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There are several environmental and genetic risk factors contributing to late onset Alzheimer’s disease (AD). Two genetic risk factors for AD are e4 allele of APOE and Brain Derived Neurotrophic Factor (BDNF) Val66Met polymorphisms. The objective of this research is to investigate the association of APOE and BDNF polymorphisms, some clinical and environmental factors either independently or in combination, with risk of AD in a population from the south west of Iran. 66 AD patients and 74 healthy controls were included in this case-control study. Participants were genotyped for the polymorphisms using Allele specific PCR. The frequency of e3, e2, and e4 alleles of APOE gene was 87.8, 6.8, and 5.4%, respectively. Frequencies were 84.5 and 15.5% for G and A allele of BDNF polymorphism, respectively. When each factor was applied as univariate, there was significant association between some factors including depression, history, smoking, education, and e4 allele carrier, with risk of developing AD. In multiple analysis, there was an association of APOE gene and smoking/history with risk of AD. However, when all factors were considered together, the effect of APOE polymorphism on the risk of AD was no longer significant. A correlation between depression and e4 allele was observed in this study. It can be concluded that environmental factors may have significant role in developing AD. In addition, a correlation between depression and APOE gene may suggest that individuals with depression and e4 allele are at greater risk for developing AD compared to people lacking depression and/or e4 allele.