Background Patients with leprosy have a very low risk of Alzheimer disease (AD)and b-amyloid (Ab) deposition is significantly lower in the brain tissue of elderlypatients with leprosy compared with age-matched controls. Apolipoprotein E(ApoE) plays a critical role in lipid metabolic pathways and in the brain, facilitat-ing the proteolytic clearance of Ab. We hypothesized that APOE confers risk ofleprosy as lipid metabolism is involved in Mycobacterium leprae infection.Objectives To investigate the potential genetic associations between APOE andleprosy in two independent Chinese case–control cohorts from the Yuxi andWenshan prefectures, Yunnan Province of Southwest China.Methods Five APOE single-nucleotide polymorphisms (SNPs) were analysed in1110 individuals (527 patients and 583 controls) from the Yuxi prefecture usinga SNaPshot assay. Genetic variations in the entire APOE exons were screened in1788 individuals (798 patients and 990 controls) from the Wenshan prefectureusing next-generation sequencing technology.Results The AD-associated SNPs rs405509 and rs439401 increased the risk ofleprosy per se and multibacillary leprosy (P < 0?005), but the APOE-e4 allele didnot. The SNPs rs405509 and rs439401 were cis expression quantitative trait loci(eQTL) for APOE expression in human skin. Differential APOE mRNA expressionwas observed in skin lesions of patients with type I reaction leprosy and thosewith multibacillary leprosy. APOE and related lipid genes are involved in an inter-action network with leprosy susceptibility genes.Conclusions The APOE gene is associated with leprosy, most likely by regulatinglipid-metabolism-related genes.