Apolipoprotein E (ApoE) plays a central role in brain physiology and pathology, acting as the most abundant apolipoprotein in the central nervous system. Synthesized primarily by astrocytes and microglia, and to a lesser extent by other brain and peripheral cells, ApoE is involved in crucial processes such as lipid transport, synaptic maintenance, and immune modulation. Variations in the APOE gene, particularly the ε2, ε3, and ε4 alleles, have profound effects on brain aging, cognitive function, and susceptibility to neurodegenerative diseases, particularly Alzheimer’s disease (AD). Although the APOEε4 allele is most commonly associated with increased risk for late-onset AD, it impacts brain structure and function in multiple ways that may lead to age-related cognitive impairment, independent from AD pathology. Conversely, APOEε2 is often considered protective, especially in the context of aging and longevity. This chapter explores the multifaceted roles of ApoE in the brain, with particular focus on genotype-specific effects on neurobiology, lipid homeostasis, immune signaling, and cellular stress responses.