Apolipoprotein E (apoE) and its receptors play critical roles in Alzheimer's disease (AD) pathogenesis. The ε4 allele of the APOE gene is a major genetic risk factor for late-onset AD (LOAD), increasing the likelihood of developing AD by 3-4 times compared to individuals without the allele. ApoE is a major apolipoprotein and cholesterol carrier in the brain, with three isoforms (apoE2, apoE3, apoE4) differing by a single amino acid. ApoE4 is associated with increased risk of AD, atherosclerosis, and other neurological disorders. ApoE receptors, particularly LDLR and LRP1, are essential for apoE/lipoprotein metabolism and Aβ clearance. ApoE4 has a higher affinity for larger lipoprotein particles and is less effective in lipid transport and Aβ clearance compared to apoE3. ApoE4 also promotes Aβ aggregation and toxicity, contributing to AD pathogenesis. ApoE and its receptors are involved in APP trafficking and processing to Aβ, with LRP1 playing a key role in accelerating APP endocytic trafficking and Aβ production. ApoE receptors also mediate neuronal signaling, including reelin signaling, which is crucial for neuronal migration and synaptic plasticity. ApoE and its receptors are involved in Aβ clearance and aggregation, with apoE3 being more effective than apoE4 in clearing Aβ. ApoE4 is associated with increased risk of cerebral amyloid angiopathy (CAA) and other neurodegenerative diseases. ApoE also influences brain cholesterol and lipid transport, with apoE4 being less efficient in transporting cholesterol compared to apoE3. ApoE isoforms differentially regulate synaptic plasticity, repair, and dendritic spine integrity, with apoE3 being more effective in maintaining synaptic function. ApoE and its receptors are promising therapeutic targets for AD, with strategies to modulate their expression and function being explored. Therapeutic approaches include targeting apoE receptors, such as LRP1 and LDLR, to enhance Aβ clearance and reduce AD pathology. ApoE4 is a major risk factor for AD, and therapies targeting apoE/apoE receptors may benefit a larger population of AD patients. Understanding the roles of apoE and its receptors in AD pathogenesis is crucial for developing effective treatments.Apolipoprotein E (apoE) and its receptors play critical roles in Alzheimer's disease (AD) pathogenesis. The ε4 allele of the APOE gene is a major genetic risk factor for late-onset AD (LOAD), increasing the likelihood of developing AD by 3-4 times compared to individuals without the allele. ApoE is a major apolipoprotein and cholesterol carrier in the brain, with three isoforms (apoE2, apoE3, apoE4) differing by a single amino acid. ApoE4 is associated with increased risk of AD, atherosclerosis, and other neurological disorders. ApoE receptors, particularly LDLR and LRP1, are essential for apoE/lipoprotein metabolism and Aβ clearance. ApoE4 has a higher affinity for larger lipoprotein particles and is less effective in lipid transport and Aβ clearance compared to apoE3. ApoE4 also promotes Aβ aggregation and toxicity, contributing to AD pathogenesis. ApoE and its receptors are involved in APP trafficking and processing to Aβ, with LRP1 playing a key role in accelerating APP endocytic trafficking and Aβ production. ApoE receptors also mediate neuronal signaling, including reelin signaling, which is crucial for neuronal migration and synaptic plasticity. ApoE and its receptors are involved in Aβ clearance and aggregation, with apoE3 being more effective than apoE4 in clearing Aβ. ApoE4 is associated with increased risk of cerebral amyloid angiopathy (CAA) and other neurodegenerative diseases. ApoE also influences brain cholesterol and lipid transport, with apoE4 being less efficient in transporting cholesterol compared to apoE3. ApoE isoforms differentially regulate synaptic plasticity, repair, and dendritic spine integrity, with apoE3 being more effective in maintaining synaptic function. ApoE and its receptors are promising therapeutic targets for AD, with strategies to modulate their expression and function being explored. Therapeutic approaches include targeting apoE receptors, such as LRP1 and LDLR, to enhance Aβ clearance and reduce AD pathology. ApoE4 is a major risk factor for AD, and therapies targeting apoE/apoE receptors may benefit a larger population of AD patients. Understanding the roles of apoE and its receptors in AD pathogenesis is crucial for developing effective treatments.