APOE genotypes modulate the relationship of hypertension with Alzheimer's Disease: associations and clues of peripheral mechanisms

Background
Gene–environment interplay contributes to the heterogeneous etiology of Alzheimer’s disease (AD). Hypertension (HTN) is a major modifiable vascular risk factor, but whether its association with AD differs across APOE genotypes remains unclear. We examined the interaction between HTN and APOE genotypes in relation to incident AD and explored plasma proteomic correlates as potential biological clues.
Methods
Longitudinal data from 318,923 dementia-free UK Biobank participants were analyzed, with a mean age of 56.24 years, an APOE ε4 frequency of 28.29%, and a median follow-up of 13 years. Cox proportional hazards models with competing-risk adjustment for death were used to assess additive and multiplicative interactions between HTN and APOE genotypes. Plasma proteomic data from 34,141 participants, covering 2,790 proteins, were further analyzed using mediation and bioinformatics approaches.
Results
HTN showed a significant multiplicative interaction with APOE ε4 status for incident AD (P < 0.001). The association between HTN and AD risk was strongest among APOE ε2 carriers, followed by ε33 individuals and ε4 carriers, with HRs of 1.570, 1.213, and 1.129. Among APOE ε2 carriers, prosaposin and ganglioside GM2 activator significantly mediated the HTN–AD association, with mediation proportions of 10.46% and 3.37%. These proteins were enriched in sphingolipid metabolism and lysosomal function.ConclusionsThe association between HTN and incident AD varies across APOE genotype strata, with the strongest relative association observed among APOE ε2 carriers. These findings suggest genotype-dependent heterogeneity in vascular contributions to AD risk. Proteomic results should be interpreted as exploratory biological clues and require further validation.