Multiplicative and additive interaction effects of vascular risk factor burden with APOE genotypes on dementia: Associations and peripheral biological mechanisms based on a large cohort study

Background
Gene-environment interaction is important for understanding precise etiology of dementia. We aimed to assess the associations of vascular risk factor (VRF) and its interaction by APOE genotypes with all-cause dementia (ACD) and Alzheimer’s disease (AD), and to delineate peripheral biological mechanisms.
Methods
A total of 264,382 participants (median age: 57 years) from the UK Biobank were followed for an average of 13 years. A VRF burden score (VRFS) was constructed incorporating hypertension, diabetes, hyperlipidemia, and current smoking. Cox proportional hazards regression was performed to explore the additive and multiplicative interactions of APOE by VRFS. Blood proteomics, bioinformatics, and mediation analyses were applied to investigate the mechanisms.
Results
An elevated VRFS was significantly linked to a 33 % higher risk of ACD and AD (P < 0.001). Significant multiplicative and additive interaction effects were detected (P < 0.001). The co-existence of higher VRFS and APOE ε4 produced significantly larger effects on dementia risk than their presence alone (attributable proportion due to interaction = 0.12). The effect magnitudes of VRFS on dementia were enlarged in the presence of APOE ε2 (risk elevation ∼70 %, P < 0.001) than APOE ε4 (∼24 %). Biological mediating mechanisms specifically for APOE ε2 were annotated with disulfide bond, TNFR, bone metabolism, and hemopoiesis.ConclusionsAPOE genotypes significantly interacts with VRFS in the development of dementia and AD. These findings highlight the importance of considering interaction of genetic predispositions with vascular risk factors when assessing an individual's overall risk for dementia and developing personalized prevention strategies.