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

BACKGROUND: Peripheral blood DNA methylation may have utility as an early dementia risk biomarker.

METHODS: We 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.

RESULTS: Cross-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 (), cg15266133 (), cg24287460 (), cg17124509 (), and cg02553054 ().

DISCUSSION: CpGs identified were enriched in pathways related to Alzheimer's disease pathology and provide promising grounds for non-invasive blood biomarkers. Future studies for replication and with longer follow-up are needed.