We previously described an association between Alzheimer's disease (AD) and a single-nucleotide polymorphism -980C/G (rs3754048) in the promoter of the anterior pharynx-defective-1a (APH-1A) gene. Here, we examine the potential of this -980C/G polymorphism to affect APH-1A transcription and confer a risk of AD. We validated the presence of APH-1A promoter polymorphism -980C/G in other two Chinese cohort sets (450 AD and 450 controls). Subsequently, we measured APH-1A mRNA and protein levels and gamma-secretase activity in C or G allele carriers. Finally, we examined the polymorphism's transcriptional function using a dual-luciferase reporter assay and also tracked transcription factor binding to the variant promoter sequence with electrophoretic mobility shift assays (EMSAs). We found that the APH-1A levels and gamma-secretase activity were higher in individuals carrying allele G. The G allele increased APH-1A transcriptional activity significantly in both N2A cells and HEK293 cells. The EMSA revealed an increased binding of the transcription factor Yin Yang 1 (YY1) to allele G. Overexpression of YY1 resulted in an activation of the APH-1A promoter (2.7-fold). Specific YY1 siRNA led to decreases in APH-1A promoter activity and mRNA and protein levels. Our data indicate that the APH-1A promoter polymorphism -980C/G might alter the binding ability of YY1 transcription factor, resulting in an increased level of APH-1A and gamma-secretase activity. These factors further facilitated beta-amyloid (Ab) 42 generation and ultimately modified patients' susceptibility to AD. The involvement of transcription factor YY1 might be a novel mechanism for the development of AD.