The apolipoprotein E (APOE) ε4 allele has been demonstrated as the preeminent genetic risk factor for late onset Alzheimer's disease (AD), which comprises greater than 90% of all AD cases. The discovery of the connection between different APOE genotypes and AD risk in the early 1990s spurred three decades of intense and comprehensive research into the function of APOE in the normal and diseased brain. The importance of APOE in the periphery has been well established, due to its pivotal role in maintaining cholesterol homeostasis and cardiovascular health. The influence of vascular factors on brain function and AD risk has been extensively studied in recent years. As a major apolipoprotein regulating multiple molecular pathways beyond its canonical lipid-related functions in the periphery and the central nervous system, APOE represents a critical link between the two compartments, and may influence AD risk from both sides of the blood-brain barrier. This review discusses recent advances in understanding the different functions of APOE in the periphery and in the brain, and highlights several promising APOE-targeted therapeutic strategies for AD.
Bibliographical noteFunding Information:
This work was supported in part by the National Institutes of Health [grant numbers AG056025 , AG058081 , and AG056976 ]. DC was supported by a predoctoral training fellowship in the PharmacoNeuroImmunology Program from the National Institutes of Health (grant number DA007097 ) and a 3M Science and Technology Training Fellowship . AG is partly supported by the Kwanjeong Educational Foundation Overseas Scholarship from South Korea .
- APOE-targeted therapeutic strategies
- Alzheimer's disease pathogenesis
- Apolipoprotein E
- Blood-brain barrier