Recent evidence has suggested that down-regulation of somatostatin (SST) expression in the human brain during early stages of aging leads to an elevation in the steady-state levels of Abeta and therefore may be involved in Alzheimer's disease (AD) progression. We hypothesized that alterations in the SST gene might alter its expression or function and also play a role in the pathogenesis of sporadic AD (SAD). First, we sequenced the entire SST gene in 25 randomly selected controls and 25 SAD patients and then screened for C/T polymorphisms (rs4988514) in the 3' un-translated region. We genotyped rs4988514 polymorphisms as well as apolipoprotein epsilon4 (APOE epsilon4) status in 309 SAD patients and 276 normal controls with restriction fragment length polymorphism (RFLP) analysis. Results showed that the C allele of the rs4988514 polymorphism had an increased incidence in the SAD group compared to the control group (p=0.042). In subjects with the APOE epsilon4 allele, the presence of both the CC genotype and the C allele of this polymorphism were elevated in the SAD group compared to the control group (genotype p=0.027, allele p=0.011). In the whole study group, the age, sex, and APOE epsilon4 adjusted OR for the risk of AD in C allele carriers was 1.313 (95%CI=1.068-2.234, p=0.027) whereas within only APOE epsilon4 allele carriers, the adjusted OR increased to 2.734 (95%CI=1.236-5.862, p=0.012). Our results supported the notion that the C allele of the rs4988514 polymorphism may increase the risk for AD in the Chinese population and possibly have additive effect with the APOE epsilon4 allele.