Genomic Characterisation of the Relationship 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 of vascular calcification-coronary artery calcification (CAC) and abdominal aortic calcification (AAC)-with Alzheimer's disease (AD), and five cognitive traits. We analyse large-scale genome-wide association studies (GWAS) summary statistics, using well-regarded methods, including linkage disequilibrium score regression (LDSC), Mendelian randomisation (MR), pairwise GWAS (GWAS-PW), and gene-based association analysis. Our findings reveal a nominally significant positive genome-wide genetic correlation between CAC and AD, which becomes non-significant after excluding the region. CAC and AAC demonstrate significant negative correlations with cognitive performance and educational attainment. MR found no causal association between CAC or AAC and AD or cognitive traits, except for a bidirectional borderline-significant association between AAC and fluid intelligence scores. Pairwise-GWAS analysis identifies no shared causal SNPs (posterior probability of association [PPA]3 < 0.5). However, we find pleiotropic loci (PPA4 > 0.9), particularly on chromosome 19, with gene association analyses revealing significant genes in shared regions, including , , , and . Moreover, we identify suggestively significant loci (PPA4 > 0.5) on chromosomes 1, 6, 7, 9 and 19, implicating pleiotropic genes, including , , , , , and . Current findings reveal limited genetic correlation and no significant causal associations of CAC and AAC with AD or cognitive traits. However, significant pleiotropic loci, particularly at the region, highlight the complex interplay between vascular calcification and neurodegenerative processes. Given 's roles in lipid metabolism, neuroinflammation, and vascular integrity, its involvement may link vascular and neurodegenerative disorders, pointing to potential targets for further investigation.