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

ABSTRACT

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.