Distinct metabolic signatures of Alzheimer's and Parkinson's disease revealed through genetic overlap with metabolic markers

ABSTRACT Metabolic dysfunction is increasingly implicated in neurodegenerative diseases, yet the genetic architecture linking metabolic markers with Alzheimer’s disease (AD) and Parkinson’s disease (PD) remains unclear. We systematically analysed phenotypic and genetic relationships between 249 circulating metabolites with AD and PD, comparing patterns to body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD) and stroke. Using linkage disequilibrium score regression and bivariate Gaussian mixture modeling, we identified distinct genetic overlap. AD correlated positively with cardiometabolic traits (BMI, r s =0.11; T2D, r s =0.23; CAD, r s =0.22; stroke, r s =0.18), whereas PD showed opposing patterns (AD–PD r s =−0.36). Mendelian randomization identified bi-directional causal effects of lipid measures on AD and divergent effects of glutamine on AD and PD. Conjunctional FDR analyses mapped 1,377 shared genes, implicating lipid metabolism in AD and synaptic processes in PD. These findings disentangle disease-specific pathways and inform therapeutic strategies targeting metabolic health.