The reported association between -491 A/T polymorphism in the regulatory region of the apolipoprotein E gene (APOE) and increased risk for Alzheimer's disease (AD) is controversial: Studies of different racial and ethnic populations have found both positive and negative associations. Examination of -491 A/T polymorphism in 216 patients with sporadic AD and 157 age- and gender-matched controls from the Japanese population revealed that, in contrast to findings for Caucasian populations, the -491 T allele, but not the A allele, was significantly more prevalent in patients with AD than in controls. This difference disappeared when the subjects were stratified by the gene dose of the APOE epsilon4 allele. Moreover, logistic regression analysis, controlling for age, sex, and the presence of the APOE epsilon4 allele, showed no association between the -491 polymorphism and AD. These results suggest that -491 polymorphism does not independently confer susceptibility to AD, but that this polymorphism is in partial linkage disequilibrium with the APOE epsilon2/3/4 polymorphism.