Early Life Vascular Risk and Midlife Markers of Brain Aging

BACKGROUND: Early-life vascular risk factors are increasingly linked to midlife cognitive decline, though critical risk periods remain unclear. These factors also relate to structural brain changes, yet midlife alterations tied to cognitive decline are poorly defined. We leveraged data from the CARDIA study (Coronary Artery Risk Development in Young Adults) to identify critical periods and factors associated with midlife cognition and neuroimaging signatures. METHODS: We utilized longitudinal cognitive and neuroimaging data from the prospective CARDIA study with vascular risk factor data spanning 35 years (1985–2020). K-means clustering of cognitive trajectories identified Declined and Stable clusters. A gradient boosting classifier identified factors predictive of cluster membership. Linear mixed-effects models assessed cluster differences in structural brain changes, and structural covariance analyses identified brain network remodeling linked to cognitive decline. Cross-sectional late-midlife cognitive data were used to examine associations between early adulthood (ages 18–40 years) systolic blood pressure strata and cognitive outcomes. RESULTS: Among 280 participants with longitudinal data (mean age, 50±3.5 years at baseline; 52% to 56% female, 40% to 41% Black race) followed for a median of 10 years, higher systolic blood pressure and smoking before age 40 years were critical factors for cognitive cluster membership in late midlife (feature importance ≈0.3 and 0.2, respectively). Accelerated accumulation of white matter hyperintensities, gray matter volume changes involving frontal and temporal association cortices, occipital pole and thalamus (β range, –0.0006 to –0.002; P ≤0.02), and network-level reorganization predominantly involving the basal forebrain spanning early- to late-midlife distinguished clusters. A stepwise, dose-dependent association between early-life systolic blood pressure strata and late-midlife cognitive performance was replicated in 720 participants (mean age, 61±3.5 years). CONCLUSIONS: Before age 40 years may be a critical window to manage vascular risk factors and preserve midlife cognition. Linked white matter hyperintensity and gray matter changes suggest that vascular factors drive both cerebrovascular and neurodegenerative injury. A basal forebrain–centered neuroimaging signature, possibly reflecting cholinergic and glial responses to early vascular stress, may serve as an early biomarker for prevention trials.