Epigenetic Aging Clocks Associate with Cognitive Status More Strongly Than Short-Term Cognitive Change: Evidence from...

Cognitive impairment is a major source of disability in Parkinsonian disorders, yet biomarkers that distinguish cognitive status from cognitive decline remain limited. DNA methylation-based epigenetic aging (EA) measures capture complementary dimensions of biological aging, but it remains unclear whether they primarily reflect stable between-person differences in cognitive performance or longitudinal cognitive change.

We examined associations between EA measures and global cognition in the Parkinson's Progression Markers Initiative (PPMI) cohort. Seven EA measures were derived from peripheral blood DNA methylation data, and cognition was assessed longitudinally using the Montreal Cognitive Assessment (MoCA). Linear mixed-effects models included baseline-plus-change-from-baseline, within-person versus between-person decomposition, baseline clock-by-time interaction, and decline-focused sensitivity models.

Higher EA was consistently associated with lower overall MoCA scores. In baseline-plus-change-from-baseline models, the analytic-baseline component showed the dominant signal, whereas the change-from-baseline terms were not significant after false discovery rate correction. In decomposition models, associations were concentrated in the between-person component, while within-person deviation terms were not significant. Secondary analyses were consistent with this pattern.

Blood-based EA measures may be more informative as markers of cognitive status than as markers of short-term cognitive progression. Larger studies with longer follow-up and more detailed domain-specific cognitive phenotyping are needed to clarify their longitudinal relevance.