APOE Genotypes Modulate the Relationship of Hypertension With Alzheimer's Disease: Associations and Clues of…

Cohort studyBiological psychiatry global open science· Sep 2026

APOE Genotypes Modulate the Relationship of Hypertension With Alzheimer's Disease: Associations and Clues of Peripheral Mechanisms.

Hong-Yu Wu, Jia-Hui Hou, Liang-Yu Huang … Wei Xu

Cognitive & DementiaCohort studyPrognosisQ1IF 3.3

Hypertension's link to Alzheimer's disease is strongest in APOE ε2 carriers

APOE Genotypes Modulate the Relationship of Hypertension With Alzheimer's Disease: Associations and Clues of Peripheral Mechanisms.

Hong-Yu Wu … Wei Xu

Biological psychiatry global open science · Sep 2026

Background

Gene-environment interplay contributes to the heterogeneous etiology of Alzheimer's disease (AD).

Methods

Plasma proteomic data from 34,141 participants, covering 2790 proteins, were further analyzed using mediation and bioinformatics approaches.

n = 34,141 participants

Results

hypertension raised alzheimer's risk most in this genotype, more than in ε33 or ε4 carriers

APOE ε2

1.57HR

APOE ε33

1.213HR

APOE ε4

1.129HR

More results

Hypertension showed a significant multiplicative interaction with APOE ε4 status for incident AD ( p < .001).

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.

More results

These proteins were enriched in sphingolipid metabolism and lysosomal function.

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Conclusion · 1 of 2

The association between hypertension and incident AD varies across APOE genotype strata, with the strongest relative association observed among APOE ε2 carriers.

Conclusion · 2 of 2

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.

APOE Genotypes Modulate the Relationship of Hypertension With Alzheimer's Disease: Associations and Clues of Peripheral Mechanisms.

APOE Genotypes Modulate the Relationship of Hypertension With Alzheimer's Disease: Associations and Clues of Peripheral Mechanisms.

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