Increasing evidences have shown that nicastrin (NCSTN) plays a crucial role in gamma-cleavage of the amyloid precursor protein (APP). Inhibition of NCSTN demonstrated an altered gamma-cleavage activity, suggesting its potential implication in developing Alzheimer's disease (AD). We detected the NCSTN gene promoter region in 359 sporadic AD (SAD) patients and 331 controls and found three promoter single nucleotide polymorphisms (SNPs): -1216C/A (rs2147471), -796T/G (rs10752637) and -436C/T (rs1324738). For -1216C/A, there were significant differences in the allele and genotype frequency between AD and control subjects (allele P=0.031, genotype P=0.017). The allele and genotype frequencies remained significant before and after APOEvarepsilon4 stratification. The -1216CC carriers increased 2-fold risk for the development of SAD compared to the carriers with -1216CA and AA genotypes (OR=2.049, 95%CI=1.410-2.976, P=0.000). For -796T/G, there were significant differences in the genotype frequency between SAD and control subjects (P=0.009). This trend is still obvious in the subjects without APOEvarepsilon4 allele. The -796GG carriers might decrease the risk compared to the carriers with -796TG and TT genotypes (OR=0.602, 95%CI=0.393-0.932, P=0.022). No significant difference was detected either in genotype or in allele frequencies between SAD and control for -436C/T, even after APOEvarepsilon4 stratification. The haplotype -1216A/-796G may be a protective factor for SAD (OR=0.795, 95%CI=0.636-0.995, P=0.045). Our investigation suggests that -1216C/A and -796T/G are probably related to the development of SAD.