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DNA methylation-wide association study of prevalent and incident dementia in the US Health and Retirement Study

Dou, J.; Cockell, S.; Wang, H.; Hemenway, N.; Ryan, L.; Zawistowski, M.; Ware, E.; Bakulski, K. M.

2025-11-13 epidemiology
10.1101/2025.11.10.25339919 medRxiv
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BACKGROUNDPeripheral blood DNA methylation may have utility as an early dementia risk biomarker. METHODSWe analyzed DNA methylation (blood collected 2016) and cognitive impairment in the Health and Retirement Study, a longitudinal study representative of US adults over age 50 (3,921 individuals and 585,356 CpG sites). We analyzed methylation associations with cognitive status both cross-sectionally and prospectively among participants with normal cognition at baseline with four years follow-up. RESULTSCross-sectionally, 5,322 CpGs were associated (p-value<0.01) with cognitive impairment non-dementia, and 14,366 (166 genome-wide FDR<0.05) with dementia. Prospectively, 4,898 CpGs were associated with any-impairment. Enriched biologic pathways include ion transport, ligand-gated channel, and neuron differentiation. Nine CpGs overlapped all analyses including cg02583484 (HNRNPA1), cg15266133 (LOC102724084), cg24287460 (CCDC48), cg17124509 (C17orf57), and cg02553054 (SMARCD1). DISCUSSIONCpGs identified were enriched in pathways related to Alzheimers disease pathology and provide promising grounds for non-invasive blood biomarkers. Future studies for replication and with longer follow-up are needed.

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