The APOE4 allele is widely accepted as a major risk factor for late-onset Alzheimer's disease (AD). Recently, it has been reported that polymorphisms in the APOE promoter and in the alpha2-macroglobulin gene (A2M) are associated with AD. We have analyzed the distribution of APOE alleles, -219T/G APOE promoter polymorphism, and A2M/A2Mdel polymorphism in a large case-control study. Our results showed that APOE genotype was the only informative marker of AD risk contrary to -219T/G and A2M/A2Mdel polymorphism. In AD patients however, a strong linkage disequilibrium was observed between the T allele of -219T/G polymorphism and APOE4 allele. This result indicates that -219T/G APOE promoter polymorphism is a risk factor for AD by increasing the APOE4-associated risk.