Apolipoprotein E (APOE) is a gene that provides instructions for a protein that transports fats, such as cholesterol, within the body. This protein is primarily produced in the liver and brain, where its role in managing lipids is particularly important for maintaining the health of the central nervous system.
The Biological Function of APOE
The APOE protein’s primary job is to transport lipids. It combines with fats to form molecules called lipoproteins, which move cholesterol and other fats through the bloodstream. This function is particularly active in the liver, where APOE helps clear triglyceride-rich lipoproteins from the blood.
Within the central nervous system, APOE has a specialized role in redistributing lipids to support neuron health, repair, and growth. Astrocytes, a type of glial cell in the brain, produce APOE to transport cholesterol to neurons. This localized system is necessary because the blood-brain barrier restricts most lipoprotein particles from entering the brain.
Variations of the APOE Gene
The APOE gene exists in several different forms, or alleles, with the three most common being APOE2, APOE3, and APOE4. Every individual inherits two copies of the gene, one from each parent, leading to different combinations. These genetic variations are defined by small differences in the gene’s sequence that cause slight changes to the protein’s structure.
APOE3 is the most prevalent allele, found in over 70% of people, and is considered to have a neutral impact on Alzheimer’s risk. The APOE2 allele is the least common and is associated with a reduced risk for Alzheimer’s disease. Conversely, the APOE4 allele, present in about 15-25% of the population, is linked to an increased risk. The different alleles influence how effectively the APOE protein functions.
The Link Between APOE and Alzheimer’s Disease
The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease. Possessing one copy of APOE4 can increase the risk two to three times, while having two copies may increase it by as much as 15-fold. However, APOE4 is a risk factor, not a direct cause. Many individuals with the allele never develop Alzheimer’s, and many with the disease do not carry it.
The mechanisms linking APOE4 to Alzheimer’s are complex. One primary way it contributes to risk is by impairing the clearance of amyloid-beta from the brain. Amyloid-beta is a protein fragment that can clump together to form the plaques characteristic of Alzheimer’s disease. The APOE4 protein is less efficient at removing amyloid-beta, leading to its accumulation.
The APOE4 variant is also associated with increased neuroinflammation, another process in Alzheimer’s pathology. It can trigger a more aggressive inflammatory response from microglia, the brain’s immune cells, which can damage neurons over time. The APOE4 allele has also been connected to tau tangles, another hallmark of the disease. In contrast, the APOE2 allele appears protective, being more efficient at amyloid clearance and associated with a lower risk.
Considerations for Genetic Testing
Deciding whether to undergo genetic testing for APOE status is a personal choice with several considerations. The test reveals genetic risk, not a definitive diagnosis. Medical organizations do not recommend routine testing for asymptomatic individuals, as no treatment can prevent the disease based on this information alone.
Learning one carries a high-risk allele like APOE4 can cause psychological distress. It is also important to be aware of potential discrimination, as laws like the Genetic Information Nondiscrimination Act (GINA) do not protect against discrimination from life, disability, or long-term care insurance providers. For those considering anti-amyloid therapies, APOE testing may be recommended, as the APOE4 allele can increase the risk of certain side effects. An informed decision is best made after discussing the implications with a doctor or genetic counselor.