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. 2025 Dec 1;8(12):e2545862.
doi: 10.1001/jamanetworkopen.2025.45862.

Longitudinal Blood-Based Biomarkers and Clinical Progression in Subjective Cognitive Decline

Calvin Trieu  1   2   3   4 , Argonde C van Harten  1   2 , Mardou S S A van Leeuwenstijn  1   2 , Lisa-Marie Schlüter  1   2 , Lynn Boonkamp  3 , Azzam Aladdin  3 , Sietske A M Sikkes  1   2   4 , Elsmarieke van de Giessen  5 , Inge M W Verberk  1   3 , Charlotte E Teunissen  3 , Wiesje M van der Flier  1   2
Affiliations

Longitudinal Blood-Based Biomarkers and Clinical Progression in Subjective Cognitive Decline

Calvin Trieu et al. JAMA Netw Open. .

Abstract

Importance: Blood-based biomarkers identify Alzheimer disease and hold promise for monitoring disease progression, even in the preclinical disease stages.

Objective: To investigate longitudinal trajectories of blood-based biomarkers and association with cognitive decline and risk of progression in individuals with subjective cognitive decline (SCD).

Design, setting, and participants: This prospective cohort study (Subjective Cognitive Impairment Cohort) of individuals with SCD evaluated at a memory clinic underwent biennial biomarker collection and annual cognitive assessment and diagnostic evaluation from January 1, 2005, to December 31, 2023, with follow-up through 2023.

Exposure: Amyloid status was determined using positron emission tomography or cerebrospinal fluid. Plasma Aβ42/40, phosphorylated tau 217 (pTau217), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were measured biennially.

Main outcomes and measures: Cognitive trajectories in memory, attention, language, executive function, and global cognition and clinical progression to mild cognitive impairment or dementia.

Results: A total of 298 individuals (mean [SD] age, 61.55 [8.08] years; 174 [58.4%] male) with SCD were included, of whom 80 were amyloid-positive (A+) and 218 were amyloid-negative (A-). Mean (SD) follow-up was 4.8 (2.6) years. Individuals with SCD A+ were older (mean [SD] age, 65.25 [7.14] years; 42 [52.5%] male) than those with SCD A- (mean [SD] age, 60.19 [8.00] years; 132 [60.6%] male). For pTau217, GFAP, and NfL, baseline levels were higher in the A+ group compared with A- group (estimates [SE] amyloid β, 1.11 [0.11], 0.69 [0.13], and 0.36 [0.10], respectively; P < .001 for all). Additionally, these biomarkers showed steeper increases over time in the A+ group than in A- group (estimates [SE] time × amyloid status β, 0.07 [0.02], P < .001; 0.07 [0.02], P < .001; and 0.05 [0.02], P = .005, respectively). Longitudinal increases in pTau217 and GFAP were associated with cognitive decline over time in all domains (β time × biomarker slope = -0.02 to -0.04). Longitudinal decreases in Aβ42/40 and increases in NfL were associated with cognitive decline in global cognition (β = 0.03 [0.01], P = .04) and language (β = 0.04 [0.02], P = .03), and increases in NfL were also associated with decline in global cognition (β = -0.02 [0.01], P = .004), language (β = -0.03 [0.01], P = .007), and executive functioning (β = -0.03 [0.01], P = .02). Steeper pTau217 slope was associated with progression from SCD to mild cognitive impairment or dementia (hazard ratio [HR], 3.6; 95% CI, 1.8-7.4 per 0.05 SD increase per year; C index, 0.89; 95% CI, 0.84-0.93), as were steeper GFAP slope (HR, 1.5 [95% CI, 1.0-2.2]; C index, 0.81 [95% CI, 0.73-0.88]) and steeper NfL slope (HR, 2.6 [95% CI, 1.3-5.2]; C index, 0.77 [95% CI, 0.69-0.85]). Aβ42/40 slope was not associated with progression.

Conclusions and relevance: This cohort study of individuals with SCD suggests that longitudinal plasma pTau217 and GFAP are suitable biomarkers for monitoring AD pathology. Their changes were associated with cognitive decline and clinical progression, supporting their potential utility for early intervention and disease monitoring.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr van Harten reported receiving personal fees from Lilly and grants from Azheimer Nederland and Dutch Research Council outside the submitted work. Dr Sikkes reported receiving grants from Health~Holland, Topsector Life Sciences & Health, Dutch Research Council, Alzheimer Nederland SPREAD+, Ministry of Health, Welfare and Sports Academic Workplace, Innovative Health Initiative Joint Undertaking, the Real-World Implementation, Deployment, and Validation of Early Detection Tools and Lifestyle Enhancement (AD-RIDDLE), Joint Programme–Neurodegenerative Disease Research (JPND) Remote Digital Assessment and Monitoring for Early Alzheimer's Disease (REMOTE-AD), consulting fees from Nationale Nederlanden Ventures, Prothena Biosciences, Aribio Co Ltd, and Cogstate Ltd, and lecture fees from Bohn Stafleu van Loghum outside the submitted work. In addition, Dr Sikkes had a patent for Amsterdam IADL licensed to Amsterdam UMC. Dr van de Giessen reported receiving grants from the Dutch Research Council, Alzheimer Nederland, Hersenstichting, Health~Holland, KWF, Roche, and AC Immune and personal fees from LMI and Ixico outside the submitted work. Dr Verberk reported receiving personal fees from Neurogen Biomarking, Quanterix, and Nitrase Therapeutics Collaborative and grants from TKI Health~Holland and Amsterdam UMC outside the submitted work. Dr Teunissen reported receiving grants from the European Commission, Innovative Medicines Initiatives 3TR, EPND, JPND, European Partnership on Metrology, Horizon Europe, Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, the Dutch Research Council, Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, and Alzheimer Netherlands and has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, C2N diagnostics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Merck, Muna, Nitrase Therapeutics, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Sysmex, Toyama, Vaccinex, and Vivoryon; she is editor in chief of Alzheimer Research and Therapy and serves on editorial boards of Molecular Neurodegeneration, Alzheimer’s & Dementia, Neurology: Neuroimmunology & Neuroinflammation, and Medidact Neurologie/Springer and is a committee member to define guidelines for cognitive disturbances and one for acute neurology in the Netherlands; and she has a consultancy and/or speaker contracts for Aribio, Biogen, Beckman-Coulter, Cognition Therapeutics, Danaher, Eisai, Eli Lilly, Janssen, Merck, Neurogen Biomarking, Nordic Biosciences, Novo Nordisk, Novartis, Olink, Quanterix, Roche, Sanofi, and Veravas. Dr van der Flier reported receiving grants from Edwin Bouw Fonds, Stichting Dioraphte, Stichting Houbolt, and Noaber during the conduct of the study and funding from ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, Stichting Dioraphte, Noaber Foundation, Pieter Houbolt Fonds, Gieskes-Strijbis fonds, Stichting Equilibrio, Edwin Bouw Fonds, Pasman Stichting, Philips, Biogen MA Inc, Novartis-NL, Life-MI, AVID, Roche BV, Eli-Lilly-NL, Fujifilm, Eisai, Combinostics, ABOARD, Health~Holland, Topsector Life Sciences & Health, TAP-dementia, IHI- PROMINENT, IHI-AD-RIDDLE, Biogen MA Inc, Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, and European Brain Council, has served as a consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc, Eisai, Eli-Lilly, Owkin France, and Nationale Nederlanden Ventures, and has participated in advisory boards of Biogen MA Inc, Roche, and Eli Lilly. Dr van der Flier is member of the steering committees of phase 3 EVOKE/EVOKE+ studies, op phase 3 Trontinemab study (Roche), PAVE, and Think Brain Health, is the chair of the Scientific Leadership Group of InRAD, was associate editor of Alzheimer, Research & Therapy in 2020 to 2021, is associate editor at Brain, and is a supervisory board member (Raad van Toezicht) of Trimbos Instituut. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association Between Amyloid Status and Blood-Based Biomarkers Over Time
The figure shows the trajectories of blood-based biomarkers over time presented as z scores standardized to baseline biomarker values. The models were stratified by amyloid status and adjusted for age and sex, with values centered around the overall sample mean age and sex (mean age of 61.6 years and sex distribution of 58.4% male). Shaded areas indicate 95% CIs. Aβ42/40 indicates amyloid-β42/40 ratio; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain.
Figure 2.
Figure 2.. Associations Between Biomarker Slopes and Cognitive Trajectories Over Time
The figure presents results from linear mixed models examining trajectories of cognitive domain scores (global cognition) over time in relation to biomarker slopes. Biomarker slopes were categorized into tertiles (low, medium, or high) for visualization. Cognitive scores are expressed as z scores. P values shown in the figure represent the biomarker × time interaction, derived from models using continuous biomarker slopes. Models were adjusted for baseline levels (and age, sex, and educational level) to isolate the independent effect of the slope over time. Shaded areas indicate 95% CIs. Aβ42/40 indicates amyloid-β42/40 ratio; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain.
Figure 3.
Figure 3.. Associations Between Biomarker Slopes and Clinical Progression
The figure presents results from Cox proportional hazards regression models showing trajectories of adjusted survival probabilities over time, stratified by tertiles of blood-based biomarker slopes (low, medium, and high). Models were adjusted for age and sex, and survival probabilities reflect the likelihood of progression from subjective cognitive decline to mild cognitive impairment or dementia. Shaded areas indicate 95% CIs. Aβ42/40 indicates amyloid-β42/40 ratio; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain.
See this image and copyright information in PMC

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