- Apolipoprotein E (APOE) is a protein involved in the metabolism of fats.
APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease.
Defects in APOE result in familial dysbetalipoproteinemia, type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL.
APOE studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer’s disease (AD), immunoregulation, and cognition.
Isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury.
APOE’s interact 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 produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in blood and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.
A subtype is implicated in Alzheimer’s disease and cardiovascular disease.
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.
Almost all people who inherit two identical copies of the APOE4 variant have abnormally high levels of amyloid in their CSF and brain by 65 years.
Up to 60% of individuals who are homozygous for APOE4 developed dementia by 85 years.
About 2% of people are homozygous for APOE4.
This may be caused by an interaction with amyloid.
Alzheimer’s disease is characterized by build-ups of aggregates of the peptide beta-amyloid.
One or 2 APOE4 alleles are present in approximately half of patients with Alzheimer’s disease.
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 promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.
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.
In Alzheimer’s disease, the most prevalent protective allele is APOE2 which has a population allele frequency of approximately 10%.
Sporadic Alzheimer’s disease is delayed by approximately 10 years in person with APOE2 homozygosity as compared with the general population.
The genotype most at risk for Alzheimer’s disease and at an earlier age is APOE4.
Estimated worldwide human allele frequencies of APOE in Caucasian population
Allele ε2 ε3 ε4
General Frequency 8.4% 77.9% 13.7%
AD Frequency 3.9% 59.4% 36.7%
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.
It is 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.
It is encoded by the APOE gene, which is located on chromosome 19.
APOE is 299 amino acids long and contains multiple amphipathic α-helices.
APOE is primarily produced by the liver, but it is also produced by other cells such as macrophages, kidneys, spleen and brain cells.
It interacts with lipoproteins, which transport cholesterol and other lipids throughout the body.
In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.
The Apolipoprotein E allele 4 is a major genetic risk factor for Alzheimer’s disease, and this lipid carrier is important for maintaining homeostasis necessary for a healthy environment of the brain.
Apolipoprotein E is concentrated in astrocytic processes at the pial surface and around the blood vessels
In addition, the choroid plexus and cells in the wall of the third ventricle also produce Apolipoprotein E.
Thus, Apolipoprotein E production is co-localized with CSF production sites and transport pathways suggesting that lipids are transported by the glymphatic system.
The C-terminal region also contains a low density lipoprotein receptor (LDLR)-binding site.
SNP: Apolipoprotein E
Gene ApoE
It is a checkpoint inhibitor of the classical complement pathway by complex formation with activated C1q.
It has three major human alleles (E4, E3, E2)
APOE is polymorphic, with three major alleles (epsilon 2, epsilon 3, and epsilon 4).
These genetic variants determine the structure of the corresponding APOE protein and have been linked to different health outcomes.
Genetic variants alone do not determine health outcomes, as lifestyle factors such as diet, exercise, and smoking can also heavily influence health outcomes.
There are several low-frequency polymorphisms of APOE.
The apolipoprotein ε4 isoform is more protective against cognitive decline than other isoforms.
Apolipoprotein E (APOE) is a protein that plays a crucial role in the metabolism of lipids and cholesterol in the body.
E4 has been implicated in atherosclerosis, Alzheimer’s disease, impaired cognitive function, reduced hippocampal volume, HIV, faster disease progression in multiple sclerosis, unfavorable outcome after traumatic brain injury, ischemic cerebrovascular disease, sleep apnea, accelerated telomere shortening, reduced neurite outgrowth, and COVID-19.
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.
The E4 variant was the largest known genetic risk factor for late-onset sporadic Alzheimer’s disease (AD) in a variety of ethnic groups.
The E4 variant does not correlate with risk in every population.
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.
Caucasians who were homozygous for the allele had 12.5 times the odds.
Nigerian people have the highest observed frequency of the APOE4 allele in world populations, but AD is rare among them.
APOE transports lipids, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood.
APOE2, on the other hand, has been associated with a reduced risk for developing Alzheimer’s disease and improved outcomes following a traumatic brain injury.
E4 is associated with enhanced vitamin D and calcium status, higher fecundity, protection against early childhood infection and malnutrition, and decreased fetal, perinatal, and infant mortality.
Human studies have shown that the APOE2 polymorphism correlates with earlier infection, and APOE3/4 polymorphisms increase likelihood of severe malaria.
APOE3 is considered the most common variant and has been associated with an average risk for Alzheimer’s disease.
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.
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.
The gene, APOE, is mapped to chromosome 19 in a cluster with apolipoprotein C1 (APOC1) and the apolipoprotein C2 (APOC2).
The APOE gene consists of four exons and three introns, totaling 3597 base pairs.
APOE is transcriptionally activated by the liver X receptor and peroxisome proliferator-activated receptor γ.
APOE is 299 amino acids long.
It contains multiple amphipathic α-helices.
APOE belongs to a family of fat-binding proteins called apolipoproteins.
APOE is primarily produced by the liver and macrophages.
APOE is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen.
APOE mediates cholesterol metabolism.
Apolipoprotein E transports cholesterol from astrocytes to neurons and other glial cells, regulating cell signaling in the brain.
In the central nervous system it is mainly produced by astrocytes and transports cholesterol to neurons via APOE receptors, which are members of the low density lipoprotein receptor gene family.
In the nervous system, astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.
Defects in APOE result in familial dysbetalipoproteinemia-type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL.
APOE transports lipids, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood.
It is the principal cholesterol carrier in the brain, and is required for cholesterol transportation from astrocytes to neurons.
APOE is present as part of several classes of lipoprotein particles, including chylomicron remnants, VLDL, IDL, and some HDL.
It interacts significantly with the low-density lipoprotein receptor (LDLR), which is essential for the normal catabolic processing of triglyceride-rich lipoproteins.
Common variants alleles APOE2, APOE3, and APOE4 modulate lipoprotein metabolism, are expressed in the kidney and differ in frequency based on race.
APOE4 alleilic variant associated with increased risk of Alzheimer’s disease.
The APOEe4-allele and age are the two main risk factors for late onset Alzheimer’s disease.
The alzheimer’s disease risk associated with common APOE alleles e4 and e2 is well-established in European ancestry individuals.
In individuals of African ancestry APOE e3/e4 genotype is associated with an increased risk of Alzheimer’s disease.
The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer’s disease (AD) in a variety of ethnic groups.
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.
Allele ε2 ε3 ε4 frequency 8.4% 77.9%13.7% vs.
Alzheimer’s disease frequency 3.9% 59.4% 36.7%
ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer’s.
Alzheimer’s disease is characterized by build-ups of aggregates of the peptide beta-amyloid, and 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 promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.
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.
Individuals with two ε4 alleles have up to 20 times the risk of developing AD.
APOE2 allele may serve a protective role in AD.
The genotype most at risk for Alzheimer’s disease and at an earlier age is APOE4,4.
Individuals with genotype APOE4,4 have an odds ratio of 14.9 of developing Alzheimer’s disease.
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.
It is hypothesized 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.
The E4 variant does not correlate with risk in every population.
Caucasian and Japanese carriers of two APO 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.
Nigerian people have the highest observed frequency of the APOE4 allele in world populations, but AD is rare among them, and it may be due to their low cholesterol levels.
Women with a single copy of APOE-4 are at greater risk of Alzheimer’s disease than men.
Women’s risk for AD is equivalent to men with two copies.
APOE4 has worse outcomes after stroke and traumatic brain injuries.
The increased APOE-4 related risk in women is associated with an increase in phosphorylated tau, a second pathological hallmark of Alzheimer’s disease.
Tau protein accumulates in intracellular neurofibrillary tangles.
Women, particularly APOE-4 carriers, are more vulnerable to tau accumulation in the presence of beta-amyloid than men.
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.
In 350 adult soccer players those with at least one copy of APOE4 gene allele had a stronger association between a 12-month soccer ball heading experience and worse verbal memory performance than their peers without the allele.
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 disorder type III hyperlipoproteinemia.
94.4% of sufferers of type III hyperlipoproteinemia 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 not replicated in a larger population association study.
APOE e2 allele is associated in some studies with increased lifespan and lower risk for dementia.
ε3 variant is considered the neutral APOE genotype.
Studies have shown that the APOE2 polymorphism correlates with earlier infection, and APOE3/4 polymorphisms increase likelihood of severe malaria.