Apolipoprotein E (ApoE) genotype is a significant risk factor for the development of Alzheimer disease (AD) and the ApoE protein is associated with senile plaques (SP) and neurofibrillary tangles (NFT), the pathological lesions of AD. Despite this data, the relevance of ApoE to the disease pathogenesis is unknown. In this study we sought to understand the role that ApoE protein could play in the pathogenesis of AD. Using an in situ binding technique, we showed that ApoE bound avidly to SP and NFT in diseased brain. Molecular characterization of ApoE binding suggested that binding to NFT was mediated by tau, the main protein component of NFT, and that ApoE binding to SP was mediated by amyloid-beta, the main protein component of SP. There was no significant difference in binding or binding characteristics between the different ApoE isoforms, ApoE3 and ApoE4. These findings suggest that the interaction of ApoE with tau and amyloid-beta proteins in AD could play a important role in the formation of NFT and SP, respectively, contributing to the pathogenesis of AD.