Assessing shared genetic and causal links between vascular calcification, Alzheimer's disease, and cognitive traits

Observational studies suggest a link between vascular calcification and dementia or cognitive decline, but the evidence is conflicting, and the underlying mechanisms are unclear. Here, we investigate the shared genetic and causal relationships between vascular calcification—coronary artery calcification (CAC) and abdominal aortic calcification (AAC)—and Alzheimer’s disease (AD), as well as cognitive traits, by analysing large-scale genome-wide association studies summary statistics. We observed a nominally significant positive genome-wide genetic correlation between CAC and AD, which became non-significant after excluding the APOE region. CAC and AAC demonstrate significant negative correlations with cognitive performance and educational attainment. Mendelian randomisation revealed no causal association between CAC or AAC and AD or cognitive traits, except for a bidirectional borderline significance of AAC with fluid intelligence scores. Pairwise-GWAS analysis identified no shared causal SNPs (posterior probability of association [PPA]3 < 0.5). However, we found pleiotropic loci (PPA4 > 0.9), particularly on chromosome 19 with ‘mBAT-combo’ analyses revealing significant genes in shared regions, including APOE, TOMM40, NECTIN2 , and APOC1 . Moreover, we identified suggestively significant loci (PPA4 > 0.5) on chromosomes 1, 6, 7, 9 and 19, highlighting pleiotropic genes, including NAV1, IPO9, PHACTR1, UFL1, FHL5 , and FOCAD . Current findings reveal limited genome-wide genetic correlation and no significant causal associations of CAC and AAC with AD or cognitive traits. However, significant pleiotropic loci and genes underscore shared genetic susceptibility of CAC and AAC with AD and cognitive traits, identifying targets for further investigation.