Shared genetic architecture between Alzheimer’s disease and blood pressure implicates ACE and NBEAL1 in individuals of European ancestry

Abstract Background Vascular dysfunction is increasingly recognized as a contributor to Alzheimer’s disease (AD), yet the genetic mechanisms linking blood pressure (BP) and AD remain incompletely understood. We investigated shared genetic architecture between AD and systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to identify locus-specific mechanisms connecting vascular regulation and neurodegeneration. Results We analyzed genome-wide association study summary statistics from individuals of European ancestry using global and local genetic correlation and conjunctional false discovery rate (conjFDR), followed by cis-Mendelian randomization (cis-MR), functional annotation, expression quantitative trait locus associations, and AD-specific multi-omic evidence. AD showed modest negative global genetic correlations with BP but significant local genetic correlation at eight regions. ConjFDR identified 42 high-confidence variants across 22 independent LD regions, with PRKD3 , NBEAL1 , NDUFAF6 , SPI1 , and the APOE region supported by both local genetic correlation and conjFDR. Cis-MR provided evidence for effects of BP on AD at multiple regions, with ACE and the APOE region showing significant effects for all three BP traits. Integrative analysis most strongly prioritized the APOE region, with convergent evidence at ACE and NBEAL1 and additional signals implicating immune and mitochondrial pathways. Conclusions The genetic relationship between AD and BP is characterized by heterogeneous, locus-specific overlap not fully captured by genome-wide genetic correlation. Convergent evidence implicates APOE , ACE , NBEAL1 , and other loci involved in vascular, immune, and mitochondrial biology, supporting multiple, partially BP-trait-specific mechanisms linking vascular regulation to AD.