Background: An increasing number of studies have suggested a link between cholesterol metabolism and Alzheimer's disease (AD), which may be mediated by its effect on amyloid processing. Intracranial cholesterol is primarily eliminated into the bloodstream through conversion into 24-hydroxycholesterol by the enzyme cholesterol 24-hydroxylase (encoded by the CYP46A1 gene). CYP46A1 is an essential gene modulating cholesterol metabolism in the brain.

Method: To investigate whether polymorphisms in the CYP46A1 gene modulate the risk of AD, we studied four common polymorphisms (IVS1-192, IVS2-150, IVS3-128 and IVS4-122) in 182 Chinese AD patients and 179 age-matched healthy Chinese subjects.

Results and conclusion: We found that the IVS3-128 polymorphism was associated with the risk of AD (p < 0.05). Subjects homozygous for the C alleles were protected from AD with an adjusted odds ratio (OR) of 1.53 [95% confidence interval (95% CI) 0.98–2.37, p = 0.047]. However, another minor allele, IVS1-192 C, was more prevalent in the AD group and was associated with an increased risk. Haplotype analysis revealed that two of the eight common haplotypes formed by the four polymorphisms were rarely found in the AD group, suggesting a protective effect of these two haplotypes (GTCA and CCTA). The results supported the involvement of the CYP46A1 gene and cholesterol metabolism in the pathogenesis of AD.