Apolipoprotein (apo) E, a multifunctional protein with central roles in lipid metabolism and neurobiology, has three common isoforms (apoE2, apoE3, and apoE4) with different effects on lipid homeostasis and neurobiology. Unlike apoE3, the most common isoform, apoE4, is associated with increased risk of developing Alzheimer disease (AD) and other neurodegenerative disorders. Although the mechanisms underlying apoE4's action in AD pathogenesis are still poorly understood, emerging data strongly suggest that apoE4 contributes to this disease by interacting with different factors through various pathways. Thus, multiple molecular and cellular mechanisms should be considered when anti-AD drugs are developed based on apoE studies.