Reduced LACTB expression in myeloid cells is associated with elevated succinyl-carnitine levels and reduced Alzheimer’s disease risk

Lactamase B (LACTB) is a mitochondrial protease previously related with cancer progression, and lipid metabolism. Our mendelian randomization analyses indicate that lower LACTB expression in myeloid cells is protective for Alzheimer’s Disease (AD) and is genetically associated with increased succinyl-carnitine, a poorly characterized metabolite that independently correlates with reduced AD risk. We identify LACTB as a primary enzyme responsible for succinyl-carnitine hydrolysis. Using human LACTB knockdown and knockout macrophage and microglial systems, we show that loss of LACTB enhances oxidative phosphorylation, reduces protein synthesis, and alters lipid profiles. LACTB expression is increased upon IFN/TNF stimulation, and LACTB loss modifies efferocytosis-related pathways following inflammatory activation. In vivo, xenotransplanted human LACTB knockout microglia show enhanced association with amyloid plaques in the mouse brain. Together, these findings define a previously unrecognized metabolic pathway linking LACTB and succinyl-carnitine to myeloid cell function and AD risk. Given its enzymatic druggability and the potential to leverage succinyl-carnitine as a translational biomarker, LACTB represents a promising therapeutic target.