@article{8a69a2e94d9b4758a369a654c2a3794c,
title = "MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology",
abstract = "Objective: Tau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer{\textquoteright}s disease (AD). However, it remains unclear whether other tauopathies induce pT217 modifications. To determine if pT217 modification is specific to AD, CSF pT217 was measured in AD and other tauopathies. Methods: Using immunoprecipitation and mass spectrometry methods, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid-beta (Aβ) 42/40 ratio in cognitively normal individuals and those with symptomatic AD, progressive supranuclear palsy, corticobasal syndrome, and sporadic and familial frontotemporal dementia. Results: Individuals with AD had high CSF pT217/T217 and low Aβ42/40. In contrast, cognitively normal individuals and the majority of those with 4R tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio, most of whom were MAPT R406W mutation carriers. Diagnostic accuracies of CSF Aβ 42/40 and CSF pT217/T217, alone and in combination were compared. We show that CSF pT217/T217 × CSF Aβ 42/40 is a sensitive composite biomarker that can separate MAPT R406W carriers from cognitively normal individuals and those with other tauopathies. Interpretation: MAPT R406W is a tau mutation that leads to 3R+4R tauopathy similar to AD, but without amyloid neuropathology. These findings suggest that change in CSF pT217/T217 ratio is not specific to AD and might reflect common downstream tau pathophysiology common to 3R+4R tauopathies.",
keywords = "Alzheimer's Disease, Tauopathies, biomarker, cerebrospinal fluid, mass spectrometry, tau phosphorylation",
author = "Chihiro Sato and Nipun Mallipeddi and Nupur Ghoshal and Wright, {Brenton A.} and Day, {Gregory S.} and Davis, {Albert A.} and Kim, {Albert H.} and Zipfel, {Gregory J.} and Bateman, {Randall J.} and Audrey Gabelle and Barth{\'e}lemy, {Nicolas R.}",
note = "Funding Information: This work was supported by Barnes Jewish Hospital Foundation (BJHF) pilot grant #3945 (CS) and NIH/NIA K01AG062796 (CS). Additionally, samples analyzed in this study were obtained with support from Tau Foundation Plan Alzheimer (AG), BIRCWH K12 HD001459 (NG), NIH/NIA K23 AG064029 (GSD), NIH K08 NS101118 (AAD), NIH/NINDS RF1NS103276 (GJZ), NIH R01NS065667 (RJB), NIH R01NS095773 (RJB), Rainwater Charitable Foundation (RJB), The Association for Frontotemporal Degeneration (RJB), and Tau SILK Consortium (RJB). This work was supported by cores, resources, and effort provided by Washington University Biomedical Mass Spectrometry Research Facility (NIH P41 GM103422) and access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at the Washington University School of Medicine. Funding Information: Washington University, with CS, NRB, and RJB as co‐inventors, have submitted the U.S. provisional patent application “Methods to detect novel tau species in CSF and use thereof to track tau neuropathology in AD and other tauopathies.” and “CSF phosphorylated tau and Amyloid beta profiles as biomarkers of tauopathies” to Washington University. RJB and NRB as co‐inventors, have submitted the non‐provisional patent application “Methods of Diagnosing and Treating Based on Site‐Specific Tau Phosphorylation.” RJB has received honoraria from AC Immune, Janssen, Pfizer, and Roche as a speaker, from AC Immune, Amgen, Eisai, and Janssen as a consultant, and from Roche as an advisory board member. RJB has an equity ownership interest in C2N Diagnostics and receives royalty income based on technology licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. NG has participated or is currently participating in clinical trials of anti‐dementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti‐Amyloid Treatment in Asymptomatic Alzheimer{\textquoteright}s Disease) trial. She receives research support from NIH, Tau Consortium, and the Association for Frontotemporal Dementia. BAW participates in research sponsored by Acadia, Biogen, Global Kinetics, Neurocrine, Roche, Vaccinex, and Wave Biosciences. GSD is supported by grants from NIH/NIA (K23AG064029); personal fees from Parabon NanoLabs, Inc, personal fees from DynaMed (EBSCO Health), outside the submitted work; and is the clinical director for the Anti‐NMDA Receptor Encephalitis Foundation (uncompensated). AHK is a consultant for Monteris Medical and has received research funding from Monteris Medical, Stryker, and Collagen Matrix. Publisher Copyright: {\textcopyright} 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association",
year = "2021",
doi = "10.1002/acn3.51435",
language = "English",
journal = "Annals of Clinical and Translational Neurology",
issn = "2328-9503",
}