Life’s Simple 7, depressive symptoms, cognitive performance, and their associations with all-cause mortality among middle-aged urban adults

Cardiovascular health, depressive symptoms, and cognitive performance are closely interconnected and jointly influence all-cause mortality. We investigated the independent associations of Life's Simple 7 (LS7), depressive symptom trajectories, and cognitive performance with all-cause mortality and conducted exploratory four-way decomposition analyses to evaluate complementary mechanistic hypotheses linking these factors. We analyzed data from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (N = 1466; mean age = 56 years; 41.7% men; 60.6% African American). Cox proportional hazards models, group-based trajectory analyses, and four-way decomposition models were used. Higher LS7 scores were associated with lower mortality, particularly among White adults, whereas persistently elevated depressive symptom trajectories were associated with higher mortality, especially among women. Poorer cognitive performance was independently associated with increased mortality (HR = 1.20, 95% CI 1.02-1.41; P = 0.035). In fully adjusted four-way decomposition analyses, little evidence supported indirect or interaction-related effects. In reduced models, depressive symptom trajectory showed a significant indirect effect in the association between LS7 and mortality in the overall sample (PIE = -0.04 ± 0.01, q = 0.030) and among women (PIE = -0.09 ± 0.03, q = 0.001) after false discovery rate correction, whereas all other indirect effects were attenuated after multiple-testing correction. Better cardiovascular health, fewer depressive symptoms, and preserved cognitive performance were independently associated with lower mortality risk. Exploratory decomposition analyses suggest that depressive symptoms may contribute modestly to the association between cardiovascular health and mortality, although evidence for broader mediation or interaction mechanisms was limited.