Journal
MOLECULAR NEURODEGENERATION
Volume 15, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13024-020-00413-4
Keywords
Apolipoprotein E2; Alzheimer’ s disease; Amyloid-β Cerebrovascular disease; Lipid metabolism; Longevity; Neuroinflammation; Neurofibrially tangles; TDP-43; α -Synuclein
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Funding
- National Institutes of Health
- Coins for Alzheimer's Research Trust (CART) Foundation
- National Center for Geriatrics and Gerontology
- Hori Sciences and Arts Foundation
- Yokoyama Foundation for Clinical Pharmacology
- Cure Alzheimer's Fund
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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*epsilon 4 increases, whereas APOE*epsilon 2 decreases the risk of late-onset AD compared with APOE*epsilon 3. Despite increased understanding of the detrimental effect of APOE*epsilon 4, it remains unclear how APOE*epsilon 2 confers protection against AD. Accumulating evidence suggests that APOE*epsilon 2 protects against AD through both amyloid-beta (A beta)-dependent and independent mechanisms. In addition, APOE*epsilon 2 has been identified as a longevity gene, suggesting a systemic effect of APOE*epsilon 2 on the aging process. However, APOE*epsilon 2 is not entirely benign; APOE*epsilon 2 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*epsilon 2 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.
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