Apolipoprotein E in Alzheimer's disease: A review of APOE receptors, signalling pathways and therapeutic opportunities.

Apolipoprotein E, a glycoprotein, is one of the strongest genetic risk factors for late-onset Alzheimer's disease. APOE is involved in the transport and metabolism of cholesterol, phospholipids and other lipids, synaptic function and neuroinflammation in the CNS. One of the key functions of APOE is to bind and deliver newly synthesized cholesterol and lipids to neurons through receptor-mediated endocytosis (LDLR, LRP1, VLDLR, APOER2). The APOE gene exists in three common isoforms: APOE2, APOE3, and APOE4, with distinct structural and functional properties. The three isoforms of APOE vary in their potential to bind and transport lipids and cholesterol, receptor affinity and clearance of Aβ. Among the three isoforms, APOE4 is one of the strongest risk factors for late-onset Alzheimer's disease, while APOE2 exerts a protective role highlighting the functional divergence among isoforms in CNS physiology. The functions of APOE are exerted through binding of APOE with members of the low-density lipoprotein receptor (LDLR) family, including LDLR, LRP1, VLDLR, and APOER2. So, approaches that potentiate the protective effects of APOE, like APOE mimetics, ABCA1 agonists, targeting APOE receptors like LDLR, LRP1, APOER2, and TREM2, might offer significant therapeutic benefits in Alzheimer's disease.