The article reviews the role of apolipoprotein E (APOE) in the pathogenesis of Alzheimer's disease (AD). APOE polymorphisms, particularly the *APOE*ε4 allele, are major genetic risk factors for late-onset AD, which is characterized by amyloid plaques and neurofibrillary tangles. APOE4 is associated with earlier and more extensive amyloid pathology, impaired lipid transport, synaptic integrity, glucose metabolism, and cerebrovascular function. The article discusses the mechanisms by which different APOE isoforms contribute to or mitigate AD pathogenesis through Aβ-dependent and Aβ-independent pathways. It also explores strategies for targeting APOE to develop AD therapies, including modulating APOE quantity and lipidation, targeting APOE structural properties and interactions with Aβ, and targeting APOE receptors. The potential benefits and challenges of these approaches are discussed, highlighting the need for further research to understand the complex interactions of APOE in AD pathobiology.The article reviews the role of apolipoprotein E (APOE) in the pathogenesis of Alzheimer's disease (AD). APOE polymorphisms, particularly the *APOE*ε4 allele, are major genetic risk factors for late-onset AD, which is characterized by amyloid plaques and neurofibrillary tangles. APOE4 is associated with earlier and more extensive amyloid pathology, impaired lipid transport, synaptic integrity, glucose metabolism, and cerebrovascular function. The article discusses the mechanisms by which different APOE isoforms contribute to or mitigate AD pathogenesis through Aβ-dependent and Aβ-independent pathways. It also explores strategies for targeting APOE to develop AD therapies, including modulating APOE quantity and lipidation, targeting APOE structural properties and interactions with Aβ, and targeting APOE receptors. The potential benefits and challenges of these approaches are discussed, highlighting the need for further research to understand the complex interactions of APOE in AD pathobiology.