Depression may underlie the association between cardiovascular disease and dementia, yet the causal mechanism is unclear. Methodology for causal mediation was implemented to examine whether persistent depressive symptoms, defined as two consecutive scores ≥8 on the 10-item Center for Epidemiologic Studies-Depression Scale, may partially mediate the association of baseline subclinical cardiovascular disease (CVD) with MCI/dementia onset in an analytic sample from the Cardiovascular Health Study (n=2,450). Participants with baseline clinical CVD, MCI/dementia occurring before 5 years from baseline, and missing persistent depressive symptoms were excluded from the analysis (n=3,438). Total effect was decomposed into direct and indirect effects (via persistent depressive symptoms), obtained from a marginal structural accelerated failure time model. Weights for the marginal structural model were derived from a multivariable logistic regression of persistent depressive symptoms on subclinical CVD. All analyses were adjusted by baseline covariates, including age, race, sex, poverty status, marital status, and depressive symptoms. Participants contributed 20,994 person-years of follow-up with a median follow-up time of 9.4 years. Time to MCI/dementia onset is lower by a factor of 0.88 among those with subclinical CVD than those without subclinical CVD (95% Confidence Interval, [CI]: 0.83, 0.93). The total effect of subclinical CVD on MCI/dementia onset was decomposed into a direct effect (Time Ratio, [TR]=0.95, 95% CI: 0.92, 0.98) and indirect effect via persistent depressive symptoms (TR=0.92, 95% CI: 0.88, 0.97). The proportion of the total effect mediated through persistent depressive symptoms was 64.5%. Persistent depressive symptoms partially mediate the association of subclinical CVD with MCI/dementia onset. Depression screenings among older adults with detectable vascular damage prior to clinical cardiovascular disease could be beneficial in reducing the risk of MCI/dementia onset.