α-Synuclein has been isolated as a component of amyloid in addition to the major Aβ peptide in Alzheimer disease (AD). However, there are conflicting reports regarding the association of α-synuclein gene polymorphism with AD. Using a novel and common polymorphism in intron 3, we examined the relationship between AD and α-synuclein and apolipoprotein E (ApoE) genes in 183 Japanese AD patients and 210 controls. Carriers of the α-synuclein deletion (D) allele had a 2.2-fold increased risk of developing AD than noncarriers in women. The odds ratio for the ApoE Ε4 and the α-synuclein D allele was 11.4 in women. The results showed that the α-synuclein gene is associated with sporadic AD in women, independent of ApoE Ε4 status.