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Apolipoprotein E ( Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases.

(2025). 9783540686989, Springer.
It is encoded in humans by the APOE.

Apo-E belongs to a family of fat-binding proteins called . In the circulation, it is present as part of several classes of lipoprotein particles, including chylomicron remnants, , IDL, and some HDL. Apo-E interacts significantly with the , which is essential for the normal processing () of -rich lipoproteins. In peripheral tissues, Apo-E is primarily produced by the and , and mediates metabolism. In the central nervous system, Apo-E is mainly produced by and transports to via Apo-E receptors, which are members of the low density lipoprotein receptor gene family. Apo-E is the principal cholesterol carrier in the brain. Apo-E qualifies as a checkpoint inhibitor of the classical complement pathway by complex formation with activated C1q.


Evolution
Apolipoproteins are not unique to mammals. Many terrestrial and marine have versions of them. It is believed that APOE arose via gene duplications of APOC1 before the fish– split ca. 400 million years ago. Proteins similar in function have been found in , suggesting that they are a very old class of proteins predating the dawn of all living animals.

The three major human ( E4, E3, E2) arose after the primate–human split around 7.5 million years ago. These alleles are the by-product of non-synonymous mutations which led to changes in functionality. The first allele to emerge was E4. After the primate–human split, there were four amino acid changes in the human lineage, three of which had no effect on protein function (V174L, A18T, A135V). The fourth substitution (T61R) traded a threonine for an arginine altering the protein's functionality. This substitution occurred somewhere in the 6 million year gap between the primate–human split and the –human split, since exactly the same substitutions were found in Denisovan APOE.

About 220,000 years ago, a cysteine to arginine substitution took place at amino acid 112 (Cys112Arg) of the APOE4 gene, and this resulted in the E3 allele. Finally, 80,000 years ago, another arginine to cysteine substitution at amino acid 158 (Arg158Cys) of the APOE3 gene created the E2 allele.


Structure

Gene
The gene, APOE, is mapped to chromosome 19 in a with the apolipoprotein C1 ( APOC1) gene and the apolipoprotein C2 ( APOC2) gene. The APOE gene consists of four and three , totaling 3597 . APOE is transcriptionally activated by the liver X receptor (an important regulator of , , and ) and peroxisome proliferator-activated receptor γ, that form with retinoid X receptors. In APOE gene expression may be regulated by MITF.


Protein
Apoe-E is 299 long and contains multiple α-helices. According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein. The N-terminal region (residues 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. Meanwhile, the C-terminal domain (residues 206–299) contains three α-helices which form a large exposed surface and interact with those in the N-terminal helix bundle domain through and salt-bridges. The C-terminal region also contains a low density lipoprotein receptor (LDLR)-binding site.


Polymorphisms
APOE is polymorphic, with three major (epsilon 2, epsilon 3, and epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (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.

There are several low-frequency polymorphisms of APOE. APOE5 comes in two subtypes E5f and E5s, based on migration rates. APOE5 E5f and APOE7 combined were found in 2.8% of Japanese males. APOE7 is a mutation of APOE3 with two lysine residues replacing glutamic acid residues at positions 244 and 245.

ε2 (rs7412-T, rs429358-T)8.4%This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well. Individuals with an E2/E2 combination may clear dietary fat slowly and be at greater risk for early vascular disease and the type III hyperlipoproteinemia—94.4% of people with such disease are E2/E2 but only ~2% of E2/E2 develop it, 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, but this finding was not replicated in a larger population association study.
ε3 (rs7412-C, rs429358-T)77.9%This variant is considered the "neutral" APOE genotype.
ε4 (rs7412-C, rs429358-C)13.7%E4 has been implicated in , , Lewy body dementia, Type 2 diabetes, , corticobasal degeneration, frontotemporal dementia, myocardial infarction, vascular dementia, Herpes simplex virus 1, , , Alzheimer's disease, impaired cognitive function, reduced volume, , faster disease progression in multiple sclerosis, unfavorable outcome after traumatic brain injury, ischemic cerebrovascular disease, , both the extension and shortening of , and reduced outgrowth. However, E4 has also been associated with increased episodic memory ability and neural efficiency, decreased risk for , , , Macular degeneration, and Chronic obstructive pulmonary disease, enhanced health, enhanced , resistance to vitamin D deficiency, enhanced and status, higher , protection against early childhood and , and decreased , , and mortality.
Much remains to be learned about the APOE isoforms, including the interaction of other protective genes.Sundermann EE, Wang C, Katz M, et al. Cholesteryl ester transfer protein genotype modifies the effect of apolipoprotein ε4 on memory decline in older adults. Neurobiol Aging. 2016;41:200.e7-200.e12. doi:10.1016/j.neurobiolaging.2016.02.006 Indeed, the apolipoprotein ε4 isoform is more protective against cognitive decline than other isoforms in some cases, so caution is advised before making determinant statements about the influence of APOE polymorphisms on cognition, development of Alzheimer's disease, cardiovascular disease, telomere shortening, etc. Many of the studies cited that purport these adverse outcomes are from single studies that have not been replicated and the research is based on unchecked assumptions about this isoform. As of 2007, there was 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 that the APOE4 isoform places individuals at increased risk for any infectious disease.

However, the association between the APOE4 allele and Alzheimer's disease has been shown to be weaker in minority groups differently compared to their Caucasian counterparts. Hispanics/Latinos and African Americans who were homozygous for the APOE4 allele had 2.2 and 5.7 times the odds, respectively of developing Alzheimer's disease. The homozygous APOE4 allele has an even stronger effect in East Asian populations, with Japanese populations have 33 times the odds compared to the heterozygous population. Caucasians who were homozygous for the allele had 12.5 times the odds.


Function
As a component of the lipoprotein lipid transport system, APOE facilitates the transport of , fat-soluble , and via the blood. It interacts with the LDL receptor to facilitate endocytosis of VLDL remnants. It is synthesized principally in the , but has also been found in other tissues such as the , , and .
(2025). 9781849964715, Springer.
APOE synthesized in the liver associates with HDL which can then distribute it to newly formed or particles to facilitate their eventual uptake by the liver.

In the nervous system, non-neuronal cell types, most notably and , are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family.

APOE was initially recognized for its importance in lipoprotein and cardiovascular disease. Defects in APOE result in familial dysbetalipoproteinemia aka type III hyperlipoproteinemia (HLP III), in which increased plasma and triglycerides are the consequence of impaired clearance of , and . More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), , and . Though the exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury.

In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing proliferation, functioning regulation, lipid antigen presentation facilitation (by CD1) to natural killer T cell as well as modulation of and . APOE is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.


Clinical significance

Alzheimer's disease
As of 2012, the E4 variant was the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups. However, the E4 variant does not correlate with risk in every population. Nigerian people have the highest observed frequency of the APOE4 allele in world populations, but AD is rare among them. This may be due to their low cholesterol levels. Caucasian and Japanese carriers of two 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. This may be caused by an interaction with . Alzheimer's disease is characterized by build-ups of aggregates of the . Apolipoprotein E enhances break-down of this peptide, both within and between cells. The APOE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.

The amyloid hypothesis of Alzheimer's disease has been questioned, and an article in Science claimed that "Just as removing smoke does not extinguish a fire, reducing amyloid plaques may not affect the course of Alzheimer's disease." The role that the E4 variant carries can still be fully explained even in the absence of a valid amyloid hypothesis given the fact that signaling emerges to be one of the key processes involved in Alzheimer's disease and the E4 variant is shown to interact with ApoER2, one of the neuronal reelin receptors, thereby obstructing reelin signaling.

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 one-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's disease and at an earlier age is APOE4,4. Using genotype APOE3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0) and for white populations only, individuals with genotype APOE4,4 have an of 14.9 of developing Alzheimer's disease. Individuals with the APOE3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (APOE2,4), have an odds ratio of 2.6. Persons with one copy each of the 2 allele and the 3 allele (APOE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (APOE2,2) also have an odds ratio of 0.6.

Estimated worldwide human allele frequencies of APOE in Caucasian population
General frequency8.4%77.9%13.7%
AD frequency3.9%59.4%36.7%
While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer's, a 2002 study concluded, that in persons with any combination of APOE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop AD. Projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person's risk for Alzheimer's disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.

Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.

APOE-ε4 increases the risk not only for AD but also for dementia in pure alpha-synucleinopathies. The influence of APOE-ε4 on hippocampal atrophy was suggested to be more predominant early in the course of AD at milder stages prior to more widespread neurodegeneration.

With the approval of the first disease-modifying therapies for Alzheimer's disease based on monoclonal antibodies against amyloid-beta, which delay disease progression, APOE genotyping has also become important in assessing a patient’s risk of side effects under therapy. In November 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency following a re-examination procedure, adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Leqembi, intended for the treatment of early Alzheimer's disease in apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. The applicant for this medicinal product is Eisai GmbH. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.


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