Changes in DNA methylation–based aging predicts brain damage and dementia and reflects life‐course cardiovascular risk

INTRODUCTION: There is well-established evidence showing an association between accelerated biological aging (BA) and brain pathology. However, it remains unclear whether dynamic change in BA during adulthood is directly associated with brain health or primarily reflects cumulative life-course environmental and lifestyle exposures. METHODS: We analyzed data from the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-RS; n = 2081), with assessments at midlife (≈50 [SD 6.3] years) and late-life (baseline ≈76 [4.8]; follow-up ≈81 [4.8] years). We identified individuals with substantial change in BA (measured by DunedinPACE) and examined associations with brain magnetic resonance imaging (MRI) and cognitive outcomes. Mediation analyses tested whether late-life BA mediated associations between midlife cardiovascular health and later-life brain health. RESULTS: Shifting to accelerated BA was associated with lower brain volumes and incident dementia. Associations with brain infarcts and cognitive function largely reflected cumulative life-course exposure. DISCUSSION: These findings underscore the need for further investigation into the timing, reversibility, and pathways linking BA to brain health.