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Review
. 2019 Sep;15(9):501-518.
doi: 10.1038/s41582-019-0228-7. Epub 2019 Jul 31.

Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies

Yu Yamazaki  1 , Na Zhao  1 , Thomas R Caulfield  1 , Chia-Chen Liu  1 , Guojun Bu  2
Affiliations
Review

Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies

Yu Yamazaki et al. Nat Rev Neurol. 2019 Sep.

Abstract

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-β (Aβ)-dependent and Aβ-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Figure 1:
Figure 1:. Structure of lipid-free and lipid-bound APOE3.
The structure of apolipoprotein E3 (APOE3) in the lipid-free state is shown on the left. APOE consists of multiple helices: a 4-helix bundle that consists of helix 2 (red), helix 3 (blue), helix 4 (green) and helix 5 (yellow and orange), hinge helices (pink and brown), and carboxyl-terminal domains that include lipid-binding residues and helices (translucent grey). The receptor-binding region (orange) is located on helix 5. The APOE isoforms differ at two residues only, and the residue composition for each isoform is given in the inset box. Isoform-specific residues (Arg158 and Cys112) are indicated on the structure of APOE3, with labels and carbons, shown as a van der Waals representation and coloured to match the helix with the residue. The lipid-bound structure of APOE3 is shown on the right. In its lipid-bound state, APOE3 demonstrates release of both the hinge region and the lipid-binding region, which causes the receptor binding region to be exposed. The crucial lipid-binding region includes residues 244–272. The lipid particle is shown in cross-section to allow better visualization of the APOE binding region. Water molecules depicted within the lipid particle illustrate the aqueous conditions and demonstrate the exclusion of water on binding of APOE3. The positively charged residues within the receptor-binding region in helix 5 (residues 136–150) interact with the negatively charged residues in the ligand-binding domains of LDL receptor family members; however, the precise binding structure of APOE with its receptors remains to be determined.
Figure 2:
Figure 2:. APOE genotype and amyloid positivity.
Estimated probabilities of amyloid positivity according to apolipoprotein E (APOE) genotype, plotted against age in cognitively healthy individuals and individuals with mild cognitive impairment (MCI). Shaded areas represent 95% CIs. In both groups, APOE*ε4/ε4 individuals are more likely to be positive for amyloid pathology than individuals with any other genotype, whereas APOE*ε2/ε2 individuals have the lowest probability of amyloid positivity. Also note that APOE*ε4 is a strong driver of Aβ positivity irrespective of the presence of APOE*ε2 or APOE*ε3. Data for APOE*ε2/ε2 individuals are not shown in the right panel owing to a small sample size. Adapted with permission from REF., American Medical Association.
Figure 3:
Figure 3:. APOE isoforms and Aβ aggregation and clearance.
a | Amyloid-β (Aβ) production and clearance pathways. Aβ is produced primarily in neurons through proteolytic cleavage of amyloid precursor protein (grey arrow). Aβ is then removed from the brain by multiple Aβ clearance pathways (green boxes), including cellular uptake and subsequent degradation, enzymatic degradation, clearance through the blood–brain barrier (BBB), and clearance via interstitial fluid (ISF) bulk flow and, potentially, the glymphatic pathway. LDL receptor-related protein 1 (LRP1), LDL receptor (LDLR) and heparan sulfate proteoglycan (HSPG) are major APOE receptors that mediate cellular uptake of Aβ. Apolipoprotein E (APOE) is produced and lipidated primarily by astrocytes (brown arrow). A sub-pool of APOE lipoprotein particles interacts with soluble Aβ released into the brain interstitial fluid by neurons. b | Insufficient Aβ clearance from the brain leads to Aβ accumulation. This accumulation initiates Aβ oligomerization and accelerates subsequent aggregation and fibrillogenesis, leading to deposition of insoluble Aβ in the brain parenchyma (amyloid plaques) and in the vascular wall (cerebral amyloid angiopathy). APOE promotes the formation of Aβ fibrils by accelerating the initial seeding or nucleation of Aβ peptides. APOE can influence Aβ clearance and aggregation, either directly or indirectly, in an isoform-dependent manner. The relative abilities of APOE3 and APOE4 to promote each pathway are indicated alongside the arrows. ABCA1, ATP-binding cassette sub-family A member 1; ABCG1, ATP-binding cassette sub-family G member 1; CSF, cerebrospinal fluid.
Figure 4:
Figure 4:. Effects of APOE4 on AD pathogenesis pathways.
Apolipoprotein E4 (APOE4) affects multiple different pathways in Alzheimer disease (AD) pathogenesis. Key functional pathways are shown, and the arrows within the boxes depict the effects of APOE4 compared with APOE3. Pathways are shown in red boxes if evidence suggests that APOE4 increases risk of AD via a gain of toxic function. The effects on the lipid transport pathway, shown in blue, represent a potential loss of physiological function of APOE4 relative to APOE3. Pathways shown in grey are unclassified either owing to insufficient evidence or the potential for both gain of toxic and loss of physiological function. The two thicker arrows indicate the importance of the Aβ-related pathway as the key mechanism by which APOE influences AD. Aβ, amyloid-β; α-syn, α-synuclein; BBB, blood–brain barrier; TDP43, TAR DNA-binding protein 43.
Figure 5:
Figure 5:. Model of precision medicine based on APOE genotype.
Although all apolipoprotein E (APOE) isoforms seem to promote amyloid-β (Aβ) deposition in the brain, the disease-driving effect is more pronounced with the presence of APOE*ε4 than of APOE*ε2 or APOE*ε3. Therefore, a precision medicine approach in which different treatment strategies are developed for individuals with different genotypes might be beneficial. The figure lists the potential therapeutic options according to the individuals who are most likely to benefit and whether the strategy attempts to correct APOE pathobiology or restore APOE physiological function. Modulation of Aβ pathology in individuals with different APOE genotypes is likely to require a combination of strategies.
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