[Gene of the Week] Alzheimer's Disease and Genes - APOE (Apolipoprotein E)

In our fourth Gene of the Week article, we continue covering genes related to the development of Alzheimer's disease (AD). Several mutations in APOE (Apolipoprotein E) have been identified to not only increase the risk of developing AD, but other neurological and cardiovascular diseases. As scientists continue to evaluate potential therapies for AD, we hope to provide insights into various genes, related pathways, and research accomplishments in every Gene of the Week article. Herein, we summarize the current research progress on APOE functionality and review its role in Alzheimer's disease (AD).

Background Information – APOE & Homologs Across Species

APOE Aliases: Apolipoprotein E, ApoE4, Apo-E, APO-E, Alzheimer Disease 2 (APOE*E4-Associated, Late Onset), AD2, LDLCQ5, Apolipoprotein E3, LPG

Related Diseases: Mutations cause Lipoprotein Glomerulopathy and Type 3 Hyperlipoproteinemia (HLP III); polymorphisms related to Alzheimer’s Disease (AD) and atherosclerotic cardiovascular disease (ASCVD); implicated in type II diabetes and ischemic stroke.

Note: the mark 'Yes' represents the corresponding models that available from Cyagen Knockout Catalog Models.

APOE Gene Variants and Disease Risk

APOE is polymorphic, with three major alleles among the human population: epsilon 2 (ε2), epsilon 3 (ε3), and epsilon 4 (ε4). These allelic forms differ by 1-2 amino acids at positions 112 and 158, which result in altered APOE structure and function. APOE3 has the highest worldwide allele frequency and is considered the neutral (wild type) APOE genotype. Both APOE2 and APOE4 have unique biological implications and relevance for a range of neurological and cardiovascular diseases.

Figure 1. Three isoforms of APOE: APOE2, APOE3 and APOE4. The difference between these three isoforms lies in the changes of two sites at the level of the APOE gene, which translate to the protein level in determining whether these two sites (the 112th amino acid and the 158th amino acid) are cysteine (Cys) or arginine (Arg). APOE2 has both sites on the chromosome encoded as Cys; APOE3 encodes the 112th position as Cys and the 158th position as Arg; APOE4 encodes both sites to be Arg.

Overview of APOE Gene Research

APOE is the structural gene for apolipoprotein E (apoE), which is responsible for the transport of chylomicrons. The binding of its specific liver and peripheral cell receptor is essential for the normal catabolism of the lipoprotein component rich in triglycerides. Mutations of APOE can cause familial lipoproteinemia or type III hyperlipoproteinemia (HLP III), while Atherosclerosis and Alzheimer's disease are also closely related to the polymorphism of this gene.

Figure 2. The distribution of APOE polymorphisms among populations (Male & Female). APOE3/E3 accounted for the highest proportion – nearly 2/3 of the total population. 25% of the population carries at least one APOE4, 10% carry APOE2/E3, and the remaining 1% carry APOE2/E2.

Figure 3. The impact of APOE polymorphism on the incidence of AD. Taking the incidence of AD in APOE3 homozygous populations as a benchmark, the incidence in populations carrying APOE4 is all higher than that carrying APOE3 homozygous. The prevalence of E4/E2 and E4/E3 heterozygotes is 2.6 and 3.6 times of APOE3 homozygous populations respectively, while the incidence of AD for E4/E4 homozygous has soared to nearly 14.5 times, indicating that E2 may reduce the incidence of AD.

Figure 4. Physiological characteristics of different APOE polymorphisms. In addition to Alzheimer's disease (AD), APOE is also related to type II diabetes, ischemic stroke, cardiovascular disease and Hyperlipoproteinemia type III.

Figure 5. APOE ε4 is a major genetic risk factor for Alzheimer disease. (a) The ApoE2, E3, and E4 isoforms, which are encoded by the ε2, ε3 and ε4 alleles of the APOE gene, respectively, differ from one another at amino acid residues 112 and/or 158 (red circles). ApoE has two structural domains: the N-terminal domain, which contains the receptor-binding region (residues 136–150), and the C-terminal domain, which contains the lipid-binding region (residues 244–272); the two domains are joined by a hinge region. A meta-analysis demonstrated a significant association between the ε4 allele of APOE and AD. (b) APOE ε4 increases the risk of AD and lowers the age of disease onset in a gene-dose-dependent manner.⁴

APOE Expression in Human Tissues

Figure 6. Expression of Human and mouse APOE gene mRNA (relative expression values). The liver is the organ with the highest expression level of APOE mRNA across both species. APOE mRNA is also highly expressed in the kidneys, adrenal glands, brain, and spleen. However, the expression of ovaries and placenta in humans and mice are completely different. (The comparison above is within the same species, there is no comparison between mice and humans.) Data source: NCBI.

Conclusions

Three major isoforms of APOE - E2, E3, and E4 – within the human population have been studied for their implication in the development of disease. Compared with the common APOE3 polymorphism, both the APOE2 and APOE4 have unique biological relevance for a range of neurological and cardiovascular diseases. These isoforms differ in amino acids at positions 112 and/or 158, which result in altered APOE structure and function.

Data has shown an increased incidence of Alzheimer's disease (AD) for populations carrying at least one APOE4 allele, with E4/E4 homozygous populations having nearly 14.5 times the AD incidence of the baseline E3/E3 population. While APOE2 may reduce the incidence of AD, this polymorphism may have relevance to other diseases. APOE ε4 increases the risk of AD and lowers the age of disease onset in a gene-dose-dependent manner. Even though the APOE4 variant is the largest genetic risk factor for late-onset sporadic AD, it is not a determinant of the disease.

There is much to be learned about these APOE isoforms, especially for how they influence cognition and the development of Alzheimer's disease (AD). The APOE polymorphisms are implicated in a variety of neurological and cardiovascular diseases, and ongoing research continues to elucidate their specific interaction pathways.

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References：

1. Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15(9):501-518. DOI: 10.1038/s41582-019-0228-7.
2. Bos MM, Noordam R, Blauw GJ, Slagboom PE, Rensen PCN, van Heemst D. The ApoEε4 Isoform: Can the Risk of Diseases be Reduced by Environmental Factors? J Gerontol A Biol Sci Med Sci. 2019 Jan 1;74(1):99-107. DOI: 10.1093/gerona/gly226. PMID: 30321297.
3. Kockx, M., Traini, M. & Kritharides, L. Cell-specific production, secretion, and function of apolipoprotein E. J Mol Med96, 361-371 (2018). DOI: https://doi.org/10.1007/s00109-018-1632-y
4. Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106-118. doi:10.1038/nrneurol.2012.263