Association of DNA methylation age acceleration with digital clock drawing test performance: the Framingham Heart Study

Abstract Background Cognitive function measured by digital clock drawing test (dCDT) has drawn attention for their precision, automation, and reproductivity. However, the relationship between digital cognitive metrics and biological aging is lacking. Methods We conducted association analyses between cognitive function measured by dCDT and biological aging metrics quantified by five DNA methylation (DNAm) age metrics (Horvath, Hannum, GrimAge, PhenoAge, and DunedinPACE) in the Framingham Heart Study (FHS). We conducted linear regression to investigate the association between cognitive functions (global cognitive function and four sub-domain functions) and DNAm age acceleration, adjusting for covariates. We used a false discovery rate (FDR) < 0.05 for significance. Results Among the 1,798 FHS participants (mean age 65±13, 53% women), we found that a lower dCDT total score is associated with DNAm age acceleration. Larger magnitudes of associations were observed in older participants (≥ 65 years). The dCDT total score showed the strongest association with the DundinPACE in the pooled sample (beta = −2.1, FDR = 0.0004), the younger (beta = −1.9, FDR = 0.02), and older age group (beta = −2.2, FDR = 0.01). The dCDT total score was significantly 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 pooled sample or younger participants (<65 years). In sub-domain cognitive functions, we found that simple motor function was significantly associated with DunedinPACE (FDR = 0.005) in both age groups and associated with GrimAge (FDR = 0.05 in older age group), indicating the deterioration in various organ systems may particularly impact this domain. Discussion Our findings suggest that cognitive function measured by a digital clock drawing test is associated with DNAm age acceleration in middle-aged and older participants in the FHS, potentially shedding light on the epigenetic mechanisms underlying digitally measured cognitive function.