Abstract
BACKGROUND: The relationship between cognitive function, measured by digital Clock Drawing Test (dCDT), and biological aging is lacking. METHODS: We used linear mixed regression to evaluate the associations between epigenetic aging metrics (Horvath, Hannum, GrimAge, PhenoAge, DunedinPACE) and dCDT scores in the Framingham Heart Study (FHS), adjusting for covariates. Significance was set at a false discovery rate (FDR) <0.05. RESULTS: Among the 1,789 FHS participants (mean age 65 ± 13, 53% women), higher epigenetic age acceleration metrics at baseline predicted lower dCDT scores approximately seven years later. The magnitude of these associations was greater in older participants (≥65 years, n = 985). The strongest association was observed between the dCDT total score and DunedinPACE in the full sample (beta = -2.1, FDR = 0.0004), the younger (<65 years; beta = -1.9, FDR = 0.02), and older (beta = -2.2, FDR = 0.01) age groups. Additionally, the dCDT total score was associated with age acceleration estimated by Horvath (beta = -1.9, FDR = 0.01) and PhenoAge (beta = -2.5, FDR = 0.01) in older participants, while not in the full sample or younger participants. Furthermore, higher levels of DNAm-based PAI1 (beta = -0.9, FDR = 0.005) and ADM (beta = -2.9, FDR = 0.01), components of GrimAge, were significantly associated with lower dCDT total scores. In analyses of cognitive subdomains, simple motor function was significantly associated with DunedinPACE (FDR = 0.005) in both age groups, and with GrimAge (FDR = 0.05) in the older age group, suggesting that deterioration in various organ systems may particularly impact this domain. CONCLUSION: Our findings suggest that advanced biological aging, particularly as captured by DunedinPACE and GrimAge components, is significantly associated with poorer cognitive performance measured by dCDT, especially in older adults, highlighting a potential link between systemic aging processes and cognitive decline.