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

DNA methylation clocks have emerged as promising biomarkers for cognitive impairment and dementia. Longitudinal studies exploring the association 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 associations between DNA methylation clocks and incident cognitive impairment using a larger and US nationally-representative sample from the Health and Retirement Study.

Methods

We measured DNA methylation age acceleration in 2016 by regressing the DNA methylation clocks, including GrimAge, against chronological age. Cognitive change over time was determined by Langa-Weir cognition status from 2016 to 2018. Multivariable logistic regression evaluated the association between DNA methylation age acceleration and cognitive change, adjusting for cell-type proportions, demographic, and health factors. We also applied inverse probability weighting to address potential selection bias from varying loss-to-follow-up rates.

Results

The analytic sample (N = 2713) was 54% female, 8.4% Black/African American, 86% White, 7.5% Hispanic, and 68 years old at baseline. During the two years of follow-up, 12% experienced cognitive change and had higher baseline GrimAge (mean = 1.2 years) acceleration compared to those maintaining normal cognition (mean = −0.8 years). A one-year increase in GrimAge acceleration was associated with 1.05 times higher adjusted and survey-weighted odds of cognitive change 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).

Conclusions

Our study offers insights into DNA methylation age acceleration associated with cognitive change over time, suggesting avenues for improved prevention, diagnosis, and treatment.