The Apolipoprotein E, or APOE, gene is the strongest genetic risk factor for late-onset Alzheimer’s disease, a neurodegenerative disorder causing gradual memory loss that appears in individuals older than 65. Understanding this gene and its variations provides insight into the biological landscape of Alzheimer’s.
The APOE Gene and Its Alleles
The APOE gene provides instructions for making apolipoprotein E, a protein that transports lipids like cholesterol in the bloodstream. In the brain, this protein distributes fats necessary for cell function and repair. The gene has three common versions, or alleles: APOE2, APOE3, and APOE4. Every person inherits two copies of the gene, one from each parent, creating one of six possible combinations.
These alleles have different implications for Alzheimer’s risk. APOE3 is the most common allele and is considered neutral, as it does not increase or decrease risk. APOE2 is the least common and appears to offer some protection, as individuals with this allele who develop Alzheimer’s may do so later in life.
The APOE4 allele is associated with an elevated risk. Inheriting one copy increases a person’s risk, while inheriting two copies results in an even greater risk. While about 14% of the population carries APOE4, its frequency is around 40% in patients with Alzheimer’s.
How the APOE4 Allele Increases Alzheimer’s Risk
The protein created from the APOE4 allele is structurally different from the others, which affects its function. One of its roles is to help clear a protein fragment called beta-amyloid. In Alzheimer’s disease, beta-amyloid accumulates into toxic amyloid plaques that disrupt brain function.
The apoE4 protein is less efficient at clearing beta-amyloid compared to the apoE2 and apoE3 proteins. This impaired clearance contributes to the buildup of beta-amyloid, accelerating plaque formation. As a result, brain beta-amyloid levels are highest in carriers of the APOE4 allele.
Beyond its role with amyloid plaques, APOE4 is also connected to neurofibrillary tangles composed of a protein called tau. The apoE4 protein may promote a chemical change in tau that causes it to form tangles inside neurons. This interaction between APOE4, beta-amyloid, and tau contributes to widespread neuronal damage.
Risk Versus Determinism
It is important to understand that carrying the APOE4 allele is a risk factor, not a deterministic gene. This means it increases the likelihood of developing a condition but does not guarantee it. Many individuals with one or even two copies of the APOE4 allele live long lives without ever developing Alzheimer’s disease.
Conversely, a significant number of people diagnosed with Alzheimer’s do not carry the APOE4 allele. This highlights that while APOE4 is a major contributor, it is not the sole cause of the disease. The risk associated with APOE4 can also vary based on factors like sex and ethnic background.
Lifestyle and environmental factors, such as diet, exercise, and cardiovascular health, also play a part in an individual’s overall risk profile. The presence of the APOE4 allele is just one piece of a much larger and more complex puzzle.
Other Genetic Factors in Alzheimer’s Disease
While APOE4 is the most impactful risk gene for late-onset Alzheimer’s, other genes are deterministic, meaning anyone who inherits one of these mutations will almost certainly develop the condition. These genes are associated with familial, early-onset Alzheimer’s, a form that accounts for less than 5% of all cases and appears before age 65.
The three known deterministic genes for Alzheimer’s are the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). Mutations in these genes directly lead to an overproduction of the toxic beta-amyloid fragment, triggering the disease process at a much younger age.
These deterministic genes are rare and are found in families where the disease appears in multiple generations. Their discovery was important in developing the “amyloid cascade hypothesis,” which posits that the accumulation of beta-amyloid is a central event in Alzheimer’s pathology. This separates the guaranteed inheritance of early-onset Alzheimer’s from the increased susceptibility conferred by risk genes like APOE4.