublingually.

73. The method according to claim 1, wherein the therapeutic agent is directly administered to the target CNS via intravenous delivery, intravascular delivery, subarachnoid delivery, cisterna magna delivery, intraspinal delivery, subpia delivery, or intraventricular delivery.

74. The method according to claim 1, wherein the subject is a preclinical stage of a neurogenic disease.

75. The method according to claim 1, wherein the subject is a prodromal stage of a neurogenesis disorder.

76. The method according to claim 1, wherein the therapeutic agent is administered in a dosage between approximately 0.1 and 100 mg / kg of body weight, according to the body weight of the subject.

77. The method according to claim 1, wherein the therapeutic agent is administered to the subject by intravenous administration in a dosage between approximately 200 and 1500 mg.

78. The method according to claim 1, wherein the therapeutic agent is administered to the subject by intravenous administration in a dosage between approximately 700 and 1400 mg.

79. The method according to claim 1, wherein the therapeutic agent is administered in a dosage of approximately 10 mg / kg of body weight according to the body weight of the subject.

80. The method according to claim 1, wherein the therapeutic agent is administered to the subject according to a treatment regimen that includes the step of administering the therapeutic agent once every two weeks (q2week).

81. The method according to claim 1, wherein the therapeutic agent is administered to the subject according to a treatment regimen comprising the step of administering the therapeutic agent once every four weeks (q4week).

82. The method according to claim 1, wherein the therapeutic agent is administered to the subject in multiple doses, and the first three doses of the multiple doses are administered to the subject in a dosage amount containing approximately 700 mg per dose.

83. The method according to claim 82, wherein the doses of the plurality of doses administered to the subject after the first three doses are amounts of medication containing approximately 1,400 mg per dose.

84. The method according to claim 1, wherein the step of administering the drug is systemic administration.

85. The method according to claim 84, wherein systemic administration includes intravenous administration.

86. The method according to claim 84, wherein systemic administration includes subcutaneous administration.

87. The method according to claim 84, wherein systemic administration includes oral administration.

88. a. A step of repeating the method after the introduction of the therapeutic agent, wherein a second level of p-tau 217 is measured in a second sample obtained from the subject after the introduction of the therapeutic agent, and 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. The step of administering another dose of the therapeutic agent to the subject. The method according to claim 1, further comprising:

89. A kit for selecting subjects for treatment of neurodegenerative diseases, a. i. A heavy chain comprising a variable heavy chain (VH) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NOs: 1 to 9, an HCDR2 sequence selected from SEQ ID NOs: 10 to 17, and an HCDR3 sequence selected from SEQ ID NOs: 18 to 23; and a light chain comprising a variable light chain (VL) domain, wherein the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs: 24 to 31, an LCDR2 sequence selected from SEQ ID NOs: 32 to 36, and an LCDR3 sequence selected from SEQ ID NOs: 37 to 43; ii. A heavy chain (HC) sequence containing any one of sequence numbers 57, 60, 62, 64, or 55; and a light chain (LC) sequence containing any one of sequence numbers 58, 59, 63, 65, or 56; or iii. Variable weight (VH) domains containing sequences having at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from sequence numbers 44-48; and variable light (VL) domains containing sequences having at least 80%, at least 85%, at least 90%, and at least 95% sequence identity with sequences selected from sequence numbers 49-54. Anti-tau antibodies or their antigen-binding fragments, including: b. Instructions for analyzing a sample obtained from the subject using the anti-tau antibody or its antigen-binding fragment in an immunoassay; c. Instructions for treating the neurodegenerative disease in the subject with a therapeutic agent comprising (i) an inhibitor of Aβ peptide or a modified form of Aβ peptide, or (ii) an inhibitor of phosphorylated tau protein; and d. If necessary, the therapeutic agent A kit that includes this.

90. The kit according to claim 89, comprising the therapeutic agent.

91. The kit according to claim 89, further comprising one or more immunoassay components, wherein the immunoassay comprises a single-molecule array (SIMOA), an enzyme-conjugated immunoassay (ELISA), a radioimmunoassay (RIA), a fluorescent immunoassay (FIA), a chemiluminescent immunoassay (CLIA), or a counting immunoassay (CIA).

92. The kit according to claim 89, further comprising a system for performing the immunoassay, wherein the immunoassay comprises a single-molecule array (SIMOA), an enzyme-conjugated immunoassay (ELISA), a radioimmunoassay (RIA), a fluorescent immunoassay (FIA), a chemiluminescent immunoassay (CLIA), or a counting immunoassay (CIA).

93. The kit according to claim 89, wherein the anti-tau antibody or the antigen-binding fragment thereof comprises a heavy chain containing a variable heavy chain (VH) domain, wherein the VH domain comprises an HCDR1 sequence selected from SEQ ID NOs: 1 to 9, an HCDR2 sequence selected from SEQ ID NOs: 10 to 17, and an HCDR3 sequence selected from SEQ ID NOs: 18 to 23; and a light chain containing a variable light chain (VL) domain, wherein the VL domain comprises an LCDR1 sequence selected from SEQ ID NOs: 24 to 31, an LCDR2 sequence selected from SEQ ID NOs: 32 to 36, and an LCDR3 sequence selected from SEQ ID NOs: 37 to 43.

94. The kit according to claim 89, wherein the anti-tau antibody or the antigen-binding fragment thereof comprises a heavy chain (HC) sequence containing any one of SEQ ID NOs: 57, 60, 62, 64, or 55; and a light chain (LC) sequence containing any one of SEQ ID NOs: 58, 59, 63, 65, or 56.

95. The kit according to claim 89, wherein the anti-tau antibody or the antigen-binding fragment thereof comprises a variable weight (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 NOs: 44-48; and a variable light (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 NOs: 49-54.

96. The inhibitors of the aforementioned therapeutic agents are ABvac40, ABBV-916, ACU193, AD-35, aducanumab (Aduhelm®), APH-1105, BPN14770, bapineuzumab, BMS-984923, contraloid acetate, CNP520 (AMG520), crenezumab, donanemab (LY3002813), donepezil (Aricept), elenbecestat (E2609), gantenerumab, brain shuttle gantenerumab (RO7126209), GV-971, HT-ALZ, KHK 66401, lanabesestat, lecanemab (BAN2401) (Leqembi®), Lu AF20513, MEDI The kit according to claim 90, comprising 1814, ponezumab, remternetsug (LY3372993), rivastigmine, SHR-1707, symphyllam (PTI-125), oligomannate sodium, solanezumab, scyllo-inositol, UB-311, valyltramiprosate (ALZ-801), baloglutamstat (PQ912), verbecestat (MK-8931), VGH-AD1, antisense RNA directed to human amyloid beta isoforms, siRNA directed to human amyloid beta isoforms, antisense oligonucleotides directed to human amyloid beta isoforms, LNA oligonucleotides directed to human amyloid beta isoforms, a CRISPRn-based therapeutic agent targeting the human APP locus, or a CRISPRi-based therapeutic agent targeting the human APP locus.

97. The kit according to claim 90, wherein the therapeutic agent comprises donanemab.

98. The kit according to claim 90, wherein the therapeutic agent comprises recanemab.

99. The kit according to claim 90, wherein the therapeutic agent comprises remternetsug.

100. The kit according to claim 90, wherein the therapeutic agent comprises aducanumab.

101. The kit according to claim 90, wherein the therapeutic agent is selected from Table 10.

102. The kit according to claim 90, wherein the therapeutic agent is the inhibitor of the phosphorylated tau protein.

103. The kit according to claim 102, wherein the inhibitor of the phosphorylated tau protein is an inhibitor of 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.

104. The kit according to claim 103, wherein the inhibitor of the phosphorylated tau protein comprises an inhibitor of p-tau 217.

105. The kit according to claim 89, wherein the instructions for analyzing the sample further include standard values ​​of p-tau 217 levels derived from a plurality of reference samples from a reference subject that does not have the neurodegenerative disease.

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