Biological psychiatry global open science · 2026
APOE Genotypes Modulate the Relationship of Hypertension With Alzheimer's Disease: Associations and Clues of Peripheral Mechanisms.
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Wu Hong-Yu, Hou Jia-Hui, Huang Liang-Yu, Tan Lan, Xu Wei
Аннотация
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 UK Biobank participants without dementia were analyzed; participants had a mean age of 56.24 years, an APOE ε4 frequency of 28.29%, and a median follow-up period 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 2790 proteins, were further analyzed using mediation and bioinformatics approaches.
RESULTS: HTN showed a significant multiplicative interaction with APOE ε4 status for incident AD (p < .001). The association between HTN and AD risk was strongest among APOE ε2 carriers, followed by ε33 carriers and ε4 carriers, with hazard ratios of 1.570, 1.213, and 1.129, respectively. Among APOE ε2 carriers, prosaposin and ganglioside GM2 activator significantly mediated the HTN-AD association, with mediation proportions of 10.46% and 3.37%, respectively. These proteins were enriched in sphingolipid metabolism and lysosomal function.
CONCLUSIONS: The 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.
METHODS: Longitudinal data from 318,923 UK Biobank participants without dementia were analyzed; participants had a mean age of 56.24 years, an APOE ε4 frequency of 28.29%, and a median follow-up period 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 2790 proteins, were further analyzed using mediation and bioinformatics approaches.
RESULTS: HTN showed a significant multiplicative interaction with APOE ε4 status for incident AD (p < .001). The association between HTN and AD risk was strongest among APOE ε2 carriers, followed by ε33 carriers and ε4 carriers, with hazard ratios of 1.570, 1.213, and 1.129, respectively. Among APOE ε2 carriers, prosaposin and ganglioside GM2 activator significantly mediated the HTN-AD association, with mediation proportions of 10.46% and 3.37%, respectively. These proteins were enriched in sphingolipid metabolism and lysosomal function.
CONCLUSIONS: The 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.