A number of studies suggest that increased cellular cholesterol levels induce high amyloid beta (Abeta) production, which is central to the pathogenesis of Alzheimer's disease (AD). In the brain, glial cells have hydroxy-methylglutaryl-coenzyme A reductase (HMGCR) as the major rate-limiting enzyme in the novo synthesis of cholesterol, which once synthesized, is secreted via the cholesterol transporter ABCA1. Overexpression of HMGCR in concert with underexpression of ABCA1 would result in increased cholesterol accumulation, induction of Abeta production, and increased AD risk. We examined two HMGCR polymorphisms located in 5'-UTR (rs3931914) and promoter (-911, rs3761740) regions of the gene, and two ABCA1 polymorphisms (-14, rs1800977; and -477, rs2422493) located in promoter region of the gene, in a group of 325 Spanish AD patients and 383 controls. Subjects carrying both the HMGCR (5'-UTR) GG genotype and the ABCA1 (-14) TT genotype (adjusted by age, sex and APOE status OR=2.77; 95% CI=1.16-6.61; p=0.02), or the ABCA1 (-477) TT genotype (adjusted by age, sex and APOE status OR=2.07; 95% CI=1.14-3.78; p=0.02) had a higher risk of developing AD than subjects without these risk genotypes, and this genetic interaction was observed in either the presence or the absence of the APOE epsilon4 allele. Considering synergistic effects between polymorphisms in synthesis and secretion cholesterol-related genes may help in determining the risk profile for AD.