Amyloid beta-peptide (A beta) deposition in brain is important in the development of sporadic Alzheimer's disease (SAD) and A beta is produced through sequential cleaving of amyloid precursor protein (APP) by beta-secretase and gamma-secrease. Anterior pharynx-defective-1 (APH-1) is an important subunit of the gamma-secretase complex, and its expression level was associated with the activity of gamma-secrease. We hypothesized that alterations in the APH-1 promoter region might alter APH-1 expression and the activity of gamma-secrease, thus be involved in the SAD process. In the present study, we sequenced APH-1 a promoter region in 20 randomly selected controls and 20 SAD patients and detected two polymorphisms which were -980C/G (rs3754048) and -21C/A (rs2275780). Then, we investigated genotypes and allele of these two polymorphisms as well as apolipoprotein epsilon 4 (APOE epsilon 4) status in 256 SAD patients and 276 normal controls with restriction fragment length polymorphisms analysis and sequencing. Results showed the GG genotype and G allele of -980C/G polymorphism were more frequent in the SAD group than that in the controls not only in the whole subjects (genotype P = 0.038, allele P = 0.01 respectively) but also in the APOE epsilon 4 + subjects (genotype P = 0.048, allele P = 0.016 respectively). There was no statistical difference between SAD group and controls regarding to the frequency of alleles and genotypes of -21C/A whenever before or after stratification by APOE epsilon 4. Our results suggest that there is an association between -980C/G and the development of SAD in the Northern Han Chinese population and that allele G may interact synergistically with the APOE epsilon 4 allele to increase the risk of SAD. (C) 2009 Elsevier Ireland Ltd. All rights reserved.