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Genetic Risk Factors for Alzheimer's Disease: Understanding Your Risk

September 1, 2022Neelem Sheikh

Alzheimer’s disease, a degenerative neurological disease characterized by a gradual decline in neurocognitive function, is the leading cause of dementia, accounting for approximately 60% to 80% of all dementia cases. Currently, experts believe that Alzheimer's disease is caused by a combination of genetic, environmental, and lifestyle factors.

Understanding and characterizing the genetic landscape of Alzheimer’s disease is important not only for identifying and monitoring patients at risk but also for the ability to better understand the pathophysiological processes associated with the disease.

In this article, we will discuss genetic risk factors for Alzheimer’s disease, including risk and deterministic genes, as well as important implications for patients at higher risk of developing Alzheimer’s disease.

Genetic Risk Factors for Alzheimer’s Disease

Before we delve into specific genetic risk factors for Alzheimer’s disease, let’s discuss terminology. Two types of genes, risk genes and deterministic genes, may influence Alzheimer’s disease development:

  • Risk genes are genes that increase the risk of developing a disease. However, carrying a risk gene does not directly cause disease. In other words, while it does increase disease risk, it does not guarantee disease development.
  • Deterministic genes directly cause disease. Any individual who inherits a deterministic gene is guaranteed to develop the disease.

Researchers have identified several genes within each of the above categories. Some genes are known to play a role in the development of late-onset Alzheimer’s disease, while others influence the development of early-onset Alzheimer's disease:

  • Late-onset refers to individuals 65 and older who develop Alzheimer’s disease.
  • Early-onset, or young-onset, refers to individuals under 65 who develop Alzheimer's disease. Early-onset Alzheimer's disease is far less common, accounting for approximately 5% to 6% of Alzheimer’s cases.

Genetic Risk Factors for Late-Onset Alzheimer’s Disease: Risk Genes

The most common and well-researched gene associated with late-onset Alzheimer’s disease is APOE, a gene responsible for creating a protein that helps carry cholesterol and other fats in the bloodstream. 

Genetic variants on the APOE gene on chromosome 19 are known to increase the risk of developing Alzheimer’s. APOE comes in several forms, or alleles: APOE2, APOE3, and APOE4. Individuals inherit two APOE alleles—one from each biological parent. 

APOE2 is associated with a decreased risk of developing Alzheimer's disease, while APOE4 is associated with an increased risk. APOE3 is not believed to influence Alzheimer's risk.

APOE AlleleGenetic Significance
APOE2While APOE2 is somewhat rare, it may provide individuals with some degree of protection against Alzheimer’s disease. Experts estimate that carrying two APOE2 alleles (or one APOE2 and one APOE3) may reduce the risk of developing Alzheimer’s by up to 40%. Generally speaking, if an individual with the APOE2 allele does develop Alzheimer’s, the development of the disease occurs later in life compared to an individual with the APOE4 allele.
APOE3APOE3 is the most common APOE allele and is currently believed to play no role in increasing or decreasing the risk of developing Alzheimer’s disease.
APOE4APOE4 is believed to increase the risk of developing Alzheimer’s disease and is associated with an earlier onset of the disease. Approximately 25% of people carry a single copy of APOE4, and 2% to 3% of people carry two copies. Individuals with one copy have an increased risk of developing Alzheimer’s. The presence of two copies is a stronger indicator that an individual may develop the disease. Experts estimate that carrying one copy of APOE4 may increase Alzheimer’s risk by two to three times, while carrying two copies may increase risk by up to 12 times.

With this understanding, the downregulation of APOE4 and upregulation of APOE2 has been identified as a potential target for Alzheimer’s disease gene therapy.

Genetic Risk Factors for Early-Onset Alzheimer’s Disease: Deterministic Genes

While early-onset Alzheimer's disease is less common than late-onset Alzheimer's, it has a much stronger genetic influence. So far, researchers have discovered that inherited genetic mutations on three specific deterministic genes can cause early-onset Alzheimer’s disease:

  • Amyloid precursor protein (APP) on chromosome 21
  • Presenilin 1 (PSEN1) on chromosome 14
  • Presenilin 2 (PSEN2) on chromosome 1

When mutations on the above genes are present, the result is the production of excessive amounts of beta-amyloid peptide caused by the breakdown of APP. This production causes a buildup of beta-amyloid plaques in the brain, a neuropathological hallmark of Alzheimer’s disease. 

It is also important to note that some individuals who are diagnosed with early-onset Alzheimer’s disease do not have mutations in any of these three genes. This suggests that some cases of early-onset Alzheimer’s may be linked to other genetic variants that have yet to be identified.

Environmental and Lifestyle Risk Factors for Alzheimer's Disease

In addition to genetic risk factors for Alzheimer’s disease, many other factors influence Alzheimer's disease risk. Environmental and lifestyle risk factors for Alzheimer's disease include:

  • Less education
  • Hearing loss
  • Traumatic brain injury
  • Stroke 
  • Hypertension
  • Alcohol consumption (>21 units/week)
  • Obesity
  • Smoking
  • Depression
  • Social isolation
  • Physical inactivity
  • Air pollution
  • Diabetes

Monitoring your brain health as you age is important for every individual. For those at a higher risk of developing Alzheimer’s disease, frequently assessing brain health and monitoring changes over time is fundamental to early detection, early intervention, and consequently, better health outcomes.

Altoida’s mission is to accelerate and improve drug development, neurological disease research, and patient care. To learn more about our precision-neurology platform and app-based medical device, contact us!

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