Apolipoprotein E (apoE) is a plasma protein that regulates lipid transport and cholesterol homeostasis. In humans, apoE occurs as 3 major isoforms (apoE2, E3, and E4). Genetic evidence demonstrates an overrepresentation of the apoE epsilon 4 allele in Alzheimer's disease (AD). While apoE immunoreactivity (IR) is associated with the amyloid plaques and neurofibrillary tangles of AD, few studies have characterized the localization of apoE in normal human brains. We examined the distribution of apoE in the cerebral cortex of normal aged individuals and compared the results to clinically diagnosed and pathologically confirmed AD cases. In addition, we characterized the apoE IR in brains from high plaque non-demented (HPND) cases. We observed consistent and widespread apoE staining in cortical neurons from normal and HPND individuals. This finding was confirmed by double immunostaining which colocalized apoE with microtubule-associated protein-2, as well as low density lipoprotein receptor-related protein, an apoE receptor found on neurons. In contrast, AD brains displayed apoE IR in plaques and neurofibrillary tangles with little neuronal staining. These data clearly establish the presence of apoE in normal neurons, supporting an intracellular role for apoE. Moreover, the results suggest that this function of apoE is disrupted in AD, where apoE staining of neurons was drastically reduced.