Abstract DP004: Improvements in Biological Age Acceleration Lead to Better Neuroimaging, Clinical, and Cognitive Markers of Brain Health

Background: Biological age acceleration (BAA), the discrepancy between chronological and biological age, captures multisystem aging and is associated with adverse neurological outcomes. Whether improving BAA leads to future brain health benefits remains unknown. Hypothesis: We tested whether baseline (T0) BAA and changes in BAA from baseline (T0) to the repeat visit (T1) are associated with subsequent (T2) MRI markers of small vessel disease, cognitive performance, and incident stroke (Figure 1). Methods: KDmAge, a biological age measure built from 18 routine blood biomarkers with externally calibrated weights, was derived at baseline (T0) for 258,169 UK Biobank participants (mean age 56, mean KDmAge 54, 53% female) and at the repeat visit (T1) for 6,085 participants (mean age 62, mean KDmAge 58, 50% female). BAA was obtained by residualizing KDmAge on age (3-df splines) and sex. Exposures were baseline BAA and annualized change (ΔBAA/yr). Outcomes were: (i) MRI markers at T2; (ii) cognitive performance at T2; and (iii) incident stroke and ischemic stroke over a median 10-year follow-up. Multivariable linear models were used for MRI and cognition, and Cox proportional hazards models for stroke events. Results: Higher BAA at T0 was associated with poorer MRI profiles at T2 (Figure 2), worse cognition (Figure 3), and higher risk of incident stroke (HR per 1 SD increase: 1.41, 95%CI: 1.38-1.45). Improving BAA between T0 and T1 was associated with more favorable MRI profiles at T2: lower white matter hyperintensity volume, better white-matter diffusion metrics, and smaller ventricular volume. ΔBAA was also associated with reduced risk of any stroke (HR per SD: 0.77 0.61-0.97) and ischemic stroke (HR: 0.73 0.56-0.96). Associations with fluid intelligence, pattern completion, trail completion, and reaction time at T2 were observed but confidence intervals crossed 0 after adjustment for cardiovascular risk factors, likely reflecting limited power. Conclusions: BAA and improvement in BAA are associated with lower subsequent risk of stroke and improvements in MRI markers of small vessel disease years later, independent of socioeconomic and vascular risk factors. Evidence for cognitive benefits is suggestive but less certain after adjustment. Taken together, these findings support targeting biological aging as a modifiable pathway to preserve brain health and motivate trials testing whether lowering BAA reduces later-life brain injury and disease.