Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the formation of amyloid beta-peptides (A beta peptides) and their deposition in the brain. A disintegrin and metalloproteinase (ADAM) 9 can cleave the amyloid precursor protein (APP) within the A beta domain and preclude generation of A beta peptides. We systematically screened ADAM9 gene promoter region and found four polymorphisms: -542C/T (rs10105311), -600A/C (rs7840270), -963A/G (rs6991968) and -1314T/C (rs7006414). The -1314C allele was over-represented in 345 healthy individuals when compared to that in 473 sporadic AD (SAD) patients (P = 0.005) and constructed a relatively protective haplotype -542C/-600A/-963G/-1314C (OR = 0.422, 95% CI 0.229-0.779). Luciferase reporter assay indicated that both -963G/-1314C and -963A/-1314C had higher transcriptional activity (1.5- to 1.8-fold and 1.4- to 1.7-fold respectively) than -963A/-1314T. Electrophoretic mobility shift assay (EMSA) revealed that the -1314C allele bound nuclear factors more strongly than the -1314T allele. Additionally, increased ADAM9 transcriptional activity was seen under estrogen treatment. Our data suggest that promoter polymorphisms which regulate ADAM9 transcription are protective against SAD. (C) 2009 Elsevier Inc. All rights reserved.