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. 2025 Sep;21(9):e70625.
doi: 10.1002/alz.70625.

Association of plasma Alzheimer's disease biomarkers with cognitive decline in cognitively unimpaired individuals

Petrice M Cogswell  1 , Heather J Wiste  2 , Terry M Therneau  2 , Michael E Griswold  3 , Niklas Mattsson-Carlgren  4   5 , Sebastian Palmqvist  4   5 , Alexa Pichet Binette  4 , Erik Stomrud  4   5 , Randall J Bateman  6 , Nicolas Barthelemy  6 , Joel B Braunstein  7 , Tim West  7 , Philip B Verghese  7 , Mary M Machulda  8 , Jonathan Graff-Radford  9 , Alicia Algeciras-Schimnich  10 , Val J Lowe  1 , Christopher G Schwarz  1 , Matthew L Senjem  1   11 , Jeffrey L Gunter  1 , David S Knopman  9 , Prashanthi Vemuri  1 , Ronald C Petersen  2   9 , Oskar Hansson  4 , Clifford R Jack Jr  1
Affiliations

Association of plasma Alzheimer's disease biomarkers with cognitive decline in cognitively unimpaired individuals

Petrice M Cogswell et al. Alzheimers Dement. 2025 Sep.

Abstract

Introduction: Plasma biomarkers' utility for predicting incident mild cognitive impairment (MCI) remains unclear. We evaluated associations of plasma Alzheimer's disease (AD) biomarkers and amyloid positron emission tomography (PET) with transitions from cognitively unimpaired (CU) to MCI in the Mayo Clinic Study of Aging (MCSA) and BioFINDER-2 studies.

Methods: Associations of continuous baseline plasma biomarker levels and amyloid PET Centiloid with progression to MCI, adjusting for age, sex, and education, were evaluated with Cox proportional hazards models.

Results: The study included 381 MCSA and 584 BioFINDER-2 participants. Amyloid PET and percent phosphorylated to non-phosphorylated tau217 (%p-tau217) were strong predictors of progression to MCI in both cohorts: hazard ratios of 1.49 and 1.23 in the MCSA and 1.72 and 1.65 in BioFINDER, respectively. Amyloid beta 42/40 was a significant predictor in BioFINDER-2 only (hazard ratio 2.20).

Discussion: Plasma %p-tau217 was associated with progression from CU to MCI in both cohorts, although differences in biomarker associations may be related to differences in the two cohorts.

Highlights: Mass-spectrometry-based plasma phosphorylated tau217 was associated with cognitively unimpaired to mild cognitive impairment (MCI) progression. Plasma amyloid beta 42/40 was a significant predictor in BioFINDER but not the Mayo Clinic Study of Aging (MCSA). Amyloid positron emission tomography (PET) was the strongest predictor of progression to MCI in the MCSA. Plasma had added value to amyloid PET in BioFINDER but not the MCSA. Biomarker performance may vary with cohort and biomarker measurement differences.

Keywords: Alzheimer's disease; amyloid beta 42/40; amyloid beta positron emission tomography; mild cognitive impairment; phosphorylated tau 217; plasma biomarkers.

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Conflict of interest statement

P.M.C. has consulted for Eli Lilly and received honoria from Eisai Inc., American Academy of Neurology, Kaplan, Medical Learning Institute, Peerview, and Medscape. She serves on Eisai and Lilly data safety monitoring boards but receives no compensation to self or institution. H.J.W., T.M.T., M.E.G., A.P.B., E.S., and J.L.G. have no disclosures. N.M.C. has received consultancy/speaker fees from Biogen, Eli Lilly, Owkin, and Merck. S.P. has acquired research support (for the institution) from Avid and ki elements through ADDF. In the past 2 years, he has received consultancy/speaker fees from Bioartic, Biogen, Eisai, Eli Lilly, Novo Nordisk, and Roche. R.J.B. has equity ownership interest in C2N Diagnostics; receives income from C2N Diagnostics for serving on the scientific advisory board; may receive income based on technology licensed by Washington University to C2N Diagnostics; is an unpaid scientific advisory board member of Roche and Biogen; and receives research funding from Avid Radiopharmaceuticals, Janssen, Roche or Genentech, Eli Lilly, Eisai, Biogen, AbbVie, Bristol Myers Squibb, and Novartis. N.R.B. may receive income based on technology licensed by Washington University to C2N Diagnostics. J.B.B., T.W., and P.B.V. are paid employees of C2N Diagnostics. M.M.M. receives research funding from the NIH. J.G.R. serves as an associate editor for JAMA Neurology and receives research support from the NIH. He serves on the data safety monitoring board for NINDS StrokeNET. He is site investigator for Cognition Therapeutics and Eisai. A.A.‐S. has participated in advisory boards for Roche Diagnostics, Fujirebio Diagnostics, and Siemens Healthineers. She also has received honorarium from Roche Diagnostics and Eli Lilly. V.J.L. is a consultant for AVID Radiopharmaceuticals, Eisai Co. Inc., Bayer Schering Pharma, GE Healthcare, Piramal Life Sciences, and Merck Research, and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and NIH (NIA, NCI). C.G.S. receives research support from the NIH. M.L.S. holds stock in medical related companies, unrelated to the current work: Align Technology, Inc., LHC Group, Inc., Medtronic, Inc., Mesa Laboratories, Inc., Natus Medical Inc., and Varex Imaging Corporation. He has also owned stock in these medical related companies within the past 3 years, unrelated to the current work: CRISPR Therapeutics, Gilead Sciences, Inc., Globus Medical Inc., Inovio Biomedical Corp., Ionis Pharmaceuticals, Johnson & Johnson, Medtronic, Inc., Oncothyreon, Inc., Parexel International Corporation. D.S.K. serves on a data safety monitoring board for the Dominantly Inherited Alzheimer Network Treatment Unit study sponsored by Washington University St Louis, and for the SMART‐HS clinical trial (Univ of Kentucky). He was an investigator in Alzheimer's disease clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California, which have ended, and is currently an investigator in a trial in frontotemporal degeneration with Alector. He has served as a consultant for Roche, AriBio, Linus Health, Biovie, and Alzeca Biosciences but receives no personal compensation. He receives funding from the NIH. P.V. receives research support from the NIH. R.C.P. serves as a consultant for Roche Inc., Merck Inc., and Biogen, Inc. He serves on the data safety monitoring board for Genentech, Inc. and receives royalty from Oxford University Press and UpToDate. O.H. is an employee of Lund University and Eli Lilly. C.R.J. receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Associations of demographic variables and biomarkers with progression from cognitively unimpaired to mild cognitive impairment. Hazard ratio (95% confidence interval) estimates are from Cox proportional hazards models fit separately within the MCSA and BioFINDER cohorts. The base model included age, sex, and education. PET and plasma biomarkers were added to the base model, one biomarker at a time, and additional models were fit with the base model plus Aβ42/40 and %p‐tau217 (or p‐tau217). All models were fit with and without adjusting for APOE ε4 carrier status. Aβ, amyloid beta; APOE, apolipoprotein E; APS2, Amyloid Probability Score 2; CI, confidence interval; HR, hazard ratio; MCSA, Mayo Clinic Study of Aging; PET, positron emission tomography; p‐tau, phosphorylated tau.
FIGURE 2
FIGURE 2
PET and plasma associations with progression from cognitively unimpaired to mild cognitive impairment from models including both PET and plasma measures. Hazard ratio (95% confidence interval) estimates are from Cox proportional hazards models fit separately within the MCSA and BioFINDER cohorts. All models included age, sex, education, and amyloid PET. Separate models were fit for each plasma biomarker, one at a time, or combinations of Aβ42/40 and %p‐tau217 (or p‐tau217). All models were fit with and without adjusting for APOE ε4 carrier status. Aβ, amyloid beta; APOE, apolipoprotein E; APS2, Amyloid Probability Score 2; CI, confidence interval; HR, hazard ratio; MCSA, Mayo Clinic Study of Aging; PET, positron emission tomography; p‐tau, phosphorylated tau.
FIGURE 3
FIGURE 3
Associations of demographic variables and biomarkers with progression from cognitively unimpaired to mild cognitive impairment stratified by APOE ε4 carrier status. Hazard ratio (95% confidence interval) estimates are from Cox proportional hazards models fit separately within the MCSA and BioFINDER cohorts. The base model included age, sex, education, and APOE ε4 carrier status. PET and plasma biomarkers were added to the base model, one biomarker at a time, and additional models were fit with the base model plus Aβ42/40 and %p‐tau217 (or p‐tau217). All models included interactions with APOE and the other predictor variables in the model. The interaction P values are shown above, indicating if the associations were significantly different among APOE ε4 carriers versus non‐carriers. Aβ, amyloid beta; APOE, apolipoprotein E; APS2, Amyloid Probability Score 2; CI, confidence interval; HR, hazard ratio; MCSA, Mayo Clinic Study of Aging; PET, positron emission tomography; p‐tau, phosphorylated tau.
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