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. 2025 Feb;21(2):e14577.
doi: 10.1002/alz.14577.

Plasma proteomics for cognitive decline and dementia-A Southeast Asian cohort study

Ming Ann Sim  1   2   3 , James D Doecke  4 , Oi Wah Liew  5   6 , Lee Lee Wong  5   6 , Eugene S J Tan  2   5 , Siew Pang Chan  5   6 , Joyce R F Chong  1 , Yuan Cai  7 , Saima Hilal  8 , Narayanaswamy Venketasubramanian  9 , Boon Yeow Tan  10 ; Alzheimer's Disease Neuroimaging Initiative; Mitchell K P Lai  1 , Hyungwon Choi  6   11   12 , Colin L Masters  13 , Arthur Mark Richards  5   6   14 , Christopher L H Chen  1
Affiliations

Plasma proteomics for cognitive decline and dementia-A Southeast Asian cohort study

Ming Ann Sim et al. Alzheimers Dement. 2025 Feb.

Abstract

Introduction: The prognostic utility of plasma proteomics for cognitive decline and dementia in a Southeast Asian population characterized by high cerebrovascular disease (CeVD) burden is underexplored.

Methods: We examined this in a Singaporean memory clinic cohort of 528 subjects (n = 300, CeVD; n = 167, incident cognitive decline) followed-up for 4 years.

Results: Of 1441 plasma proteins surveyed, a 12-protein signature significantly predicted cognitive decline (q-value < .05). Sixteen diverse biological processes were implicated in cognitive decline. Ten proteins independently predicted incident dementia (q-value < .05). A unified prediction model combining plasma proteins with clinical risk factors increased the area under the curve for outcome prediction from 0.62 to 0.85. External validation in the cerebrospinal fluid proteome of an independent Caucasian cohort replicated four of the significantly predictive plasma markers for cognitive decline namely: GFAP, NEFL, AREG, and PPY.

Discussion: The prognostic proteins prioritized in our study provide robust signals in two different biological matrices, representing potential mechanistic targets for dementia and cognitive decline.

Highlights: A total of 1441 plasma proteins were profiled in a Singaporean memory clinic cohort. We report prognostic plasma protein signatures for cognitive decline and dementia. External validation was performed in the cerebrospinal fluid proteome of a Caucasian cohort. A concordant proteomic signature was identified across both biofluids and cohorts. Further studies are needed to explore the therapeutic implications of these proteins for dementia.

Keywords: Southeast Asian; blood biomarker; cerebrovascular disease; cognitive decline; incident dementia; proteomics.

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Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Overview of the study. CIND, cognitive impairment no dementia; NCI, no cognitive impairment; CDR‐SB, Clinical Dementia Rating Sum of Boxes; CSF, cerebrospinal fluid. Created with biorender.com.
FIGURE 2
FIGURE 2
(A) Volcano plot of proteins significantly associated with the risk of incident cognitive decline. (B) Biological pathways with statistical overrepresentation in the predictive proteins for cognitive decline (p‐value < .05, q‐value < .2) for cognitive decline. (C) Volcano plot of significant proteins for progression from CIND to dementia. CNID, cognitive impairment no dementia.
FIGURE 3
FIGURE 3
(A) Receiver‐operating characteristic (ROC) curves of the predictive models with clinical risk factors, cognition, and plasma proteins. (B) Feature importance plot of the selected clinical risk factors and proteins. Abbreviations: AUC, area under the ROC curve; ROC, receiver‐operating characteristic; SHAP, Shapley additive values.
FIGURE 4
FIGURE 4
(A) Internal validation of Olink NPX values with paired quantitative immunoassays. (B) Heatmap of cross‐sectional associations between 12 significantly predictive plasma proteins for cognitive decline and neuroimaging markers in the MACC cohort. MACC, Memory Aging and Cognition Centre; NPX, Normalized Protein eXpression.
FIGURE 5
FIGURE 5
External validation of findings (A, B). Volcano and Forest plots of concordantly cross‐validated significant predictive proteins for cognitive decline in: (A) the plasma proteome of the MACC cohort and (B) the CSF proteome of the ADNI cohort. ADNI, Alzheimer's Disease Neuroimaging Initiative; CSF, cerebrospinal fluid; MACC, Memory Aging and Cognition Centre.
See this image and copyright information in PMC

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