Alzheimer's disease (AD) is a complex, multifactorial disorder, with many genetic and environmental factors implicated in disease onset and pathology. Increasing evidence points to a link between brain cholesterol turnover and AD. The CYP46 gene encodes for the enzyme, cholesterol 24-hydroxylase, which plays a key role in brain cholesterol turnover. A polymorphism in Intron 2 (T-->C) in the CYP46 gene has recently been reported to be associated with the risk of AD. In the present study, we examined the association of this CYP46 polymorphism with sporadic late-onset AD (LOAD) in American White (434 cases, 401 controls) and African American (54 cases, 61 controls) cohorts. No significant association was observed between the CYP46 polymorphism and LOAD. When the data were stratified by the apolipoprotein E*4 carrier status, no significant difference was observed between cases and controls for the CYP46 single nucleotide polymorphism. In addition, no significant difference in genotype or allele frequency was observed when stratified by the presence or absence of the alpha1-antichymotrypsin*A allele. Our data indicate that the Intron 2 polymorphism of CYP46 does not affect the risk of AD in our sample.