In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1)  to natural killer T cell as well as modulation of inflammation and oxidation.
ApoE is polymorphic, with three major alleles: ApoE2 (cys112, cys158), ApoE3 (cys112, arg158), and ApoE4 (arg112, arg158). Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158, these differences alter apoE structure and function. These have physiological consequences:
E2 (rs7412) has an allele frequency of approximately 7 percent. This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well. E2 is associated with both increased and decreased risk for atherosclerosis. Individuals with an E2/E2 combination may clear dietary fat slowly and be at greater risk for early vascular disease and the genetic disordertype III hyperlipoproteinemia—94.4% of such patients are E2/E2, while only ∼2% of E2/E2 develop the disease, so other environmental and genetic factors are likely to be involved (such as cholesterol in the diet and age). E2 has also been implicated in Parkinson's disease. E2 is no longer associated with Parkinson disease in a larger population association study.
E3 (rs429358) has an allele frequency of approximately 79 percent. It is considered the "neutral" Apo E genotype.
However, there is much to be learned about these APOE isoforms, including the interaction of other potentially protective genetic polymorphisms, so caution is advised before making determinant statements about the influence of APOE polymorphisms; this is particularly true as it relates to how APOE isoforms influence cognition and the development of Alzheimers Disease. In addition, there is no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor is there evidence that the APOE4 isoform places individuals at increased risk for any infectious disease.
The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer disease (AD) in a variety of ethnic groups. Caucasian and Japanese carriers of 2 E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. While the exact mechanism of how E4 causes such dramatic effects remains to be fully determined, evidence has been presented suggesting an interaction with amyloid. Alzheimer disease is characterized by build-ups of aggregates of the peptidebeta-amyloid. Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. The isoform ApoE-ε4 is not as effective as the others at catalyzing these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.
The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance while working in the Roses lab at Duke University Linkage studies were followed by association analysis confirming the role of the ApoE4 allele as a strong genetic risk factor for AD.
Although 40-65% of AD patients have at least one copy of the ε4 allele, ApoE4 is not a determinant of the disease - at least a third of patients with AD are ApoE4 negative and some ApoE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD. There is also evidence that the ApoE2 allele may serve a protective role in AD. Thus, the genotype most at risk for Alzheimer disease and at an earlier age is ApoE 4,4. The ApoE 3,4 genotype is at increased risk, though not to the degree that those homozygous for ApoE 4 are. The genotype ApoE 3,3 is considered at normal risk for Alzheimer disease. The genotype ApoE 2,3 is considered at lower risk for Alzheimer disease. Interestingly, people with both a copy of the 2 allele and the 4 allele, ApoE 2,4, are at normal risk, similar to the ApoE 3,3 genotype.
Estimated worldwide human allele frequencies of ApoE * in Caucasian population
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
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