Abstract DP384: Health-Related Behaviors, Biological Aging, and Risk of Dementia, Stroke, and Late-Life Depression

Introduction: Health-related behaviors are associated with the risk of dementia, stroke, and late-life depression (DSD), potentially via accelerated biological aging. We therefore aimed to assess: (i) associations between health-related behaviors, measured by the Brain Care Score (BCS), and methylation-based and proteomic markers of biological aging, and (ii) whether biological aging mediates associations between health behaviors and DSD incidence. Methods: We used data from the Health and Retirement Study (HRS, 2016-2022) and the UK Biobank (UKB, 2007-2022). The BCS, a validated tool assessing 12 modifiable risk factors for DSD (higher scores indicating better brain care), was derived using proxies in each cohort. Participants were categorized into low (Q1), medium (Q2–Q4), and high (Q5) BCS groups. Missing BCS variables in HRS were imputed. In HRS, we assessed methylation-based markers of age (HorvathAge, HannumAge, GrimAge, PhenoAge) and pace of aging (DunedinPoAm). In the UKB, we assessed proteomic age (ProtAge). Associations were tested using confounder-adjusted linear regression, and mediation analyses were conducted using confounder-adjusted Cox proportional hazards and linear regression models with bootstrapped confidence intervals. Results: We included 4,018 HRS participants (mean age 69.8, 58% female) and 42,594 UKB participants (mean age 56.7, 54% female). The median BCS was 13 (IQR: 11-15) of 21 in HRS and 12 (10-13) of 19 in UKB. Compared with low BCS, high BCS was associated with lower GrimAge (-2.37 years [95% CI -2.79,-1.95]), PhenoAge (-1.75 [-2.43,-1.08]), HannumAge (-0.81 [-1.29,-0.32]), ProtAge (-0.31 [-0.39,-0.22]), and a slower pace of aging (SMD -0.42 [-0.51,-0.32]; all p≤0.001). In HRS, over 7 years, 777 incident cases of DSD occurred (27.5%). Mediation analysis showed that GrimAge accounted for 12.1% (6.0–22.3%), PhenoAge for 4.5% (1.6–9.7%), and DunedinPoAm for 6.6% (1.1–14.6%) of the association between the BCS and DSD incidence. In UKB, over a median follow-up of 13.2 (IQR: 12.5-14.0) years, 2,310 incident DSD cases occurred (6.1%), with ProtAge mediating 2.9% (1.9–4.2%). Conclusion: Healthy behaviors are associated with lower biological age and slower page of aging. Accelerated biological aging mediates a significant proportion of the association between health-related behaviors and incidence of DSD, suggesting that biological aging may be an important mechanistic pathway through which health behaviors modify disease risk.