. 2025 Jun 20:10.1002/ana.27285.

doi: 10.1002/ana.27285. Online ahead of print.

Timing of Changes in Alzheimer's Disease Plasma Biomarkers as Assessed by Amyloid and Tau PET Clocks

Marta Milà-Alomà^{1

2}, Duygu Tosun^{1

2}, Suzanne E Schindler³, Isabella Hausle^{1

2}, Kellen K Petersen³, Yan Li³, Jeffrey L Dage^{4

5}, Lei Du-Cuny⁶, Ziad S Saad⁷, Benjamin Saef³, Gallen Triana-Baltzer⁷, David L Raunig⁸, Janaky Coomaraswamy⁸, Michael Baratta⁸, Emily A Meyers⁹, Yulia Mordashova⁶, Carrie E Rubel¹⁰, Kyle Ferber¹⁰, Hartmuth Kolb¹¹, Nicholas J Ashton¹², Henrik Zetterberg^{12

13

14

15

16

17}, Erin G Rosenbaugh¹⁸, Martin Sabandal¹⁸, Leslie M Shaw¹⁹, Anthony W Bannon²⁰, William Z Potter; Alzheimer's Disease Neuroimaging Initiative (ADNI); Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium Plasma Aβ and Phosphorylated Tau as Predictors of Amyloid and Tau Positivity in Alzheimer's Disease Project Team

Affiliations

¹ Northern California Institute for Research and Education, San Francisco, CA, USA.
² Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
³ Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
⁴ Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ AbbVie, Ludwigshafen am Rhein, Rheinland-Pfalz, Germany.
⁷ Neuroscience Biomarkers, Johnson and Johnson Innovative Medicine, San Diego, CA, USA.
⁸ Takeda Pharmaceutical Company Ltd., Cambridge, MA, USA.
⁹ Alzheimer's Association, Chicago, IL, USA.
¹⁰ Biogen, Cambridge, MA, USA.
¹¹ Enigma Biomedical Group, San Diego, CA, USA.
¹² Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
¹³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁴ UK Dementia Research Institute Fluid Biomarkers Laboratory, UK DRI at UCL, London, UK.
¹⁵ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
¹⁶ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹⁷ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹⁸ The Foundation for the National Institutes of Health, North Bethesda, MD, USA.
¹⁹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁰ AbbVie, North Chicago, IL, USA.

PMID: 40539416
PMCID: PMC12335434 (available on 2026-06-20)
DOI: 10.1002/ana.27285

Timing of Changes in Alzheimer's Disease Plasma Biomarkers as Assessed by Amyloid and Tau PET Clocks

Marta Milà-Alomà et al. Ann Neurol. 2025.

. 2025 Jun 20:10.1002/ana.27285.

doi: 10.1002/ana.27285. Online ahead of print.

Authors

Affiliations

¹ Northern California Institute for Research and Education, San Francisco, CA, USA.
² Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.
³ Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA.
⁴ Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁵ Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ AbbVie, Ludwigshafen am Rhein, Rheinland-Pfalz, Germany.
⁷ Neuroscience Biomarkers, Johnson and Johnson Innovative Medicine, San Diego, CA, USA.
⁸ Takeda Pharmaceutical Company Ltd., Cambridge, MA, USA.
⁹ Alzheimer's Association, Chicago, IL, USA.
¹⁰ Biogen, Cambridge, MA, USA.
¹¹ Enigma Biomedical Group, San Diego, CA, USA.
¹² Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
¹³ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁴ UK Dementia Research Institute Fluid Biomarkers Laboratory, UK DRI at UCL, London, UK.
¹⁵ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
¹⁶ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China.
¹⁷ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
¹⁸ The Foundation for the National Institutes of Health, North Bethesda, MD, USA.
¹⁹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁰ AbbVie, North Chicago, IL, USA.

PMID: 40539416
PMCID: PMC12335434 (available on 2026-06-20)
DOI: 10.1002/ana.27285

Abstract

Objective: The objective of this study was to evaluate the timing of change of Alzheimer's disease (AD) plasma biomarkers (Aβ42/Aβ40, p-tau217, p-tau181, GFAP, and NfL) from six different assay platforms, alongside established AD biomarkers, using amyloid and tau positron emission tomography (PET)-based AD progression timelines.

Methods: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 784 individuals with longitudinal amyloid PET and 359 with longitudinal tau PET, were analyzed to estimate the age at amyloid and tau PET positivity, respectively. Longitudinal plasma biomarker measurements were available from 190 individuals with an estimated amyloid PET positivity age and from 70 individuals with an estimated tau PET positivity age. In a subset of 17 clinical progressors, age at tau PET positivity strongly predicted symptom onset, allowing for estimation of symptom onset age. Biomarker trajectories based on time from amyloid or tau PET positivity or symptom onset were modelled using Generalized Additive Mixed models. Time intervals of significant biomarker change and the earliest timepoints at which biomarkers exceeded predefined abnormality thresholds were identified.

Results: All plasma biomarkers except NfL became abnormal prior to established thresholds for amyloid and tau PET positivity. Plasma Aβ42/Aβ40 became abnormal very early in both amyloid PET and tau PET timelines, while plasma GFAP became abnormal early in the tau PET timeline. Plasma Aβ42/Aβ40 levels plateaued, whereas plasma p-tau217, p-tau181, GFAP, and NfL levels increased throughout the modeled disease progression. Some variations in the timing of these changes were observed across different biomarker assays.

Interpretation: These findings suggest that the plasma Aβ42/Aβ40 may be useful in identifying individuals with very low levels of amyloid pathology, whereas p-tau, GFAP, and NfL may be useful in staging disease progression. ANN NEUROL 2025.

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Conflict of interest statement

H.K. has served on scientific advisory boards and/or as a consultant for ALZpath and Roche, and has given lectures sponsored by Fujirebio and Roche. J.L.D. has/is served/serving as a consultant or on advisory boards for AlzPath Inc., and Quanterix. J.L.D. has received research support from Fujirebio and Roche Diagnostics in the past two years. J.L.D. has stock or stock options in AlzPath Inc. Y.L. is the co-inventor of the technology “Novel Tau isoforms to predict onset of symptoms and dementia in Alzheimer’s disease” which is in the process of licensing by C2N. N.J.A has received speaking fees from Quanterix. These conflicts involved companies that are developers of the assays used in the study.

M.M.A., D.T., S.E.S., I.H., K.K.P., L.D.C., Z.S.S., B.S., G.T.B., D.L.R., J.C., M.B., E.A.M., Y.M., C.E.R., K.F., H.K., E.G.R., M.S., L.M.S., A.W.B. and W.Z.P. have nothing to report.

Update of

Timing of changes in Alzheimer's disease plasma biomarkers as assessed by amyloid and tau PET clocks.
Milà-Alomà M, Tosun D, Schindler SE, Hausle Z, Li Y, Petersen KK, Dage JL, Du-Cuny L, Saad ZS, Saef B, Triana-Baltzer G, Raunig DL, Coomaraswamy J, Baratta M, Meyers EA, Mordashova Y, Rubel CE, Ferber K, Kolb H, Ashton NJ, Zetterberg H, Rosenbaugh EG, Sabandal M, Shaw LM, Bannon AW, Potter WZ; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium Plasma Aβ and Phosphorylated Tau as Predictors of Amyloid and Tau Positivity in Alzheimer’s Disease Project Team. Milà-Alomà M, et al. medRxiv [Preprint]. 2024 Nov 14:2024.10.25.24316144. doi: 10.1101/2024.10.25.24316144. medRxiv. 2024. Update in: Ann Neurol. 2025 Jun 20. doi: 10.1002/ana.27285. PMID: 39574864 Free PMC article. Updated. Preprint.

Cited by

Cognitive impairment and p-tau217 are high in a vascular patient cohort.
French SR, Arias JC, Zahra S, Ally M, Escareno C, Heitkamp E, Vazquez F, Hillis M, Wiskoski H, Ainapurapu K, Culwell G, Howell C, Johnson K, Kraemer C, Pacanowski J, Leon L, Berman S, Yanquez F, Balderman J, Sabat J, Hung O, Lucas L, Vitali F, Bedrick EJ, Mushtaq R, Altbach M, Trouard TP, Elahi FM, Ashton NJ, Dage JL, Reiman EM, Alexander GE, Weinkauf CC. French SR, et al. Alzheimers Dement. 2025 Aug;21(8):e70565. doi: 10.1002/alz.70565. Alzheimers Dement. 2025. PMID: 40772428 Free PMC article.

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Timing of Changes in Alzheimer's Disease Plasma Biomarkers as Assessed by Amyloid and Tau PET Clocks

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Timing of Changes in Alzheimer's Disease Plasma Biomarkers as Assessed by Amyloid and Tau PET Clocks

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