Systematic characterization of cell type-specific master metabolic regulators in 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 brain cell-type specific master metabolic regulators underlying the metabolic alterations of AD, we introduce scFUMES (<b>s</b>ingle <b>c</b>ell <b>FU</b>nctional <b>ME</b>tabolite-<b>S</b>ensor), an algorithm integrating single-cell RNA sequencing, interactomics (protein-protein interactions), genomics, transcriptomics, and metabolomics from large 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 <i>APOE</i> 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. In summary, scFUMES identifies cell type-specific master metabolic regulators, offering insights into cellular metabolic heterogeneity and metabolism-targeted therapeutic strategies for AD and neurodegenerative diseases if broadly applied.