Apolipoprotein E (APOE) is reported to be a strong genetic risk factor for Alzheimer's disease (AD), broadly contributing to the AD pathologies observed in most populations. However, it is difficult to explicate these AD pathologies based only on the known functions of APOE. In this review article, we revisited the histories and functions of APOE and also reviewed its recently elucidated the pleiotropic roles in the brain.