DNA methylation age acceleration is associated with incident cognitive impairment in the health and retirement study

Background: DNA methylation clocks have emerged as promising biomarkers for cognitive impairment and dementia. Longitudinal studies exploring the link between DNA methylation clocks and cognitive decline have been constrained by limited sample sizes and a lack of diversity. Objective: Our study aimed to investigate the longitudinal associations between DNA methylation clocks and incident cognitive impairment using a larger sample size encompassing a US nationally representative sample from the Health and Retirement Study. Methods: We measured DNA methylation age acceleration in 2016 by comparing the residuals of DNA methylation clocks, including GrimAge, against chronological age. Cognitive decline was determined by the change in Langa-Weir cognition status from 2016 to 2018. Using multivariable logistic regression, we evaluated the link between DNA methylation age acceleration and cognitive decline, adjusting for cell-type proportions, demographic, and health factors. We also conducted an inverse probability weighting analysis to address potential selection bias from varying loss-to-follow-up rates. Results: The analytic sample (N=2,713) at baseline had an average of 68 years old, and during the two years of follow-up, 12% experienced cognitive decline. Participants who experienced cognitive decline during follow-up had higher baseline GrimAge (mean = 1.2 years) acceleration compared to those who maintained normal cognitive function (mean = -0.8 years, p < 0.001). A one-year increase in GrimAge acceleration was associated with 1.05 times higher adjusted and survey-weighted odds of cognitive decline during follow-up (95% CI: 1.01-1.10). This association was consistent after accounting for loss-to-follow-up (OR = 1.07, 95% CI: 1.04-1.11). Conclusion: Our study offers insights into DNA methylation age acceleration associated with cognitive decline, suggesting avenues for improved prevention, diagnosis, and treatment.