The APOE ε4 gene variant is a form of a gene that plays a role in how the body processes fats. Everyone inherits two copies of the APOE gene, one from each biological parent, and these copies can vary. While many genes influence basic characteristics, certain gene variants, such as APOE ε4, can affect a person’s health risks.
What is APOE ε4 and Its Role?
The Apolipoprotein E (APOE) gene provides instructions for making apolipoprotein E, a protein that combines with fats to form lipoproteins. Lipoproteins are responsible for packaging and transporting cholesterol and other fats through the bloodstream and brain.
There are three common variants, or alleles, of the APOE gene: APOE ε2, APOE ε3, and APOE ε4. APOE ε3 is the most common allele, found in over half of the general population, and is considered to have a neutral effect on disease risk. APOE ε2 is less common and may offer some protection against certain conditions, potentially delaying onset if a disease does occur.
These variants differ by only one or two amino acids at specific positions, 112 and 158, which subtly changes the protein’s structure and function. Such differences influence how effectively the apolipoprotein E protein binds to receptors and processes lipids.
APOE ε4 and Alzheimer’s Disease Risk
The APOE ε4 allele is strongly associated with an increased likelihood of developing late-onset Alzheimer’s disease (AD), which typically begins after age 65. This gene variant is considered the most significant genetic risk factor for this common form of AD.
Inheriting one copy of APOE ε4 can double or triple a person’s risk for late-onset Alzheimer’s disease. Individuals with two copies of the APOE ε4 allele, a condition known as homozygous, face an even higher risk, potentially increasing it by 8 to 12 times compared to those with other APOE variants. The presence of APOE ε4 may also lead to an earlier age of symptom onset, by 10 to 15 years per allele.
It is important to understand that APOE ε4 is a risk factor, not a definitive cause or a diagnosis for Alzheimer’s disease. Many individuals with one or even two copies of APOE ε4 never develop AD, and conversely, many people without this variant still develop the disease. For instance, roughly half of individuals with two copies of APOE ε4 do not go on to develop Alzheimer’s, and almost half of those with Alzheimer’s do not have any copies of the APOE ε4 allele.
How APOE ε4 Influences Brain Health
The APOE protein is involved in clearing amyloid-beta peptides from the brain. These peptides are a key component of amyloid plaques, a hallmark of Alzheimer’s disease. The APOE ε4 variant is less efficient at facilitating the removal of amyloid-beta, leading to its accumulation and the formation of these plaques.
APOE ε4 also plays a role in tau pathology, another hallmark of Alzheimer’s disease involving neurofibrillary tangles. It can promote the hyperphosphorylation of tau proteins, contributing to the formation of these tangles and exacerbating neuronal dysfunction. Furthermore, the APOE ε4 variant is linked to neuroinflammation, where it can induce the expression of pro-inflammatory cytokines that may lead to neuronal damage.
The impact of APOE ε4 on amyloid-beta clearance and tau pathology is believed to contribute to synaptic dysfunction and cognitive decline. This variant can impair the ability of brain immune cells like microglia and astrocytes to effectively clear amyloid-beta peptides, contributing to their buildup. The combined effects of impaired lipid transport, increased neuroinflammation, and reduced clearance of pathological proteins highlight how APOE ε4 can negatively affect neuronal repair and synaptic plasticity.
Genetic Inheritance and Testing for APOE ε4
The APOE gene is inherited, with each person receiving one copy from their biological mother and one from their biological father. This inheritance pattern results in six possible allele combinations:
ε2/ε2
ε2/ε3
ε2/ε4
ε3/ε3
ε3/ε4
ε4/ε4
Genetic testing for APOE ε4 is available and can identify which variants an individual carries. People might consider this testing if they have a family history of Alzheimer’s disease or are participating in research studies.
Genetic counseling is often recommended both before and after APOE ε4 testing. This counseling helps individuals understand the implications of the test results, which can include potential psychological impacts such as worry or anxiety.
Living with APOE ε4 Status
Lifestyle factors play a significant role in mitigating the risk of developing Alzheimer’s disease, even for those with the APOE ε4 allele. Maintaining a balanced diet, such as a Mediterranean-style diet rich in fruits, vegetables, whole grains, lean protein, and healthy fats, can support cognitive health. Limiting saturated and trans fats is particularly beneficial for APOE ε4 carriers, as these individuals may experience higher cholesterol levels with such diets.
Regular physical exercise, cognitive engagement through mentally stimulating activities, and active social participation are also important. Managing cardiovascular health, including blood pressure and cholesterol, contributes to overall brain health and can help reduce risk. Research into APOE ε4 and Alzheimer’s disease is ongoing, continually improving the understanding of this genetic variant and its interactions with lifestyle.