A functional polymorphism of the brain-derived neurotrophic factor (BDNF Val66Met) has been reported to affect memory-related hippocampal activity. Apolipoprotein E (ApoE) gene polymorphism is known to be associated with Alzheimer disease (AD), dementia with Lewy bodies (DLB), and Pick disease (PiD). We tested the hypothesis that BDNF Val and ApoE epsilon4 alleles confer susceptibility to AD, DLB, and PiD. The study included 160 AD, 34 DLB patients, 38 autopsy-confirmed PiD, and 164 age-matched healthy control (HC) probands. The frequency of the BDNF Val allele was significantly higher in AD, but there were no statistical differences in the allele distribution in PiD or in DLB as compared with HC. The Val/Met genotype occurred with statistically significantly higher frequency in PiD than in HC. The ApoE epsilon4 allele was significantly overrepresented in all dementias as compared with HC. Genotypes containing both ApoE epsilon4 and BDNF Val alleles occurred more frequently in all investigated dementias than in HC. We suggest that the presence of the BDNF Val allele in itself and in combination with the ApoE epsilon4 allele can be risk factors for AD, and the results indicate a synergistic effect of the 2 polymorphisms on DLB and PiD risk.