The Impact of APOE-e4 on the Probability of Developing Alzheimer’s Disease

By: Nunnaphat (Gemmi) Haripottawekul, International School Bangkok (ISB)


The APOE-e4 gene variant is one of three forms of the APOE gene, with the others being APOE-e2 and APOE-e3. It constitutes a significant genetic risk factor for the development of Alzheimer's disease. Research on APOE-e4 has shown that individuals inheriting one copy of this variant from a parent face a notably higher risk of Alzheimer's compared to those without it. Moreover, those inheriting two copies of APOE-e4, one from each parent, are at an even greater risk of developing the disease. This gene variant not only affects the likelihood of Alzheimer's onset but also influences the age at which symptoms manifest, often leading to earlier presentation within families. While genetics alone don't solely determine Alzheimer's, the presence of APOE-e4 significantly contributes to understanding associated probabilities within families.

Disease Information

Alzheimer's disease presents a range of symptoms that progress over various stages. Given its progressive nature, symptoms unfold sequentially, though the timing can differ among patients. While not all individuals experience identical symptoms, understanding common manifestations is essential. These may encompass language difficulties, memory loss, impaired judgment, problem-solving challenges, mood and behavioral shifts, repetitive questioning, recent information forgetfulness, and diminished interest or motivation. While a definitive cure for Alzheimer's remains elusive, a multitude of treatment avenues can alleviate symptoms and enhance overall quality of life. Medications like cholinesterase inhibitors and memantine are known to slow disease progression and boost cognitive function. Cognitive and behavioral therapies, including reminiscence therapy and cognitive stimulation, aid in maintaining communication and cognitive abilities. Diagnosis involves clinical assessments, cognitive tests, imaging scans (MRI or PET), and genetic testing, such as APOE-e4 variant identification. Timely diagnosis and intervention enable improved management and care. Consultation with healthcare professionals is pivotal for accurate diagnosis, personalized treatment planning, and access to support services.

Gene Level Information

Situated on chromosome 19, the APOE gene exists in three distinct common forms. Upon examining the DNA of each APOE gene variant, a noticeable differentiation emerges between APOE-e4 and APOE-e2 or APOE-e3, marked by two amino acid substitutions within the variant. These alterations induce structural changes in Apolipoprotein E (Apo-E), the protein resultant from the APOE gene's protein-level expression. Furthermore, the APOE-e4 gene variant is notably linked to heightened amyloid-beta deposition and impaired clearance, fostering the accumulation of brain plaques, a characteristic feature of Alzheimer's disease. The APOE-e4 gene variant also carries significance due to its association with increased disease risk, impacting neuronal function and tau protein pathology. Although APOE-e4 doesn't present specific isoforms, it still exerts influence over the functionality of various Apo-E isoforms.


Scientists continually engage in the study and research of APOE-e4 and its association with Alzheimer's disease, delving into mechanisms and factors that elevate risks linked to the APOE-e4 gene variant. Amidst a broad spectrum of investigations, one focus area centers on understanding how the accumulation and clearance of amyloid-beta plaques, the formation of neurofibrillary tangles, and synaptic dysfunction interplay with this gene variant. Current research also explores the intricate interplay between other genetic and environmental elements and the APOE-e4 gene variant, aiming to elucidate their contributions to disease progression.

The overarching objective is to grasp the role of APOE-e4 in Alzheimer's and develop treatments and interventions capable of postponing or preventing the onset of the disease among individuals carrying this genetic variant. It's noteworthy that approximately 20-25% of the general population possess at least one copy of this gene variant, rendering them 2-3 times more susceptible to Alzheimer's compared to those without APOE-e4. Concurrently, an estimated 50-60% of individuals inheriting two copies of APOE-e4 at birth develop Alzheimer's by age 85.

Despite these statistics, it's crucial to recognize that APOE-e4 represents just one among numerous contributing factors, including genetics and environment, in Alzheimer's development. Possessing the APOE-e4 gene does not definitively predict disease occurrence. For a comprehensive understanding of APOE-e4's specific implications and the associated probabilities of Alzheimer's, seeking proper genetic counseling and undergoing individualized risk assessments is paramount.

Model of APOE-e4 influence on AD symptoms

The APOE-e4 gene variant significantly increases the risk of Alzheimer's disease. It is associated with the accumulation of amyloid-beta plaques in the brain, a hallmark of the disease. APOE-e4 influences the clearance of amyloid-beta and impacts tau protein pathology, contributing to neurodegeneration and cognitive decline. Its presence accelerates disease onset and progression, leading to earlier symptom manifestation. Individuals inheriting even one copy of APOE-e4 from a parent face higher Alzheimer's risk, while those with two copies are at even greater risk. Although other factors also contribute, APOE-e4 plays a crucial role in the pathogenesis of Alzheimer's, making it a key focus in research and prevention strategies.

There are now many genetic testing options that can help identify people who happen to carry the APOE-e4 allele which when detected early can help with personalized treatment plans to delay or prevent the disease.

Future directions of research development

Future research could focus on unraveling the complexities of APOE-e4 and Alzheimer's disease through exploring its influence on amyloid beta aggregation, tau protein pathology, and the interplay with other genetic and environmental factors. Leveraging advanced technologies, such as single-cell genomics and imaging techniques, will enable comprehensive analysis. Longitudinal studies and precision medicine approaches will aid in identifying personalized interventions, leading to targeted therapies and preventive strategies.


Scientists are continuously conducting research to understand the connection between APOE-e4 and Alzheimer's disease, exploring mechanisms and factors that contribute to the increased risks associated with the APOE-e4 gene variant. Among various investigations, one area of focus is the influence of amyloid-beta plaque accumulation and clearance, neurofibrillary tangle formation, synaptic dysfunction, and other related factors.

Another direction of on-going research is exploring interactions between the APOE-e4 gene variant, other genetic and environmental factors. This research aims to shed light on how these elements collectively contribute to the progression of the disease. The overarching goal is to gain a comprehensive understanding of APOE-e4's role in Alzheimer's and develop treatments and interventions that can delay or prevent the disease's onset in individuals carrying this genetic variant.

It's important to note that around 20-25% of the general population carry at least one copy of the APOE-e4 gene variant, making them 2-3 times more likely to develop Alzheimer's compared to those without the variant. Additionally, an estimated 50-60% of individuals inheriting two copies of APOE-e4 at birth develop Alzheimer's by the age of 85.

However, it's essential to recognize that APOE-e4 is just one of several factors contributing to Alzheimer's development, alongside genetics and environment. Having the APOE-e4 gene variant doesn't guarantee the development of the disease. To fully understand APOE-e4's implications and probabilities in relation to Alzheimer's, seeking proper genetic counseling and undergoing individualized risk assessments are crucial steps.

Ongoing research aims to unravel APOE-e4's complexities and its connection to Alzheimer's by investigating its impact on amyloid beta aggregation, tau protein pathology, and interactions with other factors. Utilizing advanced technologies like single-cell genomics and imaging techniques will enhance analysis. While APOE-e4 is a significant factor, it's crucial to recognize that Alzheimer's development involves multiple elements. Emerging models and advancements offer hope for improved management and disease understanding, benefiting individuals with APOE-e4 and Alzheimer's disease.

Impact Statement

My name is Nunnaphat (Gemmi) Haripottawekul, I am an eighth grader at the International School of Bangkok. I was given the opportunity to participate in the genetics and genomics program, which I used further to develop my understanding of various topics such as sequencing and much more. My research was focused on the APOE-e4 gene variant and its connections to developing Alzheimer's in a family. It led me to new inquiries, understandings, and different points of view on Alzheimer's disease. It made me realize how important and significant small things, like genes and cells, can be to our bodies and that we don’t always have the power to choose and change things in life. The APOE-e4 gene variant is a variant that is inherited; we can’t control whether or not we receive the variant or not. This is why we must learn to live and adapt rather than fear it.


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_By: Nunnaphat (Gemmi) Haripottawekul_

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of Elio Academy.