Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine and reduced Alzheimer's disease risk.

Lactamase β (LACTB) is a serine β-lactamase-like mitochondrial enzyme genetically associated with obesity, kidney disease, and hyperlipidemia. LACTB is located in an Alzheimer's Disease (AD) risk locus and its expression in the brain has been genetically associated with AD susceptibility. The aim of this study was to investigate LACTB function and genetic link to AD in myeloid cells, due to their central role in modulating AD risk. Our Mendelian randomization analyses revealed that lower LACTB expression in myeloid cells is genetically associated with reduced disease susceptibility and increased succinylcarnitine, a metabolite independently associated with AD risk. We identified LACTB as a primary enzyme responsible for succinylcarnitine hydrolysis. In human macrophages and microglia, LACTB loss promoted enhanced oxidative phosphorylation, reduced protein synthesis and altered lipid homeostasis. LACTB expression was upregulated following interferon or TNF stimulation, and LACTB loss modified efferocytosis-related functions under inflammatory conditions. In vivo, xenotransplanted human LACTB knockout microglia showed enhanced association with amyloid plaques in the mouse brain. Together, these findings experimentally validated the genetic association between reduced LACTB expression and elevated succinylcarnitine and identified LACTB as an inflammation-responsive regulator of myeloid cell metabolism and function that may contribute to its protective genetic association with AD. Given its druggability and potential to use succinylcarnitine as a genetically-validated endophenotype and target engagement biomarker, LACTB represents a promising therapeutic target for AD.