Genetic Determinants of Vascular Dementia: Blood Metabolite Associations and Candidate Therapeutic Target Prioritization.

Vascular dementia (VaD), caused by reduced cerebral blood flow, is a common form of dementia lacking effective treatments. This study used genome-wide association study (GWAS) summary data, Mendelian randomization (MR), and colocalization analyzes to prioritize blood metabolites and candidate therapeutic targets associated with VaD. Key analyzes included metabolic pathway enrichment, a descriptive Phenome-Wide Association Study (PheWAS) of the broader curated association profiles of prioritized genes, mediation analysis, and in-silico compound prioritization with molecular docking. Twenty-four metabolites were associated with VaD, with taurocholate and glutaroyl carnitine prioritized as tier 1 metabolite-gene pairs. Pathway analysis implicated aminoacyl-tRNA and branched-chain amino acid biosynthesis pathways. Apolipoprotein E (APOE) and glutaryl-CoA dehydrogenase (GCDH) were prioritized candidate genes. The PheWAS recapitulated APOE's curated associations with Alzheimer's disease and lipid traits, whereas GCDH had a more restricted curated association profile dominated by glutaric acidemia type I; these patterns provide pleiotropic context but do not establish safety. Single-cell RNA-sequencing analysis localized APOE predominantly to microglia and astrocytes and GCDH predominantly to oligodendrocytes, providing cell-type-specific context. Mediation analysis identified a statistically supported indirect pathway involving alpha-2-macroglobulin receptor-associated protein for taurocholate. Aflatoxin B1 was highly ranked in an in-silico query but, because of its established toxicity, is not a therapeutic candidate. This study prioritizes metabolic and genetic candidates for experimental and clinical follow-up rather than establishing therapeutic targets.