AbstractBackgroundCholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer’s disease (AD) and results are contradictory.MethodsWe performed a gene variability screening inCYP46A1and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol.ResultsTwo of the identified 16 SNPs inCYP46A1influenced AD risk in our study (rs7157609:p= 0.016; rs4900442:p= 0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p= 0.006). Haplotypes including both SNPs were calculated and haplotype G–C was identified to influence the risk of AD (p= 0.005). AD patients and non-demented controls, who were carriers of the G–C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p= 0.001) and cholesterol (p< 0.001).ConclusionOur results suggest thatCYP46A1gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.