Multi-phenotype associations of apolipoprotein E (APOE) genotypes with cardiometabolic risk factors for Alzheimer's disease in the Finnish population

Abstract

The APOE ε4 allele is strongly associated with a higher Alzheimer’s disease (AD) risk, but its relationship with cardiometabolic traits remains less explored. This study investigated the associations and interactions between APOE genotypes and cardiometabolic risk factors for AD, including hypercholesterolemia, coronary heart disease (CHD), atrial fibrillation (AF), hypertension, type 2 diabetes (T2D), and obesity among 296,815 unrelated individuals from the FinnGen project.

Associations of APOE genotypes (ε4ε4, ε3ε4, ε2ε4, ε2ε3, and ε2ε2, with ε3ε3 as reference) with cardiometabolic traits were assessed using logistic regression. Interaction analyses evaluated whether cardiometabolic traits modified the association between APOE genotypes and AD. An FDR-adjusted p-value < 0.05 was considered statistically significant.

Hypercholesterolemia showed a clear pattern resembling that of AD, with higher risk in ε4ε4 and ε3ε4 carriers and lower risk in ε2ε3 and ε2ε2. For CHD, ε3ε4 and ε2ε3 were associated with risk in directions consistent with AD, while ε4ε4 showed no significant association. The ε2ε4 genotype, however, showed protective effects for hypercholesterolemia, CHD, and AF. Paradoxically, ε4 carriers had a lower risk of obesity, T2D, and hypertension. A significant negative interaction between AF and ε4ε4 on AD risk was observed (OR = 0.57, 95% CI: 0.43–0.76, PFDR = 0.004).

These findings highlight APOE’s broader influence beyond neurodegeneration, impacting metabolic and cardiovascular processes that may shape AD susceptibility.