Apolipoprotein E (APOE) is a major genetic risk factor for late-onset Alzheimer's disease (AD), with APOE*ε4 increasing and APOE*ε2 decreasing the risk. APOE4 is associated with earlier and more severe amyloid pathology, including amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy. APOE4 also impairs multiple brain functions, such as lipid transport, synaptic integrity, glucose metabolism, and cerebrovascular function. Recent research highlights the role of APOE in AD pathogenesis and explores strategies for targeting APOE in AD therapy. APOE4 is less efficient than APOE2 in clearing Aβ, leading to increased Aβ accumulation. APOE4 also exacerbates tau pathology and microglial responses. APOE4 is associated with increased Aβ deposition and reduced Aβ clearance, while APOE2 is protective against Aβ accumulation. APOE4 also contributes to neuroinflammation and synaptic dysfunction. APOE4 is linked to impaired glucose metabolism and insulin signaling. APOE4 is a risk factor for vascular cognitive impairment and cerebrovascular dysfunction. APOE-targeted therapies include modulating APOE quantity and lipidation, targeting APOE structural properties and interactions with Aβ, and targeting APOE receptors. Current strategies involve agonists of liver X receptor (LXR) and retinoid X receptor (RXR) to increase APOE production and reduce Aβ deposition. APOE4 overexpression exacerbates AD pathology, while APOE2 overexpression reduces Aβ levels. APOE4 deficiency reduces Aβ deposition. APOE immunotherapy with anti-APOE antibodies reduces Aβ deposition. Peptides mimicking APOE reduce Aβ and tau pathology. Targeting APOE structural properties and Aβ interactions is a promising approach for AD therapy.Apolipoprotein E (APOE) is a major genetic risk factor for late-onset Alzheimer's disease (AD), with APOE*ε4 increasing and APOE*ε2 decreasing the risk. APOE4 is associated with earlier and more severe amyloid pathology, including amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy. APOE4 also impairs multiple brain functions, such as lipid transport, synaptic integrity, glucose metabolism, and cerebrovascular function. Recent research highlights the role of APOE in AD pathogenesis and explores strategies for targeting APOE in AD therapy. APOE4 is less efficient than APOE2 in clearing Aβ, leading to increased Aβ accumulation. APOE4 also exacerbates tau pathology and microglial responses. APOE4 is associated with increased Aβ deposition and reduced Aβ clearance, while APOE2 is protective against Aβ accumulation. APOE4 also contributes to neuroinflammation and synaptic dysfunction. APOE4 is linked to impaired glucose metabolism and insulin signaling. APOE4 is a risk factor for vascular cognitive impairment and cerebrovascular dysfunction. APOE-targeted therapies include modulating APOE quantity and lipidation, targeting APOE structural properties and interactions with Aβ, and targeting APOE receptors. Current strategies involve agonists of liver X receptor (LXR) and retinoid X receptor (RXR) to increase APOE production and reduce Aβ deposition. APOE4 overexpression exacerbates AD pathology, while APOE2 overexpression reduces Aβ levels. APOE4 deficiency reduces Aβ deposition. APOE immunotherapy with anti-APOE antibodies reduces Aβ deposition. Peptides mimicking APOE reduce Aβ and tau pathology. Targeting APOE structural properties and Aβ interactions is a promising approach for AD therapy.