Understanding The APOE Gene Part I: The Basics

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Understanding The APOE Gene Part I: The Basics

Date of Content: March 19, 2024
Written by: Avanthika Nityanand
Reviewed by: Maarit Tiirikainen, PhD


Disclaimer: This article is meant for informational purposes only. LifeDNA does not offer clinical analyses nor diagnoses for any conditions discussed herein or otherwise.

A few genes and their variants stand out for their profound impact on our health in the intricate web of human genetics.  The APOE (apolipoprotein E) gene is one such gene, commanding attention for its significant role in lipid metabolism and its association with various conditions. 

The APOE gene is located on chromosome 19. It is best known for its involvement in the body’s ability to process fats and for influencing conditions ranging from cardiovascular disease, affecting the functioning of the heart, to Alzheimer’s disease. The importance of the APOE gene in medical research and personalized healthcare continues to grow as we uncover more about its diverse roles in the body. 

This article delves into the APOE gene, exploring its biological functions, genetic variations, and the implications of these variations on health and disease. By understanding the APOE gene, we can better grasp the complexities of genetic influence on health and pave the way for more personalized medical interventions.

APOE gene

The Biology of APOE

The APOE gene provides instructions for making a protein called apolipoprotein E. This protein is crucial for the normal catabolism (breakdown) of triglyceride-rich lipoprotein constituents. 

In simpler terms, it plays a vital role in metabolizing and transporting fats and cholesterol throughout the body, aiding in the clearance of these substances from the bloodstream

Apolipoprotein E is a prominent component of very low-density lipoproteins (VLDL), which are precursors to the more well-known low-density lipoprotein (LDL), often referred to as “bad cholesterol.”

Read more: How Genes Influence Cholesterol Levels.

Beyond its role in lipid metabolism, APOE plays vital roles in several other biological processes, including immune regulation and neural repair. Its presence in different tissues and organs, notably the liver and brain, underscores its multifaceted role in maintaining health and its potential implications in disease processes.

Genetic Variations of APOE and Their Significance

The APOE gene exists in three principal allele forms: ε2, ε3, and ε4, creating a genetic variant that influences the protein’s structure and function. These alleles determine the individual’s APOE genotype, which can be combinations of the three alleles (e.g., ε3/ε3, ε3/ε4, ε4/ε4).

  • ε2 allele is the least common. It is associated with a decreased risk of Alzheimer’s but an increased risk of type III hyperlipoproteinemia (a condition that can lead to cardiovascular disease).
  • ε3 allele is the most common, considered the “neutral” allele, with no increased risk of Alzheimer’s or heart disease.
  • ε4 allele is associated with an increased risk of Alzheimer’s disease and cardiovascular diseases. Carrying even one ε4 allele increases the risk, and having two ε4 alleles further elevates this risk.

The distribution of these alleles varies widely across different populations and ethnic groups, affecting the prevalence of related diseases. Understanding one’s APOE genotype can offer insights into the potential health risks and the preventive measures that may be most effective.We will cover the population-specific influence of APOE in Part II.

APOE and Its Link to Diseases

The APOE gene’s association with various diseases, most notably Alzheimer’s disease and cardiovascular disease, underscores its importance in human health and disease. The link between APOE alleles and these conditions offers a window into the genetic underpinnings of disease risk and progression.

Alzheimer’s Disease (AD)

The ε4 allele of the APOE gene is the strongest-known genetic risk factor for late-onset Alzheimer’s disease, expressed in more than half of the affected patients. Individuals carrying one ε4 allele have an increased risk of developing the disease, and the risk is even higher for those with two ε4 alleles. The presence of the ε4 allele is associated with earlier onset of AD symptoms and a more rapid progression of the disease. 

In a study examining 179 senile dementia of the Alzheimer type (SDAT) patients, 154 controls, and 167 subjects with age-related memory complaints (ARMC), it was found that the APOE-ε4 allele frequency was notably higher in SDAT patients (27%) compared to controls (10%) and stable ARMC subjects (15%). Furthermore, among ARMC subjects, those who carried the ε4 allele had a three-fold increased risk of developing dementia compared to non-carriers. Additionally, older age at the onset of memory decline and lower initial scores were also associated with an increased risk of dementia in ARMC subjects.

Two years ago popular Marvel star Chris Hemsworth discovered that he had two copies of the APOE4 gene, inherited from both his mother and father. You can read about his journey of discovery here.

Conversely, the ε2 allele may offer some protection against AD, although its protective mechanism is not fully understood.

A 2020 study revealed significant protective effects of ε2 against AD-related pathologies such as amyloid plaques and Braak stage compared to e3/e3 carriers and e4 carriers. The study also noted that, unfortunately, in ε2/ε4 carriers, the risk for AD pathologies resembles that of ε4 carriers rather than ε2 carriers. 

Cardiovascular Disease (CVD)

An early study suggested that the presence of ε2 or ε4 alleles in men is associated with a heightened risk of CVD, emphasizing the potential utility of genotype information in identifying individuals prone to CVD events.

In addition to the increased risk for AD, the APOE ε4 allele is also associated with an increased risk of cardiovascular disease. This risk is partly due to the allele’s effect on lipid metabolism, leading to higher LDL cholesterol levels and potentially a significant buildup of plaques in the arteries. 

The ε2 allele, despite its protective role against Alzheimer’s, can predispose individuals to type III hyperlipoproteinemia, a condition that elevates triglyceride levels and may increase the risk of heart disease.

Beyond these well-established links, research has suggested potential associations between APOE alleles and other conditions, including diabetes, inflammatory diseases, and age-related macular degeneration, highlighting the gene’s broad impact on health.

Implications for Personalized Medicine

Understanding an individual’s APOE genotype has significant implications for personalized medicine, offering insights that can guide preventive health strategies, lifestyle adjustments, and potentially tailored medical treatments.

  • Preventive Health Strategies: Knowledge of one’s APOE status can inform personalized approaches to disease prevention. For instance, individuals with the ε4 allele might benefit from early interventions to manage cholesterol levels and reduce Alzheimer’s risk, such as regular physical activity, a heart-healthy diet, and cognitive training exercises.
  • Lifestyle Adjustments: Awareness of APOE-related risks can motivate lifestyle changes to mitigate these risks. It could include dietary modifications, increased emphasis on cardiovascular exercise, and monitoring heart health and cognitive function regularly.
  • Tailored Medical Treatments: In the future, the APOE genotype could inform the development and application of targeted therapies, especially for conditions like Alzheimer’s, where we can customize preventive and therapeutic strategies based on genetic risk factors.

Future Directions in APOE Research

Ongoing research into the APOE gene continues to uncover its complex roles in health and disease. Future studies aim to elucidate mechanisms by which APOE alleles influence disease risk and progression to develop more effective treatments. Research also explores the gene’s potential roles in other conditions, expanding our understanding of its impact on human health.


The APOE gene’s significance extends far beyond its role in lipid metabolism, with its variants influencing the risk and progression of Alzheimer’s disease, cardiovascular disease, and potentially other conditions. Understanding the genetic variations of APOE and their associations with diseases offers valuable insights for personalized medicine, highlighting the importance of genetics in health and disease management. 

As research progresses, the potential for targeted interventions based on APOE status holds promise for improving outcomes for individuals with increased genetic risks. Embracing the advancements in genetic research can empower individuals and healthcare providers to make informed decisions, leading to better health and well-being.

Other Gene-Related Articles Covered By LifeDNA


The MTHFR gene, short for Methylenetetrahydrofolate Reductase, is crucial in the body’s metabolic processes. This gene produces the MTHFR enzyme, which plays a vital role in processing amino acids, the building blocks of all proteins

Read our complete review of this gene here: Decoding The MTHFR Gene & What It Means For Your Wellness


The COMT enzyme, encoded by the COMT gene, is particularly active in the prefrontal cortex, a brain region associated with memory, decision-making, and emotional regulation. Genetic variations in the COMT gene can affect the enzyme’s activity level, influencing how quickly catecholamines are metabolized. This can directly impact neurological and psychological processes.

Read our complete review of this gene here: COMT Gene Insights: Navigating Its Influence On Wellness


  1. https://medlineplus.gov/genetics/gene/apoe/
  2. https://www.sciencedirect.com/science/article/abs/pii/S1552526014024996
  3. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1468-1331.1996.tb00266.x
  4. https://link.springer.com/article/10.1186/s13024-022-00574-4
  5. https://www.nature.com/articles/s41467-020-18198-x
  6. https://www.sciencedirect.com/science/article/abs/pii/S0021915000005700
  7. https://link.springer.com/article/10.1186/s13024-022-00574-4

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