Interactions between the apolipoprotein E4 gene and modifiable risk factors for cognitive impairment: a nationally representative panel study

BACKGROUND: Few studies using rigorous clinical diagnosis have considered whether associations with cognitive decline are potentiated by interactions between genetic and modifiable risk factors. Given the increasing burden of cognitive impairment (CI) and dementia, we assessed whether Apolipoprotein E ε4 (APOE4) genotype status modifies the association between incident CI and key modifiable risk factors . METHODS: Older adults (70+) in the US were included. APOE4 status was genotyped. Risk factors for CI were self-reported. Cognitive status (normal, CI, or dementia) was assigned by clinical consensus panel. In eight separate Cox proportional hazard models, we assessed for interactions between APOE4 status and other CI risk factors. RESULT: The analytical sample included 181 participants (mean age 77.7 years; 45.9% male). APOE4 was independently associated with a greater hazard of CI in each model (Hazard Ratios [HR] between 1.81–2.66, p < 0.05) except the model evaluating educational attainment (HR 1.65, p = 0.40). The joint effects of APOE4 and high school education or less (HR 2.25, 95% CI: 1.40–3.60, p < 0.001), hypertension (HR 2.46, 95% CI: 1.28–4.73, p = 0.007), elevated depressive symptoms (HR 5.09, 95% CI: 2.59–10.02, p < 0.001), hearing loss (HR 3.44, 95% CI: 1.87–6.33, p < 0.0001), vision impairment (HR 5.14, 95% CI: 2.31–11.43, p < 0.001), smoking (HR 2.35, 95% CI: 1.24–4.47, p = 0.009), or obesity (HR 3.80, 95% CI: 2.11–6.85, p < 0.001) were associated with the hazard of incident CIND (compared to no genetic or modifiable risk factor) in separate models. The joint effect of Apolipoprotein ε4 and type 2 diabetes was not associated with CIND (HR 1.58, 95% CI: 0.67–2.48, p = 0.44). DISCUSSION: The combination of APOE4 and selected modifiable risk factors conveys a stronger association with incident CI than either type of risk factor alone.