Genetic factors, such as apolipoprotein E (ApoE) polymorphisms, are thought to play an important role in the etiology of Alzheimer's disease (AD). Recent association studies have suggested that the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene could play a role in the development of AD. To identify genotypic effects of the BDNF and the ApoE genes on disease progression in preclinical AD, we assessed morphological changes using serial magnetic resonance imaging during the preclinical period of AD in 35 individuals. When all subjects were analyzed as one group, progressive atrophy was noted in the limbic, paralimbic and neocortical areas. Individuals of the BDNF Val/Val genotype showed progressive atrophy in the left medial temporal areas, whereas the BDNF Met allele carriers showed additional changes in the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and the precuneus. An interaction between the BDNF genotype and progressive morphological changes was found in the PCC. The noncarriers for the ApoE epsilon4 allele showed progressive atrophy in the bilateral medial temporal areas. In addition to changes in the medial temporal areas, epsilon4 carriers showed progressive atrophy in the PCC, ACC and precuneus. An interaction between the ApoE genotype and progressive morphological change was noted in the right medial temporal area. The present preliminary study indicates that polymorphisms of the ApoE and the BDNF genes could affect disease progression in preclinical AD and implies that the Met-BDNF polymorphism could be an additional risk factor for rapid disease progression in preclinical AD.