APOE Genotype Modulates the Relationship of Stroke With Dementia Risk: Associations and Peripheral Clues for...

Stroke and APOE ε4 are established risk factors of dementia. However, it remains unclear whether stroke interacts with APOE genotypes to influence dementia occurrence. This study aims to investigate the associations of stroke and its interaction by APOE genotypes with incident risk of dementia, with a specific focus on peripheral clues for biological mechanisms.

This prospective cohort study included 336 903 participants (mean age: 56.3 years, stroke history: 1.3%, APOE ε4: 28.5%) from the UK Biobank, with a median follow-up of 13 years. Cumulative incidence curves were constructed using Fine-Gray death competing risks analysis. The additive and multiplicative interaction of stroke (including ischemic and hemorrhagic stroke) with APOE genotypes on incident risk of all-cause dementia (ACD) and Alzheimer disease were examined. Blood proteomics combined with bioinformatics analyses were used to explore the peripheral clues for biological mechanisms.

Either ischemic or hemorrhagic stroke was significantly associated with elevated risk of ACD and Alzheimer disease (P<0.001). A significant multiplicative interaction was observed between stroke and APOE ε4 (P<0.001). The association of stroke with increased risk of dementia was stronger in APOE ε4 non-carriers than carriers, for both ACD (hazard ratio [HR], 1.93 for carriers and 3.36 for non-carriers, P<0.001) and AD (HR, 1.14 for carriers and 2.67 for non-carriers, P<0.001). Inflammation-related pathways could be mechanisms underpinning the association of stroke with ACD risk. We identified 191 functionally interconnected (P<1.0×10^-16) proteins associated with both stroke and ACD only in APOE ε4 non-carriers. CD4-related and TGF-beta (transforming growth factor beta) signaling pathway could mediate the strengthened relationship in APOE ε4 non-carriers.

Stroke interacts with APOE ε4 to influence dementia, with the association being more pronounced in APOE ε4 non-carriers. Future studies are needed to verify the underpinning mechanisms to guide precise prevention.