Methods of treating based on site-specific tau phosphorylation

Abstract

The present disclosure provides methods to quantify tau phosphorylation at specific amino acid residues to predict time to onset of mild cognitive impairment due to Alzheimer's disease, stage Alzheimer's disease, guide treatment decisions, select subjects for clinical trials, and evaluate the clinical efficacy of certain therapeutic interventions.

What is claimed is: 
     
         1 . A method for selecting a therapeutic agent for a subject in need thereof, the method comprising
 (a) determining a subjects estimated years to mild cognitive impairment from Alzheimer's disease by measuring, in an isolated tau sample obtained from the subject, tau phosphorylation at T205 and T181, at T205 and T217, or at T205, T181, and T217; wherein
 (i) the subject's years to mild cognitive impairment are greater than about 10 when the isolated tau sample obtained from the subject contains tau phosphorylation at T181 and/or tau phosphorylation at T217 that significantly deviates from the mean of a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF, and tau phosphorylation at T205 that does not significantly deviate from the mean of a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF; or 
 (ii) the subject's years to mild cognitive impairment are less than about 10 when the isolated tau sample obtained from the subject contains tau phosphorylation at T181 and/or tau phosphorylation at T217 that significantly deviates from the mean of a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF, and tau phosphorylation at T205 that significantly deviates from the mean of a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF; and 
   (b) administering to the subject a therapeutic agent
 (i) that prevents amyloid deposition from increasing or reduces a subject's existing plaque load, when the subject's years to mild cognitive impairment are greater than about 10; or 
 (ii) that prevents amyloid deposition from increasing, or reduces a subject's existing plaque load, or prevents tau aggregation, or targets neurofibrillary tangles when the subject's years to mild cognitive impairment are less than about 10. 
   
     
     
         2 . The method of  claim 1 , the method further comprising administering a diagnostic test to the subject. 
     
     
         3 . The method of  claim 2 , wherein the diagnostic test is PET imaging. 
     
     
         4 . The method of  claim 1 , wherein the isolated tau sample is a composition comprising tau, wherein tau has been purified from blood obtained from a human subject. 
     
     
         5 . The method of  claim 1 , wherein the isolated tau sample is a composition comprising tau, wherein tau has been purified from cerebrospinal fluid obtained from a human subject. 
     
     
         6 . A method for selecting a therapeutic agent for a subject in need thereof, the method comprising
 (a) determining a subjects estimated years to mild cognitive impairment from Alzheimer's disease by measuring, in an isolated tau sample obtained from the subject, tau phosphorylation at (i) T205, T181, and at least one site selected from the group consisting of T111, T153, S208, or T231, or (ii) T205, T217, and at least one site selected from the group consisting of T111, T153, S208, or T231; wherein
 (1) the subject's years to mild cognitive impairment are greater than about 10 when the isolated tau sample obtained from the subject contains tau phosphorylation at T181 and/or tau phosphorylation at T217 that significantly deviates from the mean of a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF, and tau phosphorylation at T205 that does not significantly deviate from the mean of a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF; or 
 (2) the subject's years to mild cognitive impairment are less than about 10 when the isolated tau sample obtained from the subject contains tau phosphorylation at T181 and/or tau phosphorylation at T217 that significantly deviates from the mean of a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF, and tau phosphorylation at T205 that significantly deviates from the mean of a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF; and 
   (b) administering to the subject a therapeutic agent
 (i) that prevents amyloid deposition from increasing or reduces a subject's existing plaque load, when the subject's years to mild cognitive impairment are greater than about 10; or 
 (ii) that prevents amyloid deposition from increasing, or reduces a subject's existing plaque load, or prevents tau aggregation, or targets neurofibrillary tangles when the subject's years to mild cognitive impairment are less than about 10. 
   
     
     
         7 . The method of  claim 6 , the method further comprising administering a diagnostic test to the subject. 
     
     
         8 . The method of  claim 7 , wherein the diagnostic test is PET imaging. 
     
     
         9 . The method of  claim 6 , wherein the isolated tau sample is a composition comprising tau, wherein tau has been purified from blood obtained from a human subject. 
     
     
         10 . The method of  claim 6 , wherein the isolated tau sample is a composition comprising tau, wherein tau has been purified from cerebrospinal fluid obtained from a human subject. 
     
     
         11 . A method for selecting a therapeutic agent for a subject in need thereof, the method comprising
 (a) determining a subjects estimated years to mild cognitive impairment from Alzheimer's disease by measuring, in an isolated tau sample obtained from the subject, tau phosphorylation at T205, and at least one site selected from the group consisting of T217, T181, T111, T153, S208, or T231; wherein
 (i) the subject's years to mild cognitive impairment are greater than about 10 when the isolated tau sample obtained from the subject contains tau phosphorylation at T205 that does not significantly deviate from the mean of a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF; or 
 (ii) the subject's years to mild cognitive impairment are less than about 10 when the isolated tau sample obtained from the subject contains tau phosphorylation at T205 that significantly deviates from the mean of a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF; and 
   (b) administering to the subject a therapeutic agent
 (i) that prevents amyloid deposition from increasing or reduces a subject's existing plaque load, when the subject's years to mild cognitive impairment are greater than about 10; or 
 (ii) that prevents amyloid deposition from increasing, or reduces a subject's existing plaque load, or prevents tau aggregation, or targets neurofibrillary tangles when the subject's years to mild cognitive impairment are less than about 10. 
   
     
     
         12 . The method of  claim 11 , the method further comprising administering a diagnostic test to the subject. 
     
     
         13 . The method of  claim 12 , wherein the diagnostic test is PET imaging. 
     
     
         14 . The method of  claim 11 , wherein the isolated tau sample is a composition comprising tau, wherein tau has been purified from blood obtained from a human subject. 
     
     
         15 . The method of  claim 11 , wherein the isolated tau sample is a composition comprising tau, wherein tau has been purified from cerebrospinal fluid obtained from a human subject.