Long‐Term Association of Cardiovascular Risk Burden With Dementia Risk: The Role of Life‐Course Confounders in an Analysis of Cumulative and Specific Factors

BACKGROUND: Preventing dementia through risk factor modification is a global health priority. Although individual cardiovascular risk factors (CVRFs) have been linked to dementia, the cumulative burden of CVRFs, their changes over time, and the role of life-course confounders, especially early-life and psychological factors, remain poorly understood. This study aimed to estimate the longitudinal association between changes in CVRF burden and dementia risk under different hypothetical scenarios. METHODS: We analyzed 6051 participants from the ARIC (Atherosclerosis Risk in Communities) study, with a median follow-up of 21.9 years. We used the doubly robust g-formula method to estimate the 20-year risk difference for dementia under hypothetical strategies that maintain CVRF burden at different levels over time, explicitly accounting for competing mortality and time-varying confounding. RESULTS: At baseline, 23.1% had ≥3 CVRFs. During follow-up, 1008 participants (17%) developed dementia. Low birth weight, midlife depression, and poor oral health emerged as important confounders. Maintaining a low CVRF burden was associated with a lower estimated risk of dementia compared with the natural course (risk difference, -4.31% 95% compatibility interval, -7.75% to -0.80%), whereas maintaining a high CVRF burden was associated with a higher estimated risk (risk difference, 10.5% [95% compatibility interval, 5.8%-15.7%). Under model assumptions, 41.3% of dementia cases were estimated to be associated with the presence of CVRFs. CONCLUSIONS: Higher CVRF burden over time was associated with greater dementia risk. Findings suggest that early and sustained management of CVRFs, along with consideration of early-life and psychological factors, may play an important role in dementia prevention strategies.