medRxiv · May 27, 2026

DNA Methylation Signatures of Atherosclerosis and Vascular-Related Outcomes in U.S. and Irish Population-Based Cohorts

By Ammous F, Smith T, Scarlett S et al.

Atherosclerosis is a systemic vascular process linked to cardiovascular, cognitive and renal outcomes. DNA methylation (DNAm)-based scores of atherosclerosis may capture cumulative biological processes underlying vascular aging. Here, we examined associations of DNAm scores for coronary artery calcification (DNAm-CAC) and carotid plaque (DNAm-cPlaque), derived from a large study of imaging-based subclinical atherosclerosis, with prevalent and incident outcomes in two population-based cohorts of older adults: the Health and Retirement Study (HRS; n = 3,875) and The Irish Longitudinal Study on Ageing (TILDA; n = 487). Higher DNAm scores were associated with adverse cardiometabolic profiles and socioeconomic indicators. In HRS, higher DNAm-CAC was associated with prevalent cardiovascular disease (odds ratio per SD, 1.16; 95% confidence interval (CI), 1.07-1.26), lower cognitive function (β =-0.50, 95% CI-0.68 to-0.32) and lower estimated glomerular filtration rate (eGFR; -1.7 ml min ⁻¹ 1.73 m ⁻² , 95% CI-2.6 to-0.8) in unadjusted models. After adjustment for demographic and clinical risk factors, DNAm-CAC (β =-0.29, 95% CI-0.46 to-0.13) and DNAm-cPlaque (β =-0.24, 95% CI-0.42 to-0.06) remained associated with lower cognitive function, and DNAm-cPlaque was associated with incident cognitive impairment or dementia (hazard ratio per SD, 1.16; 95% CI, 1.01-1.32). Associations were attenuated after further adjustment for race/ethnicity and socioeconomic indicators. In TILDA, higher DNAm-cPlaque was associated with worse cognitive performance (incidence rate ratio, 1.11; 95% CI, 1.01-1.21), increased risk of incident cardiovascular disease (hazard ratio, 1.18; 95% CI, 1.00-1.42) and lower eGFR, with consistent associations observed for DNAm-CAC. These findings suggest that DNAm-based scores of atherosclerosis capture systemic vascular processes linked to multiple age-related outcomes across populations. Further work is needed to clarify the biological pathways reflected by these scores and their relation to cumulative and socially patterned vascular risk.

doi.org/10.64898/2026.05.25.26354072Open accessPubMed 42245044Biomarkers