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. 2023 Dec 30;147(1):5.
doi: 10.1007/s00401-023-02660-3.

Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study

Laia Montoliu-Gaya #  1 , Michael L Alosco #  2   3 , Eukyung Yhang  4 , Yorghos Tripodis  4 , Daniel Sconzo  2 , Madeline Ally  5 , Lana Grötschel  6 , Nicholas J Ashton  6   7   8   9 , Juan Lantero-Rodriguez  6 , Mathias Sauer  6 , Bárbara Gomes  6 , Johanna Nilsson  6 , Gunnar Brinkmalm  6 , Michael A Sugarman  10 , Hugo J Aparicio  2   3 , Brett Martin  11 , Joseph N Palmisano  11 , Eric G Steinberg  2   3 , Irene Simkin  12 , Katherine W Turk  2   3   13 , Andrew E Budson  2   3   13 , Rhoda Au  2   3   12   14 , Lindsay Farrer  2   3   12   14 , Gyungah R Jun  2   12 , Neil W Kowall  2   3 , Robert A Stern  2   3   15   16 , Lee E Goldstein  2   3   17   18 , Wei Qiao Qiu  2   3   19   20 , Jesse Mez  2   3 , Bertrand Russell Huber  2   3   13 , Victor E Alvarez  2   3   13   21 , Ann C McKee  2   3   13   17   22 , Henrik Zetterberg  6   23   24   25   26   27 , Johan Gobom  6 , Thor D Stein #  2   15   17   24 , Kaj Blennow #  6   23
Affiliations

Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study

Laia Montoliu-Gaya et al. Acta Neuropathol. .

Abstract

Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer's disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer's disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195-205, 212-221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (ORp-tau217 = 15.29, ORp-tau205 = 5.05 and ORp-tau231 = 3.86) and Braak staging (ORp-tau217 = 14.29, ORp-tau205 = 5.27 and ORp-tau231 = 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.

Keywords: Alzheimer’s disease; Autopsy; Biomarkers; Blood; Mass spectrometry; Phosphorylated tau.

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Conflict of interest statement

HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. PRN participated in Advisory Board for Roche, Novo Nordics and Cerveau (outside submitted work). Andrew E. Budson has served on a consultant or on advisory boards for Sage Pharmaceuticals and Cognito Therapeutics and has received grant monies from Biogen, Bristol Myers Squibb, and Cyclerion. He receives publishing royalties from Elsevier and Oxford University Press. Rhoda Au serves on the scientific advisory board of Signant Health, as consultant to Biogen and has given a lecture in a symposia sponsored by Eisai. Robert A. Stern has served as a consultant to Biogen and Lundbeck. He receives royalties for published neuropsychological tests from Psychological Assessment Resources, Inc. MLA has received honorarium from the Michael J Fox Foundation for services unrelated to this study. He also receives royalties from Oxford University Press. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Box plots of the fold-changes of the tau peptide concentrations by Alzheimer’s disease status. The non-AD group was used as a reference. National Institute on Aging-Reagan Institute criteria were used for the neuropathological diagnosis of Alzheimer’s disease. Box plots include the median (bar) and interquartile range (whiskers) as well as the individual data points
Fig. 2
Fig. 2
Box plots of the fold-changes of the tau peptide concentrations by CERAD neuritic amyloid plaque score. CERAD 0 was used as the reference group. Box plots include the median (bar) and interquartile range (whiskers) as well as the individual data points. Participants are color-coded based on the presence (red) or absence (blue) of AD brain pathology
Fig. 3
Fig. 3
Box plots of the fold-changes of the tau peptide concentrations by Braak staging for NFTs. Braak I–II was used as the reference group. Box plots include the median (bar) and interquartile range (whiskers) as well as the individual data points. Participants are color-coded based on the presence (red) or absence (blue) of AD brain pathology
See this image and copyright information in PMC

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