Beta-site APP-cleaving enzyme 1 (BACE1) gene has been suggested as a candidate gene for Alzheimer's disease (AD). However, little is known regarding the effects of polymorphisms in regulatory sequences of BACE1 on AD susceptibility. To evaluate the relationship between polymorphisms in the BACE1 promoter and sporadic AD (SAD) genetically and functionally, we performed a case-control study (429 cases and 346 controls of Han Chinese descent) and functional characterization of the polymorphisms in vitro using luciferase assay and electrophoretic mobility shift assay (EMSA). Two polymorphisms (-918G/A, rs4938369; -2014T/C, rs3017608) were identified in the BACE1 promoter. The results showed that the -918G/A polymorphism was associated with SAD and the -918GG carriers had a 1.67-fold higher risk for SAD than the carriers with -918AA and GA genotypes (OR = 1.667,95% CI = 1.087-2.556, P = 0.019). The haplotype -918G/-2014T maybe a possible risk factor for SAD (P = 0.016). Luciferase reporter assays showed the -918G allele and its resultant haplotype -918G/-2014T induced an increase of transcriptional activity. A more marked increase in -918G/-2014T transcriptional activity was seen when under hypoxia treatment. EMSA indicated that the -918G allele bound nuclear factors more strongly than -918A allele did. Our findings suggest that the BACE1 promoter polymorphisms which regulate BACE1 expression may contribute to SAD susceptibility. Further independent studies are required to verify our findings. (C) 2009 Wiley-Liss, Inc.