The APoE gene is a known genetic risk factor for dementia, Alzheimer's disease (AD), and cardiovascular diseases (CVD).
This specific gene is responsible for coding a protein called apolipoprotein E, which performs important biological functions involving lipid and cholesterol metabolism across different tissues and cells. Genetic variability of the APOE gene, however, is associated with variations of blood cholesterol levels, which can cause an individual to be more susceptible in developing Alzheimer's and, or CVD.
Everyone has two copies of the APoE gene, where one copy is inherited from each biological parent.
This specific gene comes in three genetic variants: E2, E3, and E4. The E2 variant provides more protection against certain diseases because it regulates cholesterol at an optimal level. Meanwhile, E4 is associated with higher total and low density lipoprotein (LDL) cholesterol levels. The combination of these genetic variants determine a person’s APoE genotype, along with their susceptibility to both Alzheimer's and CVD.
Out of the three APoE variants, the E4 copy is well-known for its association with a significantly higher risk of Alzheimer's along with other numerous conditions, including different forms of dementia and CVD.
The E4 variant of the APoE gene and its inheritance pattern can be seen in Figure 1.
Additionally, there has been growing evidence to support a strong association between cardiovascular disease (CVD) and its risk factors with the occurrence of dementia and Alzheimer’s disease.
Based on epidemiological and genome-wide association studies, it has been observed that individuals with premature CVD appear to be at a higher risk for dementia and Alzheimer's disease. Altogether, it’s likely that the E4 variant of the APoE gene is the bridge between Alzheimer's and CVD, making it a potentially promising genetic target to treat in the future.
Figure 1: Inheritance Pattern of E4 Variant of APoE Gene.
Alzheimer’s disease is the most common neurodegenerative disorder of dementia and is the fourth leading cause of deaths in developed countries.
It was estimated that approximately 44 million people live with dementia worldwide, and it’s predicted the numbers will be more than three-times by 2050 as the population ages.
Many people wonder if Alzheimer's runs in their family, considering a person's chance of inheriting the disease may be higher if he or she has certain genes passed down from a parent. However, having a parent with Alzheimer's does not always mean that someone will develop it.
The inheritance pattern of this particular disease follows a more complex pattern as it may skip a generation or may not be passed on at all. Most people with Alzheimer's have the late-onset form of the disease: symptoms become more apparent in their mid-60’s or later.
Researchers have not found a specific gene that directly causes late-onset of Alzheimer's, making the exact pathogenesis of the disease unclear. However, through various genetic studies, the E4 variant of the APoE gene has been established as the most susceptible gene for late-onset Alzheimer's.
APoE is one of the major apolipoproteins regulating lipid transport in the central nervous system. The brain is one of the most cholesterol-rich organs: it comprises 2-5% of the total body mass, but contains 20-25% of the body's total cholesterol.
Researchers have observed that excess cholesterol in brain increases the incidence of Alzheimer's while also promoting the development of Cardiovascular diseases.
As previously mentioned, there are three types of the APoE gene (i.e., E2, E3, and E4). Each variant of this gene acts to slightly increase or decrease the risk of a person developing Alzheimer's, but doesn’t directly cause it. For instance, the E2 variant is relatively rare and can provide some protection against the disease as carrying a single copy can reduce the risk up to 40%.
E3/E3 genetic combination is more common: almost 60% people carry E3/E3 while only 11% have E2/E3, and a barely 0.5% carry E2/E2 combination.
Although more common, the E3 variant doesn’t seem to influence risk. More specifically, researchers believe this genetic variant plays a neutral role in the development of the disease.
On the other hand, the E4 variant is considered to be a high risk gene. About 25% of people carry one copy of the E4 variant while 2-3% carry two copies. The risk for those carrying a single copy of E4 is 2-to-3 times higher. However, it rises to 12-fold for those with two copies of E4.
Inheriting an E4 variant does not necessarily mean that a person will definitely develop Alzheimer's in the future. In fact, there are some people with E4 in their genetic makeup who never get the disease while others who develop Alzheimer's do not carry the E4 variant. Researchers are still working on explaining these observations.
Coronary heart disease (CHD) is a multifactorial disease and one of the leading causes of death and disability around the world. Population-based studies report that genetic susceptibility accounts for approximately 50% of the risk for CHD.
Similar to Alzheimer's, researchers are investigating the relationship between APoE genes and CHD risk in the general population. The variance of APoE gene makes it a considerable genetic risk factor for the disease, as it has significant influence on cholesterol levels.
Plasma lipids, such as cholesterol and triglycerides, are known to associate with CHD; therefore, the APoE gene plays an important role in the susceptibility to CHD, mainly because it regulates blood lipid levels. More specifically, studies suggest that carriers for the E4 variant are at the highest risk for CHD as they tend to have higher plasma cholesterol in comparison to those who do not carry it.
In 2016, investigators compared those with the E3/E3 combination (i.e. those with average risk) to other variant genotypes to evaluate the increased risk for those who inherit an E4 variant. They concluded that individuals with an E3/E4 and E4/E4 combination of the APoE gene were associated with 22% and 45% increased risk for CHD, respectively.
The risk of atherosclerosis appears to be higher in individuals with an E4 variant due to increased cholesterol levels.
Atherosclerosis is the leading cause of cardiovascular disease and is associated with abnormalities in cellular cholesterol levels, which causes plaque formation within the arteries.
Normally, the APoE gene reduces the development of atherosclerosis, by regulating specific white blood cells, known as macrophages, to devour cholesterol and form foam cells. However, higher cholesterol levels is one of the risk factors for atherosclerosis as these foam cells begin to form within the arteries and lose their main protective function.
Those with at least one copy of the E4 variant have higher risk for atherosclerotic outcomes while individuals with two copies of the E4 variant have the highest risk.
Considering the main functions of the APoE gene, as a major regulator of blood lipid and cholesterol levels, it clearly plays a significant role in the susceptibility to coronary heart disease (CHD) and cerebrovascular diseases like dementia and Alzheimer’s.
Based on recent evidence, it’s clear that the E4 variant is associated with higher levels of total cholesterol, LDL cholesterol and triglycerides, which are also linked to numerous heart and brain conditions. Since the APoE gene has been linked to both CHD and AD, it’s possible that this particular gene also connects the two diseases together.
Epidemiological studies suggest CHD may increase the risk of Alzheimer's, as cholesterol metabolic disorders are the common cause and risk factors for both diseases. More specifically, the E4 variant is one of the major causes of cholesterol metabolic disorders by causing abnormal cholesterol plasma concentration in the blood. High cholesterol levels accelerates the progression of atherosclerosis while also damaging the central nervous system.
Altogether, the research on variants of the APoE gene can help researchers find the most effective ways to treat or prevent Alzheimer's and heart diseases.
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