Methods of treating based on site-specific tau phosphorylation
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.
1. A method for selecting a therapeutic agent for a subject in need thereof, the method comprising
(a) providing an isolated tau sample obtained from the subject and measuring, in the isolated tau sample, tau phosphorylation at T205 and T181, at T205 and T217, or at T205, T181, and T217; and
(b) administering to the subject a therapeutic agent, wherein:
(i) the isolated tau sample obtained from the subject contains tau phosphorylation at T181 that is about 1.5 σ or above and/or tau phosphorylation at T217 that is about 1.5 σ or above, and tau phosphorylation at T205 that is below about 1.5 σ, and the therapeutic agent prevents amyloid deposition from increasing or reduces a subject's existing plaque load, or
(ii) the isolated tau sample obtained from the subject contains tau phosphorylation at T181 that is about 1.5 σ or above and/or tau phosphorylation at T217 that is about 1.5 σ or above, and tau phosphorylation at T205 that is about 1.5 σ or above, and the therapeutic agent prevents amyloid deposition from increasing, or reduces a subject's existing plaque load, or prevents tau aggregation, or targets neurofibrillary tangles,
where σ is the standard deviation defined by the normal distribution of tau phosphorylation at the residue measured in a control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF.
2. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T217 that is above 1.5 σ and tau phosphorylation at T205 that is below 1.5 σ.
3. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181 that is above 1.5 σ and tau phosphorylation at T205 that is below 1.5 σ.
4. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181 and T217 that is above 1.5 σ and tau phosphorylation at T205 that is below 1.5 σ.
5. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T217 and T205 that is above 1.5 σ.
6. The method of claim 5 , wherein (i) tau phosphorylation at T217 and T205 is above 1.75a, (ii) tau phosphorylation at T217 and T205 is above 1.8a, or (iii) tau phosphorylation at T217 and T205 is above 1.9a.
7. The method of claim 5 , wherein tau phosphorylation at T217 and T205 is above 2a.
8. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181 and T205 that is above 1.5 σ.
9. The method of claim 8 , wherein (i) tau phosphorylation at T181 and T205 is above 1.75 σ, (ii) tau phosphorylation at T181 and T205 is above 1.8 σ, or (iii) tau phosphorylation at T181 and T205 is above 1.9 σ.
10. The method of claim 8 , wherein tau phosphorylation at T181 and T205 is above 2 σ.
11. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181, T205, and T217 that is above 1.5 σ.
12. The method of claim 11 , wherein (i) tau phosphorylation at T181, T205, and T217 is above 1.75 σ, (ii) tau phosphorylation at T181, T205, and T217 is above 1.8 σ, or (iii) tau phosphorylation at T181, T205, and T217 is above 1.9 σ.
13. The method of claim 11 , wherein tau phosphorylation at T181, T205, and T217 is above 2 σ.
14. The method of claim 1 , wherein the therapeutic agent is selected from the group consisting of a gamma-secretase inhibitor, a beta-secretase inhibitor, an anti-Aβ antibody, an anti-tau antibody, a p38alpha MAPK inhibitor, a passive immunotherapy, an active vaccine, a tau protein aggregation inhibitor, a kinase inhibitor, a phosphatase activator, a phosphatase inhibitor, a selective inhibitor of APP production and any combination thereof.
15. The method of claim 1 , wherein the therapeutic agent is a kinase inhibitor.
16. The method of claim 15 , wherein the kinase inhibitor inhibits a thousand-and-one amino acid kinase (TAOK), CDK, GSK-3β, MARK, CDK5, or Fyn.
17. The method of claim 1 , wherein the therapeutic agent is a phosphatase activator.
18. The method of claim 17 , wherein the phosphatase activator increases the activity of protein phosphatase 2A.
19. 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.
20. 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.