Abstract: Increasing cellular cholesterol levels results in high amyloid beta (AB) synthesis, which is central to the pathogenesis of Alzheimer's disease (AD). Heme oxygenase-1 (HO-1) stimulates oxidation of glial cholesterol to oxysterols, and increased oxysterol concentrations may protect neural tissues by activation of liver X receptor- (LXR-), which induces transcription of genes associated with reduction of cellular cholesterol concentrations and decrease of A formation. Underexpression of HO-1 in concert with underexpression of LXR- would result in increased cholesterol accumulation, induction of A production, and increased AD risk. We examined a functional polymorphism in the HO-1 promoter region (?413, rs2071746), and three LXR- polymorphisms in introns 2 (rs2695121), 5 (rs1052533), and 7 (rs1405655), in a group of 414 Spanish AD cases and 442 controls. Subjects carrying both the HO-1 (?413) TT genotype and the LXR- (intron 2) TT genotype (OR = 2.63), LXR- (intron 5) AA genotype (OR = 1.90), or LXR- (intron 7) TT genotype (OR = 1.75) had a higher risk of developing AD than subjects without these risk genotypes. Considering synergistic effects between polymorphisms in cellular cholesterol efflux-related genes may help in determining the risk profile for AD

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