APOE2: protective mechanism and therapeutic implications for Alzheimer's disease

• Published in: Molecular neurodegeneration Vol. 15; no. 1; p. 63
• Main Authors: Li, Zonghua, Shue, Francis, Zhao, Na, Shinohara, Mitsuru, Bu, Guojun
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 04-11-2020; BioMed Central; BMC
• Subjects: Advertising executives; Age; Aging; Alzheimer Disease - genetics; Alzheimer's disease; Amyloid-β; Animals; Apolipoprotein E; Apolipoprotein E2; Apolipoprotein E2 - genetics; Apolipoproteins; Binding sites; Brain; Cerebrovascular disease; Cerebrovascular diseases; Cholesterol; Comparative analysis; Genotype & phenotype; Health aspects; Health risk assessment; Heparan sulfate; Humans; Kinases; Lipid metabolism; Lipids; Lipoproteins; Longevity; Metabolism; Neural coding; Neurodegenerative diseases; Neurological diseases; Pathology; Physiological aspects; Plasma; Post traumatic stress disorder; Review; Vascular diseases; α-Synuclein; Alzheimer’s disease; TDP-43; Neurofibrially tangles; Neuroinflammation; Amyloid-β; Lipid metabolism; Longevity; Cerebrovascular disease; Apolipoprotein E2
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-020-00413-4

Investigations of apolipoprotein E (APOE) gene, the major genetic risk modifier for Alzheimer's disease (AD), have yielded significant insights into the pathogenic mechanism. Among the three common coding variants, APOE*ε4 increases, whereas APOE*ε2 decreases the risk of late-onset AD compared with APOE*ε3. Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms. In addition, APOE*ε2 has been identified as a longevity gene, suggesting a systemic effect of APOE*ε2 on the aging process. However, APOE*ε2 is not entirely benign; APOE*ε2 carriers exhibit increased risk of certain cerebrovascular diseases and neurological disorders. Here, we review evidence from both human and animal studies demonstrating the protective effect of APOE*ε2 against AD and propose a working model depicting potential underlying mechanisms. Finally, we discuss potential therapeutic strategies designed to leverage the protective effect of APOE2 to treat AD.