Methods of diagnosing and 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) measuring in a biological sample obtained from the subject (i) Nfl, and (ii) 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 biological sample obtained from the subject contains tau phosphorylation at T181 and/or tau phosphorylation at T217 that significantly deviates above 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 the control population, and an amount of Nfl that does not significantly deviate from the mean of the control population, and the therapeutic agent prevents amyloid deposition from increasing in the subject or reduces the existing plaque load in the subject, or
the biological sample obtained from the subject contains tau phosphorylation at T181 and/or tau phosphorylation at T217 that significantly deviates above 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 above the mean of the control population, and an amount of Nfl that significantly deviates above the mean of the control population, and the therapeutic agent prevents amyloid deposition from increasing in the subject, reduces the existing plaque load in the subject, prevents tau aggregation in the subject, or targets neurofibrillary tangles in the subject,
wherein the biological sample is a CSF or blood sample, and
wherein the significant deviation of tau phosphorylation at T205 and/or T217 in (b)(1) or (b)(ii) is indicative that the therapeutic agent is to be selected from 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, a selective inhibitor of APP production, 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.
2 . The method of claim 1 , wherein the biological sample is enriched for tau with an anti-tau epitope binding agent, and/or enriched for Nfl with an anti-Nfl epitope binding agent.
3 . The method of claim 1 , wherein the deviation of tau phosphorylation at T181 and/or T217 above the mean in (b)(i) or b(ii) is 1.5 σ or above,
wherein σ is the standard deviation defined by the normal distribution of tau phosphorylation at the residue, as measured in the control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF.
4 . The method of claim 3 , wherein the deviation of tau phosphorylation at T181 and/or T217 above the mean in (b)(i) or b(ii) is 2.0σ or above.
5 . The method of claim 1 , wherein the deviation of tau phosphorylation at T181 and/or T217 above the mean in (b)(i) is 1.5 σ or above, and the deviation of tau phosphorylation at T205 from the mean in (b)(1) is below 1.5 σ,
wherein σ is the standard deviation defined by the normal distribution of tau phosphorylation at the residue, as measured in the control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF.
6 . The method of claim 5 , wherein the deviation of tau phosphorylation at T181 and/or T217 above the mean in (b)(i) is 2.0 σ or above, and the deviation of tau phosphorylation at T205 from the mean in (b)(i) is 2.0 σ or below.
7 . The method of claim 1 , wherein the deviation of tau phosphorylation at T181 and/or T217 above the mean in (b)(i) is 1.5 σ or above, and the deviation of tau phosphorylation at T205 from the mean in (b)(i) is below 1.5 σ, and the deviation of the amount of Nfl from the mean in (b)(i) is below 1.5 σ,
wherein σ is the standard deviation defined by (1) the normal distribution of tau phosphorylation at the residue, or (2) the normal distribution of the amount of Nfl, as measured in the control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF.
8 . The method of claim 7 , wherein the deviation of tau phosphorylation at T181 and/or T217 above the mean in (b)(i) is 2.0 σ or above, the deviation of tau phosphorylation at T205 from the mean in (b)(i) is 2.0 σ or below.
9 . The method of claim 1 , wherein the deviation of tau phosphorylation at T181 and/or T217 above the mean in (b)(ii) is 1.5 σ or above, and the deviation of tau phosphorylation at T205 above the mean in (b)(ii) is 1.5 σ or above,
wherein σ is the standard deviation defined by the normal distribution of tau phosphorylation at the residue, as measured in the control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF.
10 . The method of claim 9 , wherein the deviation of tau phosphorylation at T181 and/or T217 above the mean in (b)(ii) is 2.0 σ or above, and the deviation of tau phosphorylation at T205 above the mean in (b)(ii) is 2.0 σ or above.
11 . The method of claim 1 , wherein the deviation of tau phosphorylation at T181 and/or T217 above the mean in (b)(ii) is 1.5 σ or above, and the deviation of tau phosphorylation at T205 above the mean in (b)(ii) is 1.5 σ or above, and the deviation of the amount of Nfl above the mean in (b)(ii) is 1.5 σ or above,
wherein σ is the standard deviation defined by (1) the normal distribution of tau phosphorylation at the residue, or (2) the normal distribution of the amount of Nfl, as measured in the control population without brain amyloid plaques as measured by PET imaging and/or Aβ42/40 measurement in CSF.
12 . The method of claim 11 , wherein the deviation of tau phosphorylation at T181 and/or T217 above the mean in (b)(ii) is 2.0 σ or above, the deviation of tau phosphorylation at T205 above the mean in (b)(ii) is 2.0 σ or above, and the deviation of the amount of Nfl above the mean in (b)(ii) is 2.0 σ or above.
13 . The method of claim 1 , wherein the subject is asymptomatic or has a CDR of 0.5 or less.
14 . The method of claim 1 , wherein the subject is identified as about 10 years to about 25 years, or about 10 years to about 20 years, from the onset of mild cognitive impairment due to Alzheimer's disease.
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 subject receives additional testing, wherein the additional testing is amyloid imaging by PET or tau imaging by PET.