Many studies have investigated APOE-related differences in cerebral structure, blood flow, metabolism, and activation in an attempt to detect early brain changes in subjects at risk for Alzheimer's disease (AD). Structural magnetic resonance imaging studies have produced conflicting results, with some failing to detect APOE-related differences and others suggesting that epsilon4 carriers have more pronounced atrophy, particularly at medial temporal structures. All functional imaging studies done during rest in middle-aged and elderly subjects have found decreased cerebral metabolism for epsilon4 carriers (mostly in areas that usually are affected by AD), and some have reported faster cerebral metabolic reductions over time. Areas with decreased resting cerebral perfusion and metabolism, in addition to other areas with increased perfusion, have been reported in young epsilon4 carriers. Imaging studies done during the performance of various cognitive tasks in middle-aged and elderly subjects, and a single study in young subjects, have produced mixed results with regionally nonspecific increased, decreased, or nondifferential APOE-related activations depending on the cognitive task used. APOE-related findings in imaging studies of nondemented subjects may be the result of incipient AD pathologic changes or of genetic heterogeneity in brain structure and function.