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:
(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; 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 at least 1.5σ above the mean of a control population and/or tau phosphorylation at T217 that is at least 1.5σ above the mean of a control population, and tau phosphorylation at T205 that is below 1.5σ above the mean of a control population, 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 at least 1.5σ above the mean of a control population and/or tau phosphorylation at T217 that is at least 1.5σ above the mean of a control population, and tau phosphorylation at T205 that is at least 1.5σ above the mean of a control population, 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 , 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 obtained from the subject contains tau phosphorylation at T217 that is at least 1.5σ above the mean and tau phosphorylation at T205 that is below 1.5σ above the mean.
5. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181 that is at least 1.5σ above the mean and tau phosphorylation at T205 that is below 1.5σ above the mean.
6. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181 and T217 that is at least 1.5σ above the mean and tau phosphorylation at T205 that is below 1.5σ above the mean.
7. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T217 and T205 that is at least 1.5σ above the mean.
8. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181 and T205 that is at least 1.5σ above the mean.
9. The method of claim 1 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181, T205, and T217 that is at least 1.5σ above the mean.
10. The method of claim 1 , wherein the therapeutic agent is a cholinesterase inhibitor, an N-methyl D-aspartate (NMDA) antagonist, an antidepressant, a gamma-secretase inhibitor, a beta-secretase inhibitor, an anti-Aβ antibody, an anti-tau antibody, an antagonist of the serotonin receptor 6, a p38alpha MAPK inhibitor, recombinant granulocyte macrophage colony-stimulating factor, a passive immunotherapy, an active vaccine, a tau protein aggregation inhibitor, an anti-inflammatory agent, a phosphodiesterase 9A inhibitor, a sigma-1 receptor agonist, a kinase inhibitor, a phosphatase activator, a phosphatase inhibitor, an angiotensin receptor blocker, a CB1 and/or CB2 endocannabinoid receptor partial agonist, a β-2 adrenergic receptor agonist, a nicotinic acetylcholine receptor agonist, a 5-HT2A inverse agonist, an alpha-2c adrenergic receptor antagonist, a 5-HT 1A and 1D receptor agonist, a glutaminyl-peptide cyclotransferase inhibitor, a selective inhibitor of APP production, a monoamine oxidase B inhibitor, a glutamate receptor antagonist, an AMPA receptor agonist, a nerve growth factor stimulant, a HMG-CoA reductase inhibitor, a neurotrophic agent, a muscarinic M1 receptor agonist, a GABA receptor modulator, a PPAR-gamma agonist, a microtubule protein modulator, a calcium channel blocker, an antihypertensive agent, a statin, or any combination thereof.
11. The method of claim 1 , wherein the therapeutic agent is a kinase inhibitor.
12. The method of claim 1 , wherein the therapeutic agent is a phosphatase activator.
13. 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.
14. 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.
15. 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 at least one site selected from the group consisting of T217, T181, T111, T153, S208, or T231,
(b) administering to the subject a therapeutic agent, wherein:
(i) the isolated tau sample obtained from the subject contains tau phosphorylation at T205 that is below 1.5σ above the mean of a control population, 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 T205 that is at least 1.5σ above the mean of a control population, 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.
16. The method of claim 15 , the method further comprising administering a diagnostic test to the subject.
17. The method of claim 16 , wherein the diagnostic test is PET imaging.
18. The method of claim 15 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T217 that is at least 1.5σ above the mean and tau phosphorylation at T205 that is below 1.5σ above the mean.
19. The method of claim 15 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181 that is at least 1.5σ above the mean and tau phosphorylation at T205 that is below 1.5σ above the mean.
20. The method of claim 15 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181 and T217 that is at least 1.5σ above the mean and tau phosphorylation at T205 that is below 1.5σ above the mean.
21. The method of claim 15 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T217 and T205 that is at least 1.5σ above the mean.
22. The method of claim 15 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181 and T205 that is at least 1.5σ above the mean.
23. The method of claim 15 , wherein the isolated tau sample obtained from the subject contains tau phosphorylation at T181, T205, and T217 that is at least 1.5σ above the mean.
24. The method of claim 15 , wherein the therapeutic agent is a cholinesterase inhibitor, an N-methyl D-aspartate (NMDA) antagonist, an antidepressant, a gamma-secretase inhibitor, a beta-secretase inhibitor, an anti-Aβ antibody, an anti-tau antibody, an antagonist of the serotonin receptor 6, a p38alpha MAPK inhibitor, recombinant granulocyte macrophage colony-stimulating factor, a passive immunotherapy, an active vaccine, a tau protein aggregation inhibitor, an anti-inflammatory agent, a phosphodiesterase 9A inhibitor, a sigma-1 receptor agonist, a kinase inhibitor, a phosphatase activator, a phosphatase inhibitor, an angiotensin receptor blocker, a CB1 and/or CB2 endocannabinoid receptor partial agonist, a β-2 adrenergic receptor agonist, a nicotinic acetylcholine receptor agonist, a 5-HT2A inverse agonist, an alpha-2c adrenergic receptor antagonist, a 5-HT 1A and 1D receptor agonist, a glutaminyl-peptide cyclotransferase inhibitor, a selective inhibitor of APP production, a monoamine oxidase B inhibitor, a glutamate receptor antagonist, an AMPA receptor agonist, a nerve growth factor stimulant, a HMG-CoA reductase inhibitor, a neurotrophic agent, a muscarinic M1 receptor agonist, a GABA receptor modulator, a PPAR-gamma agonist, a microtubule protein modulator, a calcium channel blocker, an antihypertensive agent, a statin, or any combination thereof.
25. The method of claim 15 , wherein the therapeutic agent is a kinase inhibitor.
26. The method of claim 15 , wherein the therapeutic agent is a phosphatase activator.
27. The method of claim 15 , wherein the isolated tau sample is a composition comprising tau, wherein tau has been purified from blood obtained from a human subject.
28. The method of claim 15 , wherein the isolated tau sample is a composition comprising tau, wherein tau has been purified from cerebrospinal fluid obtained from a human subject.