Social determinants of health (SDOH) are increasingly recognized as important drivers of cognitive outcomes. However, most existing evidence focuses on individual SDOH components and older populations.

To develop a comprehensive SDOH index and examine its association with subsequent changes in cognitive function and structural brain measures in midlife.

Prospective cohort study with repeated measures of cognition and brain imaging.

Community-based cohort from the Coronary Artery Risk Development in Young Adults (CARDIA) study.

A total of 3488 participants with SDOH data in early midlife (mean age 40.0 ± 3.6 years); 645 participants had repeated brain magnetic resonance imaging (MRI) data.

A weighted aggregate SDOH index was constructed from 12 items across 5 domains: economic stability, community and social context, education, neighborhood and built environment, and health care access. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST), Stroop Test, and Rey Auditory Verbal Learning Test (RAVLT). Brain MRI outcomes included white matter hyperintensities (WMHs) and total gray matter (GM) volume. Mixed linear regression models examined associations between SDOH quartiles and longitudinal cognitive and MRI outcomes, adjusting for demographics, vascular risk factors, depression, and intracranial volume (for MRI).

At baseline, participants in the most disadvantaged SDOH quartile performed worse across all cognitive tests compared with the least disadvantaged quartile ( p < 0.001). Over time, the most disadvantaged quartile showed steeper decline in DSST performance (adj. mean change: −0.72, 95% CI: −0.93 to −0.52 vs. −0.55, 95% CI: −0.76 to −0.34, p = 0.013), greater WMH accumulation (ratio: 1.07, 95% CI: 1.05 to 1.09 vs. 1.04, 95% CI: 1.03 to 1.05, p = 0.007), and steeper decline in total GM volume (−2.02 cm³, 95% CI: −2.39 to −1.65 vs. −1.46 cm³, 95% CI: −1.71 to −1.20, p = 0.011) per 5-year interval compared to the least disadvantaged quartile.

Greater social disadvantage in midlife is associated with worse baseline cognition and accelerated decline in cognitive function and brain integrity. These findings highlight the importance of SDOH as key determinants of brain health in midlife and suggest that strategies to mitigate social disadvantage may help preserve cognitive and brain health.