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

Abstract

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.

APOE: The New Frontier in the Development of a Therapeutic Target towards Precision Medicine in Late-Onset Alzheimer’s

“…Noteworthy, APOE e2 has been identified as a longevity variant, associated with beneficial effects on cognition, and accumulating evidence suggested it protects against AD (reviewed in [ 61 ]). While the mechanisms driving its protective effect remain unclear, potential therapeutic strategies designed to leverage the protective effect of APOE e2, such as viral-mediated overexpression of APOE e2 and gene-editing conversion of APOE e4 to e2, hold promise as treatment options for AD.…”

“…With that said, APOE e2 increases the risk of other diseases, including neurological disorders; thus, long-term safety concerns should be carefully evaluated when considering treatments inspired by the protective role of e2 in AD. This topic has been extensively reviewed elsewhere [ 61 , 62 ] and is outside the scope of this review.…”

Neuronal ROS-Induced Glial Lipid Droplet Formation is Altered by Loss of Alzheimer’s Disease-associated Genes

“…Homozygous carriers for APOE4 are 8-12 times more likely to develop AD than non-carriers (Michaelson, 2014). In contrast, individuals carrying the ε2 allele of APOE ( APOE2 ) have reduced risk of developing AD, supporting that it is neuroprotective against AD development (Conejero-Goldberg et al, 2014; Huang and Mahley, 2014; Huynh et al, 2017; Li et al, 2020). While APOE functions to mediate lipid transfer between cells, the APOE4 variant has reduced lipid transport capacity (Hatters et al, 2006; Liu et al, 2017).…”

Autocrine Effects of Brain Endothelial Cell-Produced Human Apolipoprotein E on Metabolism and Inflammation in vitro

“…Human APOE genotype plays an important role in the homeostasis of the central nervous system and has long been linked to neurodegenerative disorders ( Huang, 2006 ; Mahley et al, 2007 ; Yamazaki et al, 2019 ; Chen et al, 2020 ; Lanfranco et al, 2020 ; Lewandowski et al, 2020 ; Li et al, 2020 ). For example, APOE4 is associated with greater cognitive decline in aging, poorer outcomes following stroke and traumatic brain injury, and is a major genetic risk factor for Alzheimer’s disease compared to APOE3 (reviewed in Mahley et al, 2007 ; Liu et al, 2013 ; Flowers and Rebeck, 2020 ).…”