Abstract
Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman’s ρ = 0.69) than Aβ42/Aβ40 (ρ = −0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD.
| Original language | English |
|---|---|
| Pages (from-to) | 391-401 |
| Number of pages | 11 |
| Journal | Nature Aging |
| Volume | 3 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2023 |
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In: Nature Aging, Vol. 3, No. 4, 04.2023, p. 391-401.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease
AU - Barthélemy, Nicolas R.
AU - Saef, Benjamin
AU - Li, Yan
AU - Gordon, Brian A.
AU - He, Yingxin
AU - Horie, Kanta
AU - Stomrud, Erik
AU - Salvadó, Gemma
AU - Janelidze, Shorena
AU - Sato, Chihiro
AU - Ovod, Vitaliy
AU - Henson, Rachel L.
AU - Fagan, Anne M.
AU - Benzinger, Tammie L.S.
AU - Xiong, Chengjie
AU - Morris, John C.
AU - Hansson, Oskar
AU - Bateman, Randall J.
AU - Schindler, Suzanne E.
N1 - Funding Information: N.R.B., K.H., C.S., V.O. and R.J.B. are coinventors on the following US patent applications: ‘Methods to detect novel tau species in CSF and use thereof to track tau neuropathology in Alzheimer’s disease and other tauopathies’ (PCT/US2020/046224, N.R.B., K.H., C.S. and R.J.B.); ‘CSF phosphorylated tau and amyloid beta profiles as biomarkers of tauopathies’ (PCT/US2022/022906, N.R.B., C.S. and R.J.B.); ‘Plasma based methods for detecting CNS amyloid deposition’ (PCT/UC2018/030518, V.O. and R.J.B.); and ‘Methods of diagnosing and treating based on site-specific tau phosphorylation’ (PCT/US2019/030725, N.R.B. and R.J.B.). N.R.B., K.H., C.S., V.O. and R.J.B. may receive a royalty income based on technology licensed by Washington University to C2N Diagnostics. K.H. is an Eisai-sponsored voluntary research associate professor at Washington University and has received a salary from Eisai. A.M.F. has received research funding from Biogen, Centene, Fujirebio and Roche Diagnostics. She is a member of the scientific advisory boards for Roche Diagnostics, Genentech and Diadem. She consults for DiamiR and Seimens Healthcare Diagnostics Inc. T.L.S.B. has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Siemens. She participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly, Biogen, Eisai, Janssen and Roche, and serves as a consultant to Biogen, Eli Lilly, Eisai and Siemens. C.X. consulted for DIADEM and has used funding from the NIH to hire C2N Diagnostics as a vendor in another independent NIH-funded project. He received no funding from C2N Diagnostics. Neither J.C.M. nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Fujirebio, Genentech, Novartis, Novo Nordisk, Roche and Siemens. R.J.B. cofounded C2N Diagnostics. Washington University and R.J.B. have equity ownership interest in C2N Diagnostics and receive a royalty income based on technology (stable isotope labeling kinetics, blood plasma assay and methods of diagnosing AD with phosphorylation changes) licensed by Washington University to C2N Diagnostics. R.J.B. receives an income from C2N Diagnostics for serving on the scientific advisory board, and has received research funding from Avid Radiopharmaceuticals, Janssen, Roche/Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb and Novartis. S.E.S. has analyzed data provided by C2N Diagnostics to Washington University, but she has not received any research funding or personal compensation from C2N Diagnostics or any other for-profit organizations. The remaining authors declare no competing interests. Funding Information: We thank the research volunteers who participated in the studies, from whom these data were obtained, and their supportive families. We thank the Clinical, Fluid Biomarker and Imaging Cores at the Knight ADRC for sample and data collection. The present study was supported by National Institutes of Health (NIH; grant no. R01AG070941 to S.E.S.), Knight ADRC Developmental Projects (N.R.B.), Eisai industry grant (to R.J.B. and K.H.), RF1AG061900 and R56AG061900 (to R.J.B.) and P30AG066444, P01AG003991, P01AG026276, U19AG032438 and U19AG024904 (to J.C.M.). Avid Radiopharmaceuticals provided doses of [F]AV45 (florbetapir) and precursor and technology transfer for [F]AV1451 (flortaucipir) to the Washington University, but was not involved in the data analysis or interpretation. The BioFINDER-2 study was supported by the Swedish Research Council (no. 2016-00906), and all the following to O.H.: the Knut and Alice Wallenberg Foundation (no. 2017-0383), the Marianne and Marcus Wallenberg foundation (no. 2015-0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation (no. AF-939932), the Swedish Brain Foundation (no. FO2021-0293), the Parkinson foundation of Sweden (no. 1280/20), the Cure Alzheimer’s fund, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (no. 2020-O000028), Regionalt Forskningsstöd (no. 2020-0314) and the Swedish federal government under the ALF agreement (2018-Projekt0279). The precursor of [F]flutemetamol was sponsored by GE Healthcare and the precursor of [F]RO948 was provided by Roche. G.S. received funding from the European Union’s (EU’s) Horizon 2020 research and innovation program under the Marie Sklodowska-Curie action grant (no. 101061836), from Greta och Johan Kocks research grants and travel grants from the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. 18 18 18 18 Funding Information: We thank the research volunteers who participated in the studies, from whom these data were obtained, and their supportive families. We thank the Clinical, Fluid Biomarker and Imaging Cores at the Knight ADRC for sample and data collection. The present study was supported by National Institutes of Health (NIH; grant no. R01AG070941 to S.E.S.), Knight ADRC Developmental Projects (N.R.B.), Eisai industry grant (to R.J.B. and K.H.), RF1AG061900 and R56AG061900 (to R.J.B.) and P30AG066444, P01AG003991, P01AG026276, U19AG032438 and U19AG024904 (to J.C.M.). Avid Radiopharmaceuticals provided doses of [18F]AV45 (florbetapir) and precursor and technology transfer for [18F]AV1451 (flortaucipir) to the Washington University, but was not involved in the data analysis or interpretation. The BioFINDER-2 study was supported by the Swedish Research Council (no. 2016-00906), and all the following to O.H.: the Knut and Alice Wallenberg Foundation (no. 2017-0383), the Marianne and Marcus Wallenberg foundation (no. 2015-0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation (no. AF-939932), the Swedish Brain Foundation (no. FO2021-0293), the Parkinson foundation of Sweden (no. 1280/20), the Cure Alzheimer’s fund, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (no. 2020-O000028), Regionalt Forskningsstöd (no. 2020-0314) and the Swedish federal government under the ALF agreement (2018-Projekt0279). The precursor of [18F]flutemetamol was sponsored by GE Healthcare and the precursor of [18F]RO948 was provided by Roche. G.S. received funding from the European Union’s (EU’s) Horizon 2020 research and innovation program under the Marie Sklodowska-Curie action grant (no. 101061836), from Greta och Johan Kocks research grants and travel grants from the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © 2023, The Author(s).
PY - 2023/4
Y1 - 2023/4
N2 - Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman’s ρ = 0.69) than Aβ42/Aβ40 (ρ = −0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD.
AB - Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman’s ρ = 0.69) than Aβ42/Aβ40 (ρ = −0.42, P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 and n = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD.
UR - http://www.scopus.com/inward/record.url?scp=85149806213&partnerID=8YFLogxK
U2 - 10.1038/s43587-023-00380-7
DO - 10.1038/s43587-023-00380-7
M3 - Article
C2 - 37117788
AN - SCOPUS:85149806213
SN - 2662-8465
VL - 3
SP - 391
EP - 401
JO - Nature Aging
JF - Nature Aging
IS - 4
ER -