Abstract
INTRODUCTION: We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-supported Alzheimer's disease (AD). METHODS: We computed metabolite quantitative trait loci (QTL) with whole-genome sequencing (WGS) and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components. RESULTS: We identified 72 SNP-metabolite associations spanning 66 genes and 12 metabolite classes, including PYROXD2/N6-methyllysine, FAAH/myristoylglycine, and FADS2/arachidonic acid. Additionally, we found differences in genetic regulation of metabolites among individuals with clinically-defined AD compared to biomarker-defined AD based on a published plasma P-tau181 cutoff. We also found more SNP-metabolite associations among males compared to females. DISCUSSION: In summary, we identified sex- and disease-specific genetic regulators of plasma metabolites, revealing unique biological mechanisms of genetic perturbations in AD. HIGHLIGHTS: Genetic regulators of the metabolome spanned 66 genes and 12 metabolite classes. Clinically versus biomarker-defined Alzheimer's disease (AD) affects genetic regulators of the metabolome. Most metabolite quantitative trait loci (QTLs) are not shared between males and females.