Synergistic contributions of vascular risk factors and APOE ε4 carriage to cognitive performance in middle‐aged adults enrolled in the Healthy Brain Project

Abstract

AbstractBackgroundMidlife vascular risk factors (VRFs) and APOE ε4 carriage are individually associated with poor cognitive performance and increased dementia risk. However, the extent to which VRFs interact with APOE ε4 carriage to influence cognition in midlife remains unclear. This study aimed to investigate interactions between VRFs and APOE status on cognitive performance in cognitively normal (CN) middle‐aged adults.MethodCN adults aged 40‐70 enrolled in the Healthy Brain Project with ≥75% complete baseline data on five VRFs and APOE status were included (N = 1610; 546 ε4 carriers). Cardiovascular risk was operationalized by assessing history of hypertension, hypercholesterolemia, diabetes mellitus, body mass index (BMI) ≥25, and current cigarette smoking. Participants were categorized into low (0) or high vascular risk groups (≥1 VRF) determined via median split. Analyses of covariance (ANCOVAs) investigated interactions between VRF group × APOE status on attention and memory composites (derived from the Cogstate Brief Battery), controlling for age, sex, education, ethnicity, and depressive/anxiety symptoms. Linear regression analyses explored contributions of individual VRFs on memory in ε4 carriers and non‐carriers.ResultA significant VRF group × APOE status interaction was observed for memory (p = .04), but attention was lower in those at high vascular risk, regardless of APOE ε4 status (Table 1, Figure 1A and 1B). For memory, APOE ε4 carriers with high vascular risk demonstrated worse performance compared to ε4 carriers and non‐carriers with low vascular risk (Figure 1A and 1B). Linear regression analyses revealed that BMI ≥25 and hypercholesterolemia were significantly associated with worse memory performance in ε4 carriers only (Table 2).ConclusionIn CN middle‐aged adults, vascular risk significantly modified associations between APOE status and memory performance, such that ε4 carriers with high vascular risk demonstrated the lowest memory performance. More specifically, higher BMI and hypercholesterolemia were significantly associated with lower observed memory performance within this group. Results suggest that middle‐aged ε4 carriers with vascular risk factors may be an important sub‐group to target within lifestyle prevention trials to reduce future risk of cognitive impairment and decline.