Alzheimer's disease (AD) has a complex pattern of inheritance and many genes have recently been reported to contribute to the disease susceptibility. We selected 106 SNPs within 16 candidate genes and performed a multistage association study using 4 sample sets consisting of 731 AD patients and 738 control subjects to identify genetic factors for AD in Han Chinese. A single nucleotide polymorphism (SNP) in the insulin degrading enzyme gene (IDE), rs3781239, showed a significant association with AD. The C allele increased the risk of AD by 1.72 than the G allele (odds ratio [OR] = 1.72%, 95% confidence interval [CI] = 1.17–2.53, p = 0.006) and CC carriers had a 4.89-fold higher risk for AD than that of the carriers with CG and GG genotypes (odds ratio = 4.89%, 95% CI = 1.85–12.91, p = 0.001). Moreover, the CC genotype was significantly associated with earlier age at onset (p = 0.001, hazard ratio [HR] = 2.09%, 95% CI = 1.38–3.18). Our data suggest that the polymorphism of IDE is associated with susceptibility to Alzheimer's disease in Han Chinese.