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Peer-reviewedCC BY-NC-ND 4.0Journal of Neurology

Leveraging immunoprecipitation mass spectrometry and neuropathology to identify the clinical value of different blood tau species in Alzheimer’s disease

  • Jacob Labonte1
  • Annalise E. Miner1
  • Jenna R. Groh1
  • Laia Montoliu-Gaya2
  • Yorghos Tripodis3
  • Hugo J. Aparicio1,4
  • Katherine W. Turk1,4,5
  • Andrew E. Budson1,4,5
  • Lindsay Farrer1,4,6,7
  • Lee E. Goldstein1,4,8,9
  • Wei Qiao Qiu1,4,10,11
  • Jesse Mez1,4
6 more authors
  • Ann C. McKee1,4,5,11,12
  • Henrik Zetterberg2,13,14,15,16,17
  • Thor D. Stein1,8,14,18
  • Johan Gobom2
  • Nicholas J. Ashton2,19,20
  • Michael L. Alosco1,4
20 affiliations
  1. 1Boston University Alzheimer’s Disease Research Center and BU CTE Center, Boston University Chobanian and Avedisian School of Medicine, 72 E. Concord Street, Instructional Building L-5, Boston, MA 02118 USA
  2. 2Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
  3. 3Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118 USA
  4. 4Department of Neurology, Boston University, Chobanian and Avedisian School of Medicine, Boston, MA 02118 USA
  5. 5VA Boston Healthcare System, U.S. Department of Veteran Affairs, Jamaica Plain, MA 02130 USA
  6. 6Biostatistics and Epidemiology Data Analytics Center, Boston University School of Public Health, Boston, MA 02118 USA
  7. 7Department of Medicine, Boston University, Chobanian and Avedisian School of Medicine, Boston, MA 02118 USA
  8. 8Department of Psychiatry and Ophthalmology, Boston University School of Medicine, Boston, MA 02118 USA
  9. 9Department of Biomedical, Electrical and Computer Engineering, Boston University College of Engineering, Boston, MA 02215 USA
  10. 10Department of Pharmacology and Experimental Therapeutics, Boston University, Chobanian an Avedisian School of Medicine, Boston, MA 02118 USA
  11. 11Department of Psychiatry, Boston University, Chobanian and Avedisian School of Medicine, Boston, MA 02118 USA
  12. 12Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118 USA
  13. 13Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  14. 14Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK
  15. 15UK Dementia Research Institute, University College London, London, UK
  16. 16Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI USA
  17. 17Department of Medicine, UW School of Medicine and Public Health, Madison, WI USA
  18. 18Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118 USA
  19. 19Banner Alzheimer’s Institute and University of Arizona, Phoenix, AZ USA
  20. 20Banner Sun Health Research Institute, Sun City, AZ 85351 USA
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Abstract

Introduction: Advances in plasma-based assays have allowed for the study of several tau and p-tau epitopes. P-tau217 has emerged as one of the most robust markers of Alzheimer’s disease (AD) pathology. Despite their strong diagnostic performance, plasma tau biomarkers require further validation to clarify their clinical utility.

Objective: To investigate the associations between a panel of phosphorylated and non-phosphorylated tau species measured in antemortem plasma and clinical features of autopsy-confirmed AD.

Methods: Cross-sectional data from 123 participants from the BU ADRC who had antemortem blood draws and brain donation following death. Participants completed neuropsychological testing during life as part of their National Alzheimer’s Coordinating Center-Uniform Data Set (NACC UDS) evaluation. AD neuropathology was diagnosed using NIA-Reagan criteria. Time interval between testing at last visit and autopsy ranged from 0 to 12 years, mean = 5.54 years. Raw neuropsychological test scores were used for analysis. Sample size ranged from 65 to 91 across the tests. Plasma samples were analyzed using immunoprecipitation mass spectrometry (IP-MS) for phosphorylated tau species (p-tau-181, 199, 202, 205, 217, 231) and non-phosphorylated tau (195–209, 212–221) peptides. Two ratios were analyzed, p-tau217/tau212-221 and p-tau205/tau195-209.

Results: 123 participants took part in this study, 55 (44.7%) female, and 6 (4.9%) Black/African American. The mean (SD) age at blood draw was 78.17 (8.55). The strongest association between plasma biomarkers with neuropsychological test outcomes was observed with the ratio p-tau217/tau212-221 (b = − 0.564–0.404, plow-high = 0.00–0.18), followed by p-tau217 (b = − 0.478–0.377, plow-high = 0.00–0.28), both significantly correlating with six of the eight neuropsychological measures (p < 0.05). Followed by the ratio p-tau205/tau195-209 (b = − 0.513–0.356, plow-high = 0.00–0.55), p-tau205 (b = − 0.365–0.226, plow-high = 0.00–0.44), then p-tau231 (b = − 0.319–0.237, plow-high = 0.02–0.62). Fewer significant relationships and weaker effect sizes were observed among the other biomarkers. The effect sizes of the ratio p-tau217/tau212-221, followed closely by p-tau217 on neuropsychological test outcomes, were observed to be the most similar to the effect sizes of autopsy-confirmed AD (b = − 0.564–0.393).

Conclusions: Plasma p-tau217 and p-tau ratios were comparable to autopsy-confirmed AD in predicting clinical outcomes of AD. This study highlights the promise and potential utility of plasma biomarkers for symptom monitoring.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00415-026-14232-y.

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Cite

BibTeXRIS
BibTeX
@article{labonte2026leveraging,
  title = {{Leveraging immunoprecipitation mass spectrometry and neuropathology to identify the clinical value of different blood tau species in Alzheimer’s disease}},
  author = {Jacob Labonte and Annalise E. Miner and Jenna R. Groh and Laia Montoliu-Gaya and Yorghos Tripodis and Hugo J. Aparicio and Katherine W. Turk and Andrew E. Budson and Lindsay Farrer and Lee E. Goldstein and Wei Qiao Qiu and Jesse Mez and Ann C. McKee and Henrik Zetterberg and Thor D. Stein and Johan Gobom and Nicholas J. Ashton and Michael L. Alosco},
  journal = {Journal of Neurology},
  year = {2026},
  month = oct,
  doi = {10.1007/s00415-026-14232-y},
  url = {https://doi.org/10.1007/s00415-026-14232-y},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Leveraging immunoprecipitation mass spectrometry and neuropathology to identify the clinical value of different blood tau species in Alzheimer’s disease
AU  - Jacob Labonte
AU  - Annalise E. Miner
AU  - Jenna R. Groh
AU  - Laia Montoliu-Gaya
AU  - Yorghos Tripodis
AU  - Hugo J. Aparicio
AU  - Katherine W. Turk
AU  - Andrew E. Budson
AU  - Lindsay Farrer
AU  - Lee E. Goldstein
AU  - Wei Qiao Qiu
AU  - Jesse Mez
AU  - Ann C. McKee
AU  - Henrik Zetterberg
AU  - Thor D. Stein
AU  - Johan Gobom
AU  - Nicholas J. Ashton
AU  - Michael L. Alosco
PY  - 2026
DA  - 2026/10/31
JO  - Journal of Neurology
DO  - 10.1007/s00415-026-14232-y
UR  - https://doi.org/10.1007/s00415-026-14232-y
AB  - Introduction: Advances in plasma-based assays have allowed for the study of several tau and p-tau epitopes. P-tau217 has emerged as one of the most robust markers of Alzheimer’s disease (AD) pathology. Despite their strong diagnostic performance, plasma tau biomarkers require further validation to clarify their clinical utility.  Objective: To investigate the associations between a panel of phosphorylated and non-phosphorylated tau species measured in antemortem plasma and clinical features of autopsy-confirmed AD.  Methods: Cross-sectional data from 123 participants from the BU ADRC who had antemortem blood draws and brain donation following death. Participants completed neuropsychological testing during life as part of their National Alzheimer’s Coordinating Center-Uniform Data Set (NACC UDS) evaluation. AD neuropathology was diagnosed using NIA-Reagan criteria. Time interval between testing at last visit and autopsy ranged from 0 to 12 years, mean = 5.54 years. Raw neuropsychological test scores were used for analysis. Sample size ranged from 65 to 91 across the tests. Plasma samples were analyzed using immunoprecipitation mass spectrometry (IP-MS) for phosphorylated tau species (p-tau-181, 199, 202, 205, 217, 231) and non-phosphorylated tau (195–209, 212–221) peptides. Two ratios were analyzed, p-tau217/tau212-221 and p-tau205/tau195-209.  Results: 123 participants took part in this study, 55 (44.7%) female, and 6 (4.9%) Black/African American. The mean (SD) age at blood draw was 78.17 (8.55). The strongest association between plasma biomarkers with neuropsychological test outcomes was observed with the ratio p-tau217/tau212-221 (b = − 0.564–0.404, plow-high = 0.00–0.18), followed by p-tau217 (b = − 0.478–0.377, plow-high = 0.00–0.28), both significantly correlating with six of the eight neuropsychological measures (p < 0.05). Followed by the ratio p-tau205/tau195-209 (b = − 0.513–0.356, plow-high = 0.00–0.55), p-tau205 (b = − 0.365–0.226, plow-high = 0.00–0.44), then p-tau231 (b = − 0.319–0.237, plow-high = 0.02–0.62). Fewer significant relationships and weaker effect sizes were observed among the other biomarkers. The effect sizes of the ratio p-tau217/tau212-221, followed closely by p-tau217 on neuropsychological test outcomes, were observed to be the most similar to the effect sizes of autopsy-confirmed AD (b = − 0.564–0.393).  Conclusions: Plasma p-tau217 and p-tau ratios were comparable to autopsy-confirmed AD in predicting clinical outcomes of AD. This study highlights the promise and potential utility of plasma biomarkers for symptom monitoring.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00415-026-14232-y.
SN  - 0340-5354
SN  - 1432-1459
ER  -