Alzheimer's disease (AD) is the most common neurodegenerative disease influenced by genetic and environmental factors. Brain-derived neurotrophic factor (BDNF) plays an important role in the progression of AD, but the genetic association between BDNF and AD remains controversial. In this study, we aimed to explore the potential association between genetic variants in BDNF and AD in Han Chinese and to investigate whether the association is affected by gender. A 3-stage study was conducted to evaluate the genetic association between BDNF and AD. Data mining of the reported expression data, brainimaging data, and biomarker data in AD patients was also performed to further validate the results. We found a female-specific genetic association of rs6265 with AD and a gender-related messenger RNA expression of BDNF in brain tissues of AD patients. In addition, we observed a clear female-specific risk trend for the effect of rs6265 on AD endophenotypes. Our results clarified the available controversies regarding the role of rs6265 in AD and indicated that BDNF may be a female-specific risk gene for AD. (C) 2016 Elsevier Inc. All rights reserved.