What Gene Is Most Consistently Associated With Alzheimer’s?

Alzheimer’s disease is a neurodegenerative condition characterized by a progressive decline in cognitive function and memory. Its origins are multifaceted, involving a combination of genetic, environmental, and lifestyle factors. Scientific inquiry into the genetic underpinnings of the condition is substantial, as identifying associated genes provides a deeper understanding of the biological processes involved. This knowledge is fundamental for developing future strategies to address the disease.

The APOE Gene: A Key Player in Alzheimer’s Risk

The gene most consistently linked to the risk of late-onset Alzheimer’s disease (LOAD), the most prevalent form of the condition, is Apolipoprotein E (APOE). Located on chromosome 19, the APOE gene provides instructions for making a protein that transports cholesterol and other fats in the bloodstream. This gene exists in three common versions, or alleles: APOE e2, APOE e3, and APOE e4. Each person inherits two copies of the APOE gene from each parent, resulting in different combinations of these alleles.

The APOE e3 allele is the most common and does not appear to influence the risk of Alzheimer’s. The APOE e2 allele is rarer and provides a measure of protection against developing the disease. The APOE e4 allele, however, is the primary genetic risk factor for LOAD. About 25% of people carry one copy of APOE e4, and having it can double or triple the risk of developing Alzheimer’s disease compared to those with the e3 version.

Inheriting two copies of the APOE e4 allele, which occurs in about 2 to 3% of the population, elevates the risk 8 to 12 times. A 2024 study suggested having two copies of APOE e4 may represent a distinct, genetically determined form of Alzheimer’s, not just a risk factor. Carrying the APOE e4 allele is a risk factor, not a certainty, as many with this allele will not develop Alzheimer’s, while others without it will.

How APOE Influences Alzheimer’s Disease Development

The protein produced by the APOE gene plays a multifaceted role in the brain, and the e4 version appears to be less effective. One of its primary jobs is to transport lipids, like cholesterol, which are necessary for maintaining the health and structural integrity of neurons. The APOE e4 variant is less efficient at this lipid transport, which can compromise neuronal repair and the maintenance of myelin, the protective sheath around nerve fibers.

An aspect of APOE’s link to Alzheimer’s involves its interaction with amyloid-beta, the main component of the amyloid plaques found in the brains of individuals with the disease. The APOE protein helps clear amyloid-beta peptides from the brain. Research indicates the APOE e4 variant is less effective at this clearance process, allowing toxic peptides to accumulate and form plaques. APOE e4 also binds more readily to amyloid-beta, promoting its aggregation into harmful clumps.

The APOE e4 variant also contributes to other pathological features of Alzheimer’s. It has been shown to intensify tau pathology, the other hallmark of the disease characterized by neurofibrillary tangles within neurons. The e4 protein may promote the aggregation of tau or interfere with its clearance. Additionally, APOE e4 is associated with increased neuroinflammation, as it can trigger a more robust inflammatory response from the brain’s immune cells, known as microglia, which can further damage neurons.

Beyond APOE: Other Genetic Factors in Alzheimer’s

While APOE is a major factor in late-onset Alzheimer’s, it is not the only gene involved. A different set of genes is associated with early-onset Alzheimer’s disease (EOAD), a rare form that manifests before the age of 65. Mutations in three specific genes—amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2)—are known to cause EOAD. These mutations are deterministic, meaning inheriting one makes the development of Alzheimer’s highly likely.

These deterministic genes directly affect the production of amyloid-beta. Mutations in the APP gene can lead to an abnormal amyloid precursor protein, while mutations in PSEN1 and PSEN2 affect the gamma-secretase complex, an enzyme that cuts the APP. Both mutation types result in an overproduction of the toxic form of amyloid-beta, driving plaque formation. These genetic forms account for a small fraction of total Alzheimer’s cases.

For the more common late-onset form, the genetic landscape is far more complex. Genome-wide association studies (GWAS) have identified numerous other genes that each contribute a small amount to the overall risk. This illustrates that LOAD is a polygenic disease, where the cumulative effect of many different genes influences an individual’s susceptibility. Genes identified as risk modifiers include:

• TREM2, which is involved in the microglial response to brain damage
• CLU
• PICALM
• ABCA7
• SORL1

Understanding Genetic Predisposition to Alzheimer’s

The concept of polygenic risk means an individual’s overall genetic susceptibility is determined by the combined small effects of many different genes. Researchers can calculate a polygenic risk score (PRS) by analyzing numerous genetic variants to estimate a person’s risk for developing a disease like Alzheimer’s. These scores can help stratify individuals into different risk categories and have shown accuracy in predicting disease likelihood.

Genetic testing for risk alleles like APOE is available, but its use for asymptomatic individuals is a subject of debate due to complex ethical and personal considerations. Ultimately, genetics are only one piece of the puzzle. Lifestyle and environmental factors, such as diet, physical activity, and cardiovascular health, also play a substantial role, interacting with an individual’s genetic makeup to modify their overall risk.