SNP Highlight - APOE and Alzheimer’s Disease

Many individuals who have a family history of Alzheimer’s disease have heard the term APOE4 or genetic screening for Alzheimer’s disease with APOE4. For a majority of individuals, finding out they are positive for ApoE is overwhelming, but what exactly is ApoE4 and how do you know if you are at risk for developing Alzheimer’s disease?

What is APOE?

The APOE gene is responsible for making apolipoprotein E, which helps to metabolize and carry cholesterol and triglycerides throughout the body. Moreover, ApoE is the most prevalent apolipoprotein in the brain and is responsible for the transport of lipids, especially cholesterol, within the brain as well as brain lipid metabolism. The amount of ApoE protein that our bodies make is also associated with the amount of fat in the diet. The more fat we eat the more ApoE protein we synthesize. In addition to fat and cholesterol metabolism, the APOE gene plays an important role in other metabolic processes including cardiovascular function and cognitive function (1). One of the functions of the ApoE protein is to assist in the removal of beta-amyloid proteins from the brain (2). Beta-amyloid is a protein that is specific to brain tissue and is continously being produced, however, excessive levels of the amyloid protein contributes to beta-amyloid plaques. Excessive levels of beta-amyloid plaques have been shown to be a major factor in neuron degeneration as well as the onset of dementia and Alzheimer’s disease (3). 

APOE Variants

The APOE gene has 3 different isoforms or variants, ApoE2, ApoE3, and ApoE4. The variant or isoform type is determined by the amino acids located at position 112 and position 158 on the gene’s amino acid chain (4, 5). The amino acid present at either location is an important determinant in both the protein’s structure and ability to function properly. Each individual inherits 2 copies (alleles) of the APOE gene, therefore, there are 6 variant types that a person could potentially have including, E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, E4/E4. If a person has the same variant type for both copies of the allele (e.g., E2/E2) they are homozygous for that variant type. Likewise, if an individual inherits two different alleles of the APOE gene (e.g., E3/E4) they are heterozygous for that variant type. The most common variant type, which is also associated with normal cholesterol metabolism, is the ApoE3 isoform. Currently, it is estimated that approximately 78% of the general population have the ApoE3 variant type, or “parent allele”, while only about 8% and 14% have the ApoE2 and ApoE4 variant types, respectively (6). Research studies have shown an association between the ApoE2 and ApoE4 variant types and risk for cardiovascular disorders due to impaired lipid metabolism (7). However, the APOE4 variant type has received much attention due to its relationship with the development of cognitive disorders, most notably, Alzheimer’s Disease. 

APOE4 Variant and Alzheimer’s Disease

Alzheimer’s disease is an irreversible neurodegenerative disorder that significantly affects a person’s memory and cognitive function over a period of time. This disease is characterized not only by the physical and mental impairments but also by the presence of excessive amyloid plaques, tangles of nerve fibers, and decreased posterior brain volume. Having one or more ApoE4 variant alleles significantly increases a person’s risk of not only developing Alzheimer’s disease but also having an earlier onset compared to an individual who has the ApoE3/E3. In fact individuals who carry at least one ApoE4 allele will have approximately a 3x higher risk of developing Alzheimer’s disease while having 2 ApoE4 alleles increases that risk up to 12x compared to a person with the ApoE3/E3 variant type. This relationship between the ApoE4 variant type and increased risk of Alzheimer’s disease appears to be largely due to decreased beta-amyloid clearance from the brain tissue as well as impaired glucose metabolism and cholesterol transport in the brain (8).

It should be noted that a person who does not have one or more of the ApoE4 alleles can still develop Alzheimer’s disease. Likewise, an individual who is positive for the ApoE4 allele may not develop Alzheimer’s disease over the course of their lifetime. In addition to genes, other factors such as age, sex, ethinicity, diet, lifestyle, and previous head trauma can also affect a person’s risk for developing this disease. Individuals who are positive for ApoE4 can help reduce their chances of developing Alzheimer’s disease by limiting alcohol, quitting smoking, being physical active, maintaing a healthy weight and incorporating a diet rich in healthy fats, especially omega-3 fatty acids, and low in saturated fats.