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. 2025 Dec 3.
doi: 10.1186/s13195-025-01925-1. Online ahead of print.

Individualized prediction of clinical progression to dementia using plasma biomarkers in non-demented elderly

Madison I J Honey  1 , Ingrid S van Maurik  2   3 , Argonde C van Harten  4   5 , Mariam Gouda  4 , Mardou van Leeuwenstijn  5 , Arenda Mank  5 , Calvin Trieu  4   5 , Vincent Bouteloup  6 , Geneviève Chêne  6 , Isabelle Pellegrin  6 , Carole Dufouil  6 , James D Doecke  7 , Christopher J Fowler  8 , Colin L Masters  8 , Yolande Pijnenburg  5 , David Wilson  9 , Wiesje M van der Flier  5 , Charlotte E Teunissen  4 , Inge M W Verberk  4
Affiliations
Free article

Individualized prediction of clinical progression to dementia using plasma biomarkers in non-demented elderly

Madison I J Honey et al. Alzheimers Res Ther. .
Free article

Abstract

Background: We aimed to develop individualized predictions for risk of developing any-cause dementia and Alzheimer's disease (AD) dementia, in individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI), using plasma phosphorylated-tau-181 (pTau181), phosphorylated-tau-217 (pTau217; in a subset), amyloid beta1-42/1-40 (Aβ42/40), glial fibrillary acidic protein (GFAP) and/or neurofilament light (NfL).

Methods: From the Amsterdam Dementia Cohort we included 314 individuals with SCD (age 61 ± 9 years, n = 184 (59%) male, MMSE 29 ± 1) and 253 individuals with MCI (age 65 ± 7 years, n = 165 (65%) male, MMSE 27 ± 2), who had annual follow-up (median duration 2.4 years). Cox proportional hazards regression models were used to calculate probabilities for progression to dementia and were externally validated in MEMENTO and AIBL cohorts.

Results: During follow-up 20 SCD and 99 MCI patients developed dementia. For MCI patients who progressed to any form of dementia, plasma GFAP contributed on top of age, sex, and MMSE score in the parsimonious individualized prognostic model (C-index = 0.69 [95%CI = 0.63; 0.76]). With AD-dementia as the outcome, GFAP and pTau181 were selected in the parsimonious model on top of the demographic variables (C-index = 0.71 [95%CI = 0.65; 0.76]). In the subset of 197 MCI individuals with pTau217 measurements, pTau217 was selected in the parsimonious model on top of the demographic variables (C-index = 0.75 [95%CI = 0.69; 0.79]). External validation demonstrated that the models are robust in a memory clinic setting.

Conclusions: Our prediction models have utility for clinical practice to calculate progression probabilities for development of dementia in individual patients living with MCI over a 1-, 3- and 5-year time period.

Keywords: Alzheimer’s disease; Biomarkers; Blood; Dementia; Individualised; Mild cognitive impairment; Plasma; Prognosis; Risk; Subjective cognitive decline.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All human subjects provided informed consent to utilise their medical data and biospecimens for research. The study was approved by the Institutional Ethical Review Board of the Amsterdam University Medical Centers and performed in accordance with the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: This study was executed under the umbrella of the Dutch ABOARD project (http://www.aboard-project.nl). Research of the Neurochemistry Lab and Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. The chair of Wiesje van der Flier is supported by the Pasman stichting. MH, CET and WF are recipients of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health ~ Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl), one of which is the Dutch Brain Foundation (Hersenstichting). The SCIENCe project receives funding from stichting Dioraphte. AH`s research is funded by Alzheimer Nederland, ZonMW and the Alzheimer Drug Discovery Foundation. She served as a consultant for Lilly and is an advisory board member for the brain research center. IM’s research is funded by ZonMW and STI-MAG. IM received a consultancy fee (paid to the university) from Roche. IV’s research is funded by Health ~ Holland and Amsterdam UMC. She serves as a consultant for Neurogen Biomarking (paid directly to the institution). Research of CET is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE) and TAME, Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE, CCAD), European Partnership on Metrology, co-financed from the European Union’s Horizon Europe Research and Innovation Programme and by the Participating States ((22HLT07 NEuroBioStand), CANTATE project funded by the Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. CET is recipient of ABOARD, which is a public–private partnership receiving funding from ZonMW (#73305095007) and Health ~ Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). CET is recipient of TAP-dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy. CET has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vivoryon. She is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Molecular Neurodegeneration, Neurology: Neuroimmunology & Neuroinflammation, Medidact Neurologie/Springer, and serves on committee to define guidelines for Cognitive disturbances, and one for acute Neurology in the Netherlands. She had consultancy/speaker contracts for Aribio, Biogen, Beckman-Coulter, Cognition Therapeutics, Eli Lilly, Merck, Novo Nordisk, Olink, Roche and Veravas. All other authors have nothing to declare.

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