<p>Apolipoprotein E (ApoE) is highly expressed in the central nervous system (CNS) where it plays a critical role in lipid homeostasis and in the etiology of Alzheimer’s disease (AD) and related diseases. ApoE associates with lipids to form discoidal and spherical lipoproteins that carry lipid and protein cargo throughout the brain. In this review, we focus on the significance of ApoE as a lipoprotein and how this impacts the function of ApoE in homeostasis and disease. In the CNS, ApoE is primarily secreted by astrocytes, though other cells, including microglia, secrete ApoE under certain conditions. ApoE lipoproteins (LpE) secreted by different cell types carry unique lipids and proteins which alter its function. The lipidation state of ApoE alters its conformation and binding to different receptors and, consequently, its ultimate impact on AD pathology. Most dramatically, nonlipidated ApoE has minimal binding to the low density lipoprotein receptor (LDLR), while lipidation of ApoE restores high affinity binding to LDLR. Furthermore, the degree of ApoE lipidation also impacts ApoE receptor binding through changes in protein conformation and stoichiometry of ApoE molecules per lipoprotein. The lipidation state of ApoE also alters its interaction with amyloid-β and tau, the proteins involved in forming amyloid plaques and neurofibrillary tangles, the pathological hallmarks of AD. LpE also carry lipids and proteins that alter the function of ApoE. Understanding how the lipid and protein content of LpE interacts with the conformational changes that occur with lipidation and maturation are essential to mechanistically understanding the role of ApoE in homeostasis and disease pathogenesis. In this review, we highlight the current understanding of LpE biology in the CNS and delineate important areas of future research.</p>