Cell type-specific master metabolic regulators of Alzheimer's disease.

Alzheimer's disease (AD) exhibits metabolic heterogeneity; yet, the consequences on metabolic dynamics in a cell-type-specific manner and the underlying metabolite-sensor network basis remain unclear. Here, we show that neurons exhibit a striking decrease in energy and lipid-related metabolic activity, contrasted by an increase in microglial metabolism associated with neuroinflammation. To identify cell-type specific master metabolic regulators of AD underlying the metabolic alterations in AD, we introduce scFUMES (single cell FUnctional MEtabolite-Sensor), an algorithm integrating single-cell RNA sequencing, interactomics, genomics, transcriptomics, and metabolomics from human brain biobanks. Applied to two AD-vulnerable regions (middle temporal gyrus and dorsolateral prefrontal cortex), scFUMES uncovers hundreds of AD-associated regulators, with neurons and microglia showing the most interactions. Particularly, scFUMES pinpoints genetics-informed master metabolic regulators across AD severity, sex and APOE genotype (e.g., PPARD-glycerol in microglia). Experimental testing reveals that two interaction pairs predicted by scFUMES, neuronal palmitic acid bound fatty acid binding protein 3 and gut metabolite indole-3-propionic acid binding to kynurenine aminotransferase 1, both lower pathological tau species in AD. Collectively, scFUMES systematically maps AD master metabolic regulators, offering insights into cellular metabolic heterogeneity and therapeutic strategies for AD and other AD-related dementia if broadly applied.