Apolipoprotein E (ApoE) is one of the proteins the body uses to transport fats (lipids) in the bloodstream from one tissue or cell type to another. It is essential for healthy metabolism of cholesterol and triglycerides, two important types of fats the body has to deal with regularly.
The relationship between ApoE and heart disease has been studied quite intensively in recent years. Furthermore, the association between a subtype of ApoE called ApoE4 has received much attention because of its correlation with increased risk of Alzheimer’s disease.
Lipoproteins are a combination of proteins (apolipoproteins) and fats such as cholesterol, phospholipids, and triglycerides. The primary role of the apolipoproteins is to bind lipids to form a water soluble compund, enabling transport of different types of lipids through the circulatory systems.
There are several types of apolipoproteins. Despite their important role in lipid metabolism, the apolipoproteins also seem to be involved in several disease processes. For example, apolipoprotein B (apoB) is known for its association with atherosclerosis and coronary artery disease.
ApoB is present in lipoprotein particles such as low-density lipoprotein (LDL), very-low density lipoprotein (VLDL) and lipoprotein(a). These lipoproteins are often termed atherogenic because they appear to play a role in atherosclerosis and heart disease. Several studies have shown that high levels of apoB are associated with increased risk of cardiovascular disease (1).
ApoE is typically found in chylomicrons, VLDL, and intermediate density lipoproteins (IDL). In humans, ApoE is polymorphic, meaning that there are several subtypes of the protein with several different functions.
What is ApoE and What Does It Do?
ApoE is a chain of 299 amino acids. It is primarily produced by the liver and white blood cells called macrophages. In the central nervous system, ApoE is mainly generated by a type of nerve cells called astrocytes. ApoE is the principal carrier of cholesterol within the brain.
Human ApoE exists as three common isoforms, ApoE2, ApoE3, and ApoE4. The differences between the three isoforms are limited to two amino acids at spots 112 and 158 in the amino acid chain where either cysteine or arginine is present. These amino acid differences are important for the protein’s ability to bind to lipids and cell receptors.
Lipoprotein particles containing ApoE carry both cholesterol and triglycerides. ApoE appears to play a vital role in regulating the blood levels of these fats. Its primary purpose is to promote clearance of triglyceride-rich lipoproteins from the circulation.
ApoE3 is often regarded as the parent form and is associated with normal plasma cholesterol levels. The ApoE2 and ApoE4 isoforms, on the other hand, are related to lipid abnormalities mainly caused by abnormal metabolism of triglyceride-rich lipoproteins, primarily VLDL.
ApoE Metabolism – The Different Roles of ApoE3, ApoE2, and ApoE4
Following a fatty meal, triglycerides are transported in the lymphatic system and blood by lipoproteins called chylomicrons. After being broken down (lipolysis) in the circulation, chylomicrons derived from the intestine and VLDL derived from liver cells become so-called remnant lipoprotein particles. The ApoE part of the remnant particles binds to LDL receptors, primarily in the liver, hence initiating the removal of the particles from the circulation (2). This process is an essential part of healthy lipid metabolism and a key factor in maintaining normal blood levels of cholesterol and triglycerides.
Some VLDL remnants are cleared rapidly whereas others undergo further lipolysis and are converted to IDL and finally to LDL. However, the LDL particles do not contain ApoE. The primary lipoprotein in LDL is ApoB, and the clearance of LDL from the circulation is mediated by the binding of ApoB to the LDL receptor.
The ApoE2 isoform differs from ApoE3 by a single amino acid substitution located near the LDL receptor recognition site. It exhibits impaired binding to the receptor and an inability to promote clearance of triglyceride-rich lipoprotein remnant particles. Hence, ApoE2 is associated with raised levels of both cholesterol and triglycerides.
Type-III hyperlipoproteinemia is a rare genetic disorder characterized by high blood levels of VLDL, triglycerides, and cholesterol (3). Most cases result from inheritance of two genes that code for ApoE2.
ApoE4, on the other hand, seems to accelerate the clearance of VLDL and remnant lipoproteins. However, LDL levels are increased, possibly because of down-regulation of LDL receptors or due to a competition between remnant lipoproteins and LDL for a place on the receptors (4).
The Genetic Aspects of ApoE
The ApoE gene provides instructions for making the ApoE protein. There are three different types of the ApoE gene, called alleles; E2, E3, and E4.
We all carry two copies of the APOE gene. The combination of alleles determines our ApoE3 genotype.
There are six possible combinations (genotypes) for ApoE
The ApoE2 allele is the rarest, and the ApoE3 allele is the most common. ApoE3 is present in more than half of the population. Carrying at least one ApoE2 allele appears to reduce the risk of developing Alzheimer’s disease whereas the Apoe4 allele is associated with increased risk of developing the disease.
The ApoE2 allele is found in approximately 7 percent of the population (5). Individuals with the E2/E2 combination may clear dietary fat slowly and are at greater risk of heart disease.
ApoE4 and Alzheimer’s Disease
Alzheimer’s disease is the most common form of dementia. The lifetime risk of developing the disease is approximately 20 percent for women and 10 percent for men.
The science of Alzheimer’s disease has come a long way since 1906 when a German neurologist and psychiatrist named Dr. Alois Alzheimer first described the key features of the disease. He noticed abnormal deposits in the brain of a 51-year old woman who had dementia. Researchers now know that Alzheimer’s disease is characterized by brain abnormalities called plaques and tangles.
The exact cause of Alzheimer’s disease is unknown, but some risk factors have been described. The risk of developing the disease increases with age. Family history also plays a role; there’s a higher risk of Alzheimer’s if a family member has the disease.
The early-onset form of Alzheimer disease which typically develops before age 65 accounts for less than one percent of cases. It follows an autosomal dominant inheritance pattern associated with gene mutations that alter so-called amyloid-beta protein production, aggregation, or clearance in the brain.
The genetic basis of late-onset Alzheimer disease is more complex. Among the genetic factors that often appear to be involved is the presence of the ApoE4 allele. ApoE is critical for lipid transport in the brain and contributes to the maintenance and repair of nerve cells.
ApoE4 is a major genetic risk factor for late-onset Alzheimer’s disease (9). Individuals carrying the E4 allele are at increased risk of Alzheimer’s disease compared with those carrying the more common E3 allele, whereas the presence of the E2 allele decreases risk (10).
Having one allele of ApoE4 increases the risk of Alzheimer’s disease, and if two ApoE4 alleles are present, the risk is even higher.
However, it is important to acknowledge that the association between ApoE4 and Alzheimer’s disease is complex. Many individuals with the ApoE4 allele never develop the disease and many patients with Alzheimer’s disease do not have the ApoE4 allele.
The risk of developing Alzheimer’s disease also appears to be affected by environmental factors. Diabetes, high blood pressure, obesity, depression, physical inactivity, smoking, and cognitive inactivity or low educational attainment all seem to increase the risk of the disease (11).
So although there’s no definitive way to prevent the Alzheimer’s disease, not smoking, keeping blood pressure at healthy levels, regular exercise, maintaining a healthy weight and eating a healthy diet are all sensible approaches to reduce the risk of the disease.
Is It Possible To Measure ApoE Status?
Measurements of the concentration of apolipoprotein B and apolipoprotein A1 in blood or plasma are often done to assess cardiovascular risk. However, measurements of ApoE and its isoforms have limited value in clinical practice and are therefore seldom performed.
Genetic testing is available to define the ApoE genotype. The E4/E4 genotype has the strongest association with the risk of Alzheimer’s disease. The presence of the E2 allele seems to be associated with less risk of Alzheimer’s disease. However, in some cases, this allele is associated with lipid abnormalities and increased risk of heart disease.
The Take-Home Message
Apolipoprotein E (ApoE) plays a major role in the metabolism of dietary fat. It is an important regulator of blood levels of both cholesterol and triglycerides. and plays an integral part in the transport of these fats in the body.
There are three different types of the ApoE gene, called alleles; E2, E3, and E4. These genes provide code for the production of the three different isoforms of ApoE called ApoE2, ApoE3, and ApoE4.
ApoeE3 is often regarded as the parent form. The presence of ApoE2 is associated with increased risk of lipid orders and heart disease. The presence of ApoE4 is associated with increased risk of late-onset Alzheimer’s disease.
Measurements of blood levels of ApoE and its isoforms are seldom used in clinical practice. Genetic testing is available to define the ApoE genotype.