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.

Keywords: Alzheimer’s disease; Amyloid-β; Apolipoprotein E2; Cerebrovascular disease; Lipid metabolism; Longevity; Neurofibrially tangles; Neuroinflammation; TDP-43; α-Synuclein.

Fig. 1

Human APOE. a Human APOE is an O-linked glycoprotein consisting of 299 amino acids. The N-terminal domain (residues 1-167) and the C-terminal domain (residues 206-299) are linked by a flexible hinge region. The receptor binding site (residues 136-150) on the N-terminus overlaps with the heparin binding region (residues 136-147). A second heparin-binding site on the C-terminal domain adjacent to the lipid binding site (residue 244-272) requires K233. Amino acid substitutions at position 112 and 158 result in the three major isoforms: APOE2 (Cys112; Cys158), APOE3 (Cys112; Arg158) and APOE4 (Arg158; Arg158). APOE has other less common isoforms; APOE (V236E) and APOE3 Christchurch (R136S) (blue triangles) are two examples that have also been suggested to protect against AD. b Lipidated APOE-containing lipoprotein particles contain phospholipids and unesterified cholesterol in the shell, and esterified cholesterol and triglycerides form the core. APOE molecules are partially embedded in the phospholipid layer of the particles

Fig. 2

APOE*ε2 protects against AD. a Age-stratified odds ratio for AD risk (with APOE*ε3/3 as reference group) in individuals of different APOE genotypes. APOE*ε2/2 and APOE*ε2/3 individuals have reduced risk of AD (OR < 1) compared to APOE*ε3/3 individuals and the protective effect sizes are similar in different age groups. In contrast, APOE*ε4 carriers and APOE*ε2/4 individuals, have increased risk of AD (OR > 1) and the effect size varies among different age groups. b Kaplan-Meier curves showing the percentage of pathologically confirmed AD cases in individuals of different APOE genotypes. APOE*ε2 carriers are less likely to be pathologically diagnosed as AD. The protective effect is more prominent in APOE*ε2/2 homozygotes. a A reproduction of published data by Genin, et al., Mol Psychiatry. 2011 Sep;16(9):903-7, with permission. b A visual adaptation of a figure from Reiman et al., Nat Commun. 2020 Feb 3;11(1):667, with permission

Fig. 3

Potential mechanisms underlying APOE2 protective effects against AD. CNS APOE is produced primarily by astrocytes, and also by activated microglia. Newly synthesized APOE is lipidated through cell surface ABCA1 or ABCG1, generating HDL-like lipoprotein particles. In the CNS, APOE2-containing lipoprotein particles are more lipidated than APOE3 and APOE4-containing particles, thus are larger in size. The lipidation of APOE can be modulated by targeting the transcription factors, LXR, and RXR, which regulate the expression of APOE and ABCA1. Lipidated APOE plays a critical role in lipid transport from astrocytes to neurons. Due to hyperlipidation, APOE2-containing lipoprotein particles likely deliver lipids to neurons at a higher efficiency than APOE3 and APOE4. APOE2 may also maintain synaptic plasticity during AD, potentially through interacting with synaptic APOE receptors. During AD pathogenesis, Aβ is produced primarily by neurons through proteolytic processing of APP. APOE regulates Aβ metabolism in an isoform-dependent manner. APOE2 likely mediates Aβ clearance via BBB at a higher efficiency than APOE3 and APOE4. In addition, APOE2 may have a stronger effect in promoting the proteolytic degradation of Aβ by extracellular enzymes. The regulatory roles of APOE in Aβ metabolism may be partially mediated through APOE/Aβ complex formation. APOE*ε2 has also been associated with reduced neurofibrillary tangles in AD patients, though the mechanism is unclear. Additionally, APOE2 may confer protection against AD by affecting the plasma lipid and metabolomics profiles. ACID, intracellular domain of the amyloid-precursor protein; sAPPβ, soluble amyloid precursor protein β