To assess independent and joint effects of pairs of vascular and cardiometabolic risk factors (VCMRFs) in relation to risk of all-cause dementia.

Population-based longitudinal cohort study of cognitive impairment. We used an algorithm to select pairs of VCMRFs and tested their joint effects in time-dependent Cox models. We used attributable proportions (AP) to measure the proportion of risk from interactions beyond any additive effect.

Economically depressed small-town population.

Adults age 65+ years with up to 10 yearly study visits (N=1701, median (Q1, Q3) age, 78 (71.0, 83.0), 62.3% female, 94.9% white).

Among 1701 participants free from prevalent dementia with at least one follow-up visit, 109 developed incident all-cause dementia. In pairings of APOE*4 with hypertension (HTN) and congestive heart failure (CHF), the variables contributed independently and additively to all-cause dementia risk. In pairings of APOE*4 with stroke and stroke with CHF, the variables demonstrated independent contributions to all-cause dementia risk; their joint effects showed excess detriment demonstrating synergistic interactions (joint HR [95% CI]: 28.33 [6.74, 119.01] and 50.30 [14.57, 173.57] respectively, fully adjusted models). Physical activity (PA) was independently associated with lower all-cause dementia risk when paired with APOE*4, stroke, and CHF in unadjusted models; these associations did not survive covariate adjustment. The joint effect of low PA and APOE*4 was associated with additively increased all-cause dementia risk (joint HR [95% CI]: 4.61 [2.07, 10.23], fully adjusted model).

Reduction of VCMRFs, including low PA, could be valuable for dementia prevention, especially among APOE*4 carriers.