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 associated with Alzheimer disease (AD) risk. The ε4 allele increases AD risk, while the ε2 allele decreases it. ApoE isoforms differentially regulate amyloid-β (Aβ) aggregation and clearance, and have distinct functions in lipid transport, glucose metabolism, neuronal signaling, neuroinflammation, and mitochondrial function. ApoE4 is associated with increased Aβ deposition, cerebral amyloid angiopathy, and age-related cognitive decline. ApoE4 carriers exhibit greater cognitive decline and increased risk of AD compared to noncarriers. ApoE4 also contributes to vascular cognitive impairment and other AD-related conditions. ApoE4 is a risk factor for AD and cognitive decline through both Aβ-dependent and Aβ-independent mechanisms. ApoE isoforms differentially regulate Aβ production, aggregation, and clearance. ApoE4 is less efficient than ApoE3 and ApE2 in delivering cholesterol and essential lipids for synaptic integrity and plasticity. ApoE4 promotes proinflammatory responses that could exacerbate AD pathogenesis. ApoE isoforms have differential roles in maintaining vascular health, which is crucial given that vascular defects are strongly associated with AD. ApoE-based therapies are being explored as potential treatments for AD, with some showing promise in reducing Aβ deposition and improving cognitive function. Understanding the role of ApoE in AD pathogenesis is crucial for developing effective therapies.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 associated with Alzheimer disease (AD) risk. The ε4 allele increases AD risk, while the ε2 allele decreases it. ApoE isoforms differentially regulate amyloid-β (Aβ) aggregation and clearance, and have distinct functions in lipid transport, glucose metabolism, neuronal signaling, neuroinflammation, and mitochondrial function. ApoE4 is associated with increased Aβ deposition, cerebral amyloid angiopathy, and age-related cognitive decline. ApoE4 carriers exhibit greater cognitive decline and increased risk of AD compared to noncarriers. ApoE4 also contributes to vascular cognitive impairment and other AD-related conditions. ApoE4 is a risk factor for AD and cognitive decline through both Aβ-dependent and Aβ-independent mechanisms. ApoE isoforms differentially regulate Aβ production, aggregation, and clearance. ApoE4 is less efficient than ApoE3 and ApE2 in delivering cholesterol and essential lipids for synaptic integrity and plasticity. ApoE4 promotes proinflammatory responses that could exacerbate AD pathogenesis. ApoE isoforms have differential roles in maintaining vascular health, which is crucial given that vascular defects are strongly associated with AD. ApoE-based therapies are being explored as potential treatments for AD, with some showing promise in reducing Aβ deposition and improving cognitive function. Understanding the role of ApoE in AD pathogenesis is crucial for developing effective therapies.