DNA methylation clocks and cognitive status among older adults in the US, NHANES 1999-2002

Biological aging, measured using DNA methylation, is a potential biomarker for cognitive health outcomes. We evaluated associations between DNA methylation clocks and cognition in a nationally representative sample of adults aged 60+ in the National Health and Nutrition Examination Survey (NHANES), 1999-2002. Genome-wide DNA methylation data were used to create 13 measures of biological aging trained on different aging phenotypes. Cognition was assessed with the Digit Symbol Substitution Test (DSST). To evaluate associations between each DNA methylation clock and DSST score, survey-weighted linear regression models adjusted for calendar age, sex, race/ethnicity, education, smoking, serum cotinine, and BMI were run. We assessed effect modification by sex, education, and race and ethnicity. Included participants (N=1,463) were an average of 70.5 years old and 82.7% non-Hispanic White. The average DSST score was 46.9 (SD 17.6). Ten of 13 DNA methylation clocks were associated with DSST (adjusted p<0.05). One year of GrimAge2 accelerated aging was associated with -0.41 points lower DSST score (95% CI: -0.61, -0.21; adjusted p=5×10^-4). In stratified analyses, higher magnitudes of association were observed among male and non-Hispanic White participants across multiple clocks. DNA methylation clocks may be a useful biomarker of cognitive status among older adults.