Epigenetic Age and Resilience in the Framingham Heart Study

Growing evidence suggests that decreased epigenetic age relative to chronological age may be protective against late-life cognitive decline and dementia, but the mechanism leading to this resilience is unknown.

DNA methylation (DNAm), plasma total tau (t-tau), MRI total cerebral brain volume (TCBV), and neuropsychological (NP) data were obtained from Framingham Heart Study Offspring cohort participants. Three epigenetic age measures, DunedinPACE, PCPhenoAge, and PCGrimAge, were estimated from DNAm data. DunedinPACE and residuals from regressing PCPhenoAge and PCGrimAge on chronological age were standardized for analysis. Longitudinal NP factor scores were previously derived for memory, language, and executive function (EF) using confirmatory factor analysis. We tested the association of epigenetic age with cognitive trajectories using linear mixed-effects models and with time to mild cognitive impairment (MCI), Alzheimer disease dementia (AD), and all-cause dementia using Cox proportional hazard models and whether t-tau and TCBV moderated the observed relationships.

At baseline (Exam 8, 2005-2008), the sample included 2,606 participants [mean age: 66 (SD = 9) years, 55% female, mean education: 16 (SD = 3) years]. Epigenetic age measures were weakly but significantly (p < 0.001) correlated with t-tau (r: 0.08-0.12) and TCBV (r: -0.05 to -0.24). All epigenetic age measures were associated with worse baseline EF (DunedinPACE: β = -0.040, 95% CI [-0.067 to -0.012], p_adj = 0.01; PCPhenoAge: β = -0.036, 95% CI [-0.062 to -0.011], p_adj = 0.01; PCGrimAge: β = -0.049, 95% CI [-0.080 to -0.018], p_adj = 0.01). PCPhenoAge also was associated with worse baseline memory (β = -0.034, 95% CI [-0.058 to -0.010], p_adj = 0.01) and language (β = -0.032, 95% CI [-0.058 to -0.006], p_adj = 0.03). DunedinPACE was associated with time to MCI (hazard ratio [HR] = 1.16, 95% CI [1.04-1.30], p_adj = 0.04) and all-cause dementia (HR = 1.30, 95% CI [1.10-1.54], p_adj = 0.03). Epigenetic age measures were not associated with the rate of decline. Magnitudes of association for epigenetic age measures remained similar after adjustment for TCBV and t-tau. TCBV and t-tau had similar magnitudes of association in analyses stratified by median epigenetic age.

Independent of t-tau and TCBV, epigenetic age measures were associated with time to MCI, AD, and all-cause dementia and baseline cognition, but not with cognitive trajectories. The results support epigenetic age measures as markers of resilience through brain reserve. The findings may have important implications regarding use of epigenetic age measures as biomarkers to track the success of interventions targeting resilience.