Apolipoprotein E (ApoE) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. The *APOE* gene has three polymorphic alleles—ε2, ε3, and ε4—which are the main genetic determinants of Alzheimer disease (AD) risk. Individuals carrying the ε4 allele are at increased risk of AD compared to those with the more common ε3 allele, while the ε2 allele decreases risk. The presence of the *APOE* ε4 allele is also associated with increased risk for cerebral amyloid angiopathy and age-related cognitive decline. ApoE binds to cell-surface receptors to deliver lipids and hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events leading to synaptic dysfunction and neurodegeneration in AD. ApoE isoforms differentially regulate Aβ aggregation and clearance in the brain and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signaling, neuroinflammation, and mitochondrial function. This review describes current knowledge on ApoE in the CNS, focusing on clinical and pathological features associated with different ApoE isoforms. It also discusses Aβ-dependent and Aβ-independent mechanisms linking ApoE4 status to AD risk and considers strategies for AD therapy by targeting ApoE.Apolipoprotein E (ApoE) is a major cholesterol carrier that supports lipid transport and injury repair in the brain. The *APOE* gene has three polymorphic alleles—ε2, ε3, and ε4—which are the main genetic determinants of Alzheimer disease (AD) risk. Individuals carrying the ε4 allele are at increased risk of AD compared to those with the more common ε3 allele, while the ε2 allele decreases risk. The presence of the *APOE* ε4 allele is also associated with increased risk for cerebral amyloid angiopathy and age-related cognitive decline. ApoE binds to cell-surface receptors to deliver lipids and hydrophobic amyloid-β (Aβ) peptide, which is thought to initiate toxic events leading to synaptic dysfunction and neurodegeneration in AD. ApoE isoforms differentially regulate Aβ aggregation and clearance in the brain and have distinct functions in regulating brain lipid transport, glucose metabolism, neuronal signaling, neuroinflammation, and mitochondrial function. This review describes current knowledge on ApoE in the CNS, focusing on clinical and pathological features associated with different ApoE isoforms. It also discusses Aβ-dependent and Aβ-independent mechanisms linking ApoE4 status to AD risk and considers strategies for AD therapy by targeting ApoE.