Causal Effects Between Blood Pressure Variability and Alzheimer's Disease: A Two‐Sample Mendelian Randomization Study

ABSTRACT Alzheimer's disease (AD), an escalating global public health concern, demonstrates complex pathogenesis involving both genetic predisposition and vascular components. Blood pressure variability (BPV) has been implicated in neurodegenerative diseases, but its causal relationship with AD remains unclear. This study aims to explore the causal relationship between BPV and AD by applying Mendelian randomization (MR) to genome‐wide association study (GWAS) summary data. Genetic instruments were selected from BPV GWAS based on UK Biobank data, ensuring relevance and significance( p < 5 × 10⁻⁶). Genetic estimates on exposure were obtained from three databases: The The International Genomic of Alzheimer's Project (IGAP); Maternal family history of AD from UK Biobank (MFH‐UKBB), and Paternal family history of AD from UK Biobank (PFH‐UKBB). Proxy SNPs were manually selected if SNPs were not available in the exposure GWAS. Data harmonization was performed to ensure consistency in effect and reference alleles. Three MR statistical methods were employed to assess causal effects, including inverse variance weighting (IVW) with random or fixed effect, MR‐Egger regression, and the Weighted Median Method. Sensitivity analyses to evaluate robustness were also employed. Six SNPs associated with systolic BPV and six SNPs associated with diastolic BPV were included. Significant causal effects of SBPV on AD were found on the PFH‐UKBB dataset in all four methods. The odds ratios for AD per 10‐unit increment in SBPV were 1.028, 1.015, and 1.015 for MR‐Egger, IVW‐MR, and weighted median, respectively. In contrast, only IVW methods found significant results for DBPV in the MFH‐UKBB dataset. SBPV is a possible causal risk factor for AD, while the evidence for DBPV needs further study. BPV control should be an important treatment target in preventing dementia.