The rs3851179 which located at upstream of PICALM was reported to be associated with Alzheimer's disease (AD); however, the relationship is still undefined. To gain a more precise understanding of the association, we conducted a meta-analysis: a comprehensive survey of 16 case-control studies that evaluated the role of rs3851179 gene variants in AD patients. The overall analysis revealed a significant association between the polymorphism and AD in the allelic, homozygote, heterozygote, dominant, and recessive models (p < 0.05). When stratified by ethnicity, a significant association was observed between AD development in Caucasian populations and the five-genetic models; Asian populations, however, featured a significant association in only the allelic, homozygote, and recessive models. We did not observe any influence of APOE epsilon 4 carrier status on the incidence of AD and rs3851179 (p > 0.05). Our meta-analysis thus suggested that the PICALM rs3851179 polymorphism was associated with AD; the APOE epsilon 4 status did not influence the relationship. Nevertheless, considering the limitations of our meta-analysis, further large-scale studies should be conducted to gain a more comprehensive understanding.