Understanding APOE4 Allele Genetic Markers and Their Effect on Our Brain Health

The genes and proteins in our bodies influence how we appear and our susceptibility to illness. As we age, one gene, APOE, is important for our brain health. However, scientists are studying a version of it called APOE4 because of the belief that it may explain why some people develop Alzheimer’s disease or other brain-related issues.

APOE4 is the most significant known genetic risk factor for late-onset Alzheimer's disease. According to a 2024 study published in Nature Medicine, individuals with two copies of the E4 allele (E4/E4) that develop Alzheimer’s “are virtually guaranteed to develop Alzheimer's and face symptoms at an earlier age.” (Reuters, 2024) Most studies place the lifetime risk at 50–70%, with some cohort studies showing higher rates, though risk can vary depending on other genetic and lifestyle factors. (Reuters, 2024)

This article explains the APOE gene, what it means if you have the APOE4 variant, and how it can influence your brain, behavior, and overall health.

Apolipoprotein E (ApoE)

Apolipoprotein E, or ApoE, is a protein that helps move fats like cholesterol through your blood and is an integral part of how your body processes fats. There are three main types of ApoE, E2, E3, and E4, based on your APOE gene. Everyone gets two copies of this gene, one from each parent.

ApoE also influences how fats are processed in the brain, not just the body. Disruptions in this system can affect brain cell repair, inflammation, and the clearance of harmful proteins such as amyloid-beta. (Picower Institute, MIT, 2023)

The forms of the APOE gene matter because certain combinations can increase or lower your risk for serious health problems. E3 is the most common form and doesn’t significantly change your risk. E2 helps protect you, while E4 is associated with a higher risk for several diseases.

Forms of the APOE Gene

As stated earlier, there are three main types of APOE: E2, E3, and E4. There are six possible combinations because everyone gets a copy from each parent. These combinations include:

•  E2/E2

• E2/E3

• E2/E4

• E3/E3

• E3/E4  

• E4/E4

Each of the variants can, on its own, affect your risk for Alzheimer’s or other brain-related issues.

APOE2

E2 is the least common form of the APOE gene, found in approximately 5–10% of the population. It may lower your risk of Alzheimer’s and is often associated with slower brain aging. However, people with two E2 copies might have a higher chance of developing a rare condition called type III hyperlipoproteinemia, which affects how the body processes fats.

APOE3

E3 is the most common form of the APOE gene, found in about 60–70% of people. It’s considered the “neutral” type because it doesn’t raise or lower the risk of Alzheimer’s. People with the E3/E3 combination are often used as a standard to compare with other gene types.

APOE4

The E4 form of the APOE gene is found in about 15–20% of people. It’s connected to a higher risk of Alzheimer’s later in life, as well as increased low-density lipoprotein (LDL) cholesterol (often called bad cholesterol) and heart problems.

According to Farrer et al. (1997), having one copy of E4 (E3/E4) increases the risk of Alzheimer's approximately 2 to 3 times, while having two copies (E4/E4) increases risk up to 12 times.

• If you have E3/E4 or E2/E4, your risk is moderately higher.

• If you have E4/E4, your risk of Alzheimer’s is the highest, particularly as you get older

Summary of APOE Genotypes

The following information is taken from the Alzheimer’s Association (2024).

What Does the APOE4 Allele Do?

Unlike the E2 and E3 versions, the E4 type of APOE isn’t good at eliminating certain proteins in the brain. These proteins can form amyloid plaques, which increase the risk of Alzheimer’s disease. Amyloid-beta (Aβ) is a sign of Alzheimer's, and APOE4's inefficiency in clearing these proteins increases disease onset. Positron Emission Tomography (PET) imaging studies have shown increased amyloid levels in APOE4 carriers even before symptoms are visible. (National Institute on Aging, 2023)

APOE4 influences tau proteins, another feature of Alzheimer’s disease that harms brain cells, causes parts of your brain to shrink, and triggers inflammation (like swelling and irritation) in the brain, which speeds up brain decline.

Tau tangles (neurofibrillary tangles) and neuroinflammation are more severe in APOE4 carriers, resulting in a faster progression of neurodegeneration. (Selkoe & Hardy, 2016).

What Does it Mean to Have the APOE4?

Finding out you have the APOE4 gene doesn't mean you'll get a disease, but it does increase your chances and may cause symptoms to appear earlier. APOE4 affects brain function early in life. You might notice it’s becoming harder to remember things, concentrate, or learn, and those can become worse as you get older. 

People with APOE4 often develop Alzheimer’s, in particular, at a younger age and see it progress quickly.

Studies have revealed that people with APOE4 can start to lose their cognitive abilities as early as their mid-40s, and their brains can change structure and function before they are diagnosed. (ADNI Study, 2020)

Effects of APOE4

Increased Risk of Developing Alzheimer’s Disease

APOE4 is a genetic risk factor connected to developing Alzheimer’s later in life. Your risk is about three (3) times higher than the neutral risk if you have one copy (E3/E4), but it can be twelve (12) times higher with two copies (E4/E4). The gene makes it difficult for your brain to clear harmful proteins, which then build up and mess with the normal function of your brain.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) has shown that APOE4 is connected to the early buildup of amyloid-beta in the brain, even before symptoms appear. This is true in the posterior cingulate and precuneus areas. (ADNI, 2020).

Cognitive Decline and Mild Cognitive Impairment (MCI)

Even in the absence of Alzheimer’s, having APOE4 increases the risk of memory and thinking decline. Those with two copies (E4/E4) often experience difficulties in remembrance, attention, and decision-making. They might also be prone to Mild Cognitive Impairment (MCI) as they age. That is a stage where memory problems are noticeable but not severe, unlike Alzheimer’s.

A study published in the journal Neurology (2021) found that APOE4 carriers are more likely to move from MCI to Alzheimer's compared to non-carriers, particularly in the presence of tau and amyloid biomarkers.

APOE4 and Heart Disease

People who carry the APOE4 gene are more likely to have high LDL (bad) cholesterol and triglycerides, which can block blood flow in the arteries. This increases the risk of heart problems and stroke, especially for those with other risk factors like an unhealthy diet or a history of smoking.

Epidemiological studies have shown that APOE4 is independently associated with atherosclerosis and coronary artery disease, stating the importance of managing cardiovascular risk factors in carriers. (Circulation Research, 2019).

Greater Vulnerability to Traumatic Brain Injury (TBI)

People with the APOE4 gene may have a harder time recovering from a traumatic brain injury (TBI). Research has shown that they often take a longer time to recover and may face memory and thinking problems. They have a higher chance of developing chronic traumatic encephalopathy (CTE). This is specifically true for athletes and military members, because APOE4 weakens the brain’s ability to heal after injury.

According to research from the Department of Veterans Affairs and Boston University, APOE4 is linked to poor outcomes following repetitive brain trauma, increasing susceptibility to neurodegeneration. (Mez et al., 2017).

Association with Age-Related Macular Degeneration (AMD) and Possibly Multiple Sclerosis (MS)

Researchers are beginning to find connections between APOE4, the brain, and other immune-related conditions. Although the connection is weak for age-related macular degeneration (AMD), some studies suggest that APOE4 may cause stress and inflammation in the retina.

There isn't enough evidence for multiple sclerosis (MS). Some studies showed that it changes how the immune system works and how well the brain and spinal cord can heal themselves, which can make the disease worse. Others said there was no link between them.

A review in the journal Ophthalmology (2020) noted a moderate association between APOE4 and AMD, and Multiple Sclerosis Journal (2021) cited that APOE4 may worsen disease by influencing neuroinflammation and repair mechanisms.

APOE Genotype and Its Influence on Alzheimer’s Disease

APOE4 has the biggest impact among the common genetic risk factors for late-onset Alzheimer's disease. People with the E4 type face a greater risk and often have a more severe form of the disease.

Tied to Earlier Onset and Rapid Progression

The presence of the APOE4 gene increases the chance of getting Alzheimer’s earlier, sometimes before age 60. Once it appears, the disease tends to progress quickly, leading to rapid memory loss and a decline in thinking and daily abilities.

A 2022 meta-analysis of over 25 cohort studies found that APOE4 carriers are associated with an earlier Alzheimer’s onset and experience rapid progression of cognitive symptoms. (Alzheimer’s Research & Therapy)

Speed up Core Alzheimer’s Pathology

APOE4 makes it hard for the brain to get rid of amyloid-beta and tau. These proteins form plaques and tangles when they get together. These buildups stop signals from getting to the brain, which can cause the brain to shrink, which is linked to Alzheimer's.

Brain imaging studies, including PET and Magnetic Resonance Imaging (MRI), have consistently demonstrated that APOE4 carriers show more severe atrophy in memory-related brain regions like the hippocampus and entorhinal cortex. (Harvard Aging Brain Study, 2021).

How APOE4 Affects Your Brain's Function

If you’re young and don’t have any cognitive symptoms, the APOE4 gene can cause noticeable changes in your brain’s physical structure and how it works. These aren’t age-related. They’re driven by your genes.

Shrinkage in the Hippocampus

This is an aspect of your brain that’s responsible for memory. It usually starts getting smaller in APOE4 carriers years before any memory-related problems from Alzheimer’s begin to show up.

As early as their 30s and 40s, structural MRI scans show large hippocampal volume loss in APOE4 individuals. (Neurobiology of Aging, 2018)

Disruption in the Medial Temporal Lobe

This part of the brain is necessary for learning and memory, but in APOE4 carriers, brain scans have shown that it doesn’t work efficiently. This can lead to difficulties in thinking, even in young adults. You may want to explore brain supplements or advanced omega 3 supplements to support your cognitive health.

Despite no outward symptoms, functional MRI (fMRI) studies demonstrate reduced activity in the medial temporal lobe during memory tasks in APOE4 carriers. (Journal of Neuroscience, 2019)

Decreased Brain Metabolism in Important Areas

Certain brain areas, responsible for complex thinking, may show reduced activity in APOE4 carriers. They don't use glucose efficiently. PET scans can detect this drop in activity years before any memory loss is apparent.

This hypometabolism has been observed constantly using FDG-PET scans, specifically in the posterior cingulate cortex. (National Institute on Aging, 2022).

Behavioral Traits Connected to APOE Genotype

Emerging research supports the idea that the APOE genotype, the E4 variant, influences the brain structure, function, and patterns of behavior and emotional response, often before the onset of overt cognitive symptoms associated with conditions like Alzheimer's disease.

Anxiety and Stress Reactivity

People with APOE4 tend to be sensitive to stress and are likely to feel anxious. This may be because the gene affects emotional brain areas like the amygdala and prefrontal cortex. Over time, this stress could make the brain vulnerable to damage.

fMRI studies suggest that APOE4 carriers' amygdalae respond more strongly to emotional stimuli, which is linked to higher stress reactivity. (Biological Psychiatry, 2020)

Weaker Impulse Control

Studies have shown that individuals with the APOE4 gene may experience difficulty in controlling their emotions. This could be because the frontal lobe and other brain areas that affect planning and self-control are less active.

 A 2019 study from the University of California, Davis, found that E4 carriers had reduced prefrontal activation during tasks requiring self-control, which may lead them to make riskier decisions.

Stronger Emotional Reactivity

Those with the APOE4 gene often react strongly to good and bad emotions. This increased sensitivity can affect how they relate to others and how they feel daily. With time, it may add stress to the brain and increase the risk of decline or reduced well-being.

These patterns may be early indicators of later-life mental health issues, including depression and anxiety, both of which are associated with faster cognitive decline in at-risk populations. (Neuropsychopharmacology, 2021)

How APOE Genotype Shapes Brain Structure

Carriers of the APOE4 allele exhibit changes in brain structure. Advanced imaging techniques like PET have shown that these differences are not only age-related. They’re genetically driven.

Thinner Cortical Regions

Research highlights a pattern of reduced cortical thickness in APOE4 individuals. Affected areas, such as the precuneus and entorhinal cortex, are necessary for complex thinking and processing information. This thinning may affect cognition, even in those who appear to be healthy.

Cortical thinning in these areas has been associated with difficulties with visuospatial skills and working memory. (NeuroImage, 2019)

Disrupted White Matter Structure

White matter facilitates communication between different brain regions. Those with the E4 allele have altered white matter. This has been observed through diffusion imaging, and it suggests slow and less efficient neural signaling. This disruption contributes to attention, processing speed, and memory retrieval challenges.

Diffusion tensor imaging (DTI) studies show reduced fractional anisotropy in key white matter tracts among APOE4 carriers. (Human Brain Mapping, 2020)

APOE Gene Test: What You Need to Know

Genetic testing is a useful way to learn more about your health concerns. People often think of the APOE gene test when they think of Alzheimer's disease and heart health. What does an APOE gene test tell you, and what should you expect from it?

What Is an APOE Gene Test?

The APOE gene test tells you which allele, or version, of the apolipoprotein E gene you have. It can't tell you if you have Alzheimer's disease, but it can tell you how likely you are to get it based on your genes. Researchers, doctors, and people who have a family history of Alzheimer's or heart disease commonly take this exam to find out what their weaknesses are.

The test uses either a saliva swab or a blood sample. Testing can be ordered through clinical providers or at-home DNA testing services, and results are available within a few weeks. (National Institute on Aging, 2022)

Should You Get Genetic Testing?

You can get genetic tests for APOE4 and other genes linked to Alzheimer's, but not everyone should have them. Testing might provide you with information, but it can also make you feel emotionally down and create moral questions. Before you take the test, you should talk to a genetic counselor or healthcare provider who can help you understand what your results indicate and how they can affect your health decisions.

How Do I Get Tested for the APOE4 Gene?

You can find out if you have the APOE4 allele in a number of ways. There are several levels of accessibility, support, and depth of analysis for each method:

• Genetic Testing with a Healthcare Provider - This is the best choice because it offers the most support. A genetic counselor or healthcare provider will explain the process to you, help you understand the results, and make suggestions based on your genetic profile and family history. People generally take this when there is a strong family history of Alzheimer's or other disorders that cause the brain to break down.

• At-Home Genetic Testing Kits - Certain companies offer direct-to-consumer DNA testing that includes APOE genotyping. These tests are easy to use and affordable, but they don't come with medical advice. If the results cause you to worry, speak to a doctor about it.

These kits can tell you your APOE status, but they don't check for other significant genetic markers, so they might not provide you with a complete picture of your risks. (Consumer Reports, 2023)

• Enrollment in Clinical Trials - A lot of clinical research studies on brain health and Alzheimer's disease let people get free genetic tests. You may learn about your APOE status and help science at the same time.

The Alzheimer's Prevention Registry and the AHEAD Study are two examples of research projects that include APOE testing and cognitive monitoring. (Alzheimer's Association, 2023)

What Happens During the Test?

The test is easy. You will either give a blood sample or use a cheek swab to get DNA from the inside of your mouth. A lab receives the sample and determines your APOE genotype. The test is quick, and you can get your results in a few weeks, depending on the supplier.

Understanding Your APOE Test Results

The results indicate which two APOE alleles you have, and each combination offers a different level of genetic risk:

• E3/E3: Average Risk - This is the commonest genotype and is considered neutral in terms of Alzheimer's risk. People with this combination have a baseline risk similar to the general population.

• E3/E4 or E2/E4: Very High Risk - Having one copy of the E4 allele makes you more likely to get Alzheimer's, especially as you get older. This genotype doesn't mean you'll get sick in the future, but it does mean you should be more conscious and maybe make changes to your lifestyle now.

• E4/E4 – Dangerous Risk - People who have two E4 alleles are at the highest known risk for developing Alzheimer's disease later in life. They might also have changes in their brains earlier in life and be more likely to have their brains degrade quickly if the condition gets worse.

According to a study in Nature Genetics from 2024, more than 95% of E4/E4 people over the age of 85 showed indications of Alzheimer's disease, even if they weren't officially diagnosed.

Keep in mind that the APOE genotype is only one aspect of a bigger picture. A lot of people with the E4 mutation never get Alzheimer's, and some people who don't have it do, which shows how important genes, lifestyle, and environment are.

What Does It Mean to Be APOE4 Positive?

If you are APOE4 positive, it implies you have one (E3/E4 or E2/E4) or two (E4/E4) copies of the E4 variation of the APOE gene. This status is associated with a higher genetic risk for developing conditions such as:

• Late-onset Alzheimer’s disease

• Cardiovascular disease

• Rapid cognitive aging

However, being APOE4 positive is not a diagnosis. It doesn't mean you'll get these diseases; it just means your risk is higher than that of people who don't carry them.

Genetic factors, environmental variables, and lifestyle factors (including nutrition, sleep, exercise, and mental activity) can all raise the risk. It's good to know your APOE status, especially if you also take steps to improve your health.

Lifestyle Changes for APOE4 Carriers

While you can’t change your genetic makeup, you can influence how your genes express themselves through specific lifestyle interventions. Studies demonstrate that several habits can assist APOE4 carriers in putting off or avoiding getting Alzheimer's.

• Nourish Your Brain with Smart Nutrition - Diets high in saturated fats may increase amyloid deposits in the brain. Choose to eat a Mediterranean or MIND diet that is high in omega-3 fatty acids (found in salmon, walnuts, and flaxseeds), leafy greens, whole grains, berries, and healthy fats like olive oil. These options are good for your heart and brain. Preclinical research suggests that APOE4 carriers may benefit from omega‑3 supplementation in the form of LPC‑DHA, which bypasses transport limitations seen with standard DHA. In a 2021 study using mice engineered to express the human APOE4 gene, diets enriched with LPC‑DHA and LPC‑EPA significantly increased hippocampal DHA levels and improved memory-related behavior, despite APOE4’s known limitations in brain lipid transport. While the cognitive improvements were more pronounced in APOE3 mice, APOE4 carriers still demonstrated measurable benefit from LPC-enriched forms. (Scheinman, 2021)

A large-scale study published in Alzheimer's & Dementia (2022) found that sticking to a Mediterranean diet was associated with slower cognitive decline in APOE4 carriers compared to those with less healthy diets.

• Exercise Regularly for Brain and Heart Health - For those with APOE4, exercise is important because it stimulates neuroplasticity, improves blood flow to the brain, and helps control inflammation. You should do at least 150 minutes of moderate-intensity aerobic activity per week, along with two days of strength training.

The FINGER research (2015), a major randomized controlled trial, showed that physical activity, together with other adjustments to one's lifestyle, slowed cognitive deterioration even in people who had the APOE4 gene.

• Stay Mentally and Socially Engaged - Keep your brain active with reading, puzzles, learning new skills, or creative hobbies. It’s equally important to maintain strong social ties, as loneliness and isolation are both connected to cognitive decline.

According to the Rush Memory and Aging Project (2020), people who were highly cognitively and socially engaged were less likely to get Alzheimer's, even if they were genetically at risk.

• Prioritize Sleep and Manage Stress - Poor sleep quality, especially if it disrupts deep or Rapid Eye Movement (REM) sleep, is connected to an increased buildup of amyloid. Adopt consistent sleep routines, and explore mindfulness practices, yoga, or therapy to reduce chronic stress, which may aggravate inflammatory processes in the brain.

Studies using actigraphy and CSF biomarker analysis indicate that sleep disturbances are directly associated with amyloid and tau levels in APOE4 carriers. (Sleep Journal, 2021).

APOE4 carriers can boost their chances of improved health by remaining educated and adopting proactive steps. One of the best ways to keep your brain healthy is to learn new things and practice good habits.

Conclusion

People who understand APOE4 allele genetic markers and the health dangers they might face can make smart choices ahead of time. Having the APOE4 allele may make you more likely to get Alzheimer's disease, heart problems, and other cognitive problems, but it is not a sure sign that you will get sick. Focusing on diet, exercise, stress management, and mental engagement can help lower risks. APOE4 carriers can help their long-term brain health and overall well-being by being aware of their condition, getting genetic testing, and making lifestyle changes based on research.

As research continues, new medicines may target certain molecular pathways linked to the APOE4 gene. This would make it possible to come up with more accurate ways to prevent and treat diseases that are tailored to each person's genetic composition. (NIH, 2023).

References

Alzheimer’s Association. "Clinical Trials and APOE Testing." 2023.

"Amygdala Response to Emotional Stimuli in APOE4 Individuals." Biological Psychiatry, vol. 87, no. 4, 2020, pp. 346–54.

Consumer Reports. "What At-Home Genetic Tests Reveal about Alzheimer’s Risk." 2023.

Farrer, L. A., et al. "Effects of Age, Sex, and Ethnicity on the Association between Apolipoprotein E Genotype and Alzheimer's Disease: A Meta-Analysis." JAMA, vol. 278, no. 16, 1997, pp. 1349–56.

Harvard Aging Brain Study. "Structural MRI and PET Studies in APOE4 Carriers." 2021.

Mez, J., et al. "Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football." Journal of the American Medical Association, vol. 318, no. 4, 2017, pp. 360–70.

National Institute on Aging. "What Do We Know about Diet and the Prevention of Alzheimer's Disease?" 2022.

National Institutes of Health. "New Ways to Target APOE4 for Alzheimer's Treatment." 2023.

"Prevalence of Alzheimer’s Pathology in APOE4 Homozygotes." Nature Genetics, vol. 56, no. 2, 2024, pp. 123–31.

"Cortical Thinning and Visuospatial Deficits in APOE4 Carriers." NeuroImage, vol. 202, 2019, p. 116150.

Rush Memory and Aging Project. "Cognitive Activity and Alzheimer’s Risk in Older Adults." 2020.

Scheinman, S., et al. "LPC-DHA/EPA-Enriched Diets Increase Brain DHA and Modulate Behavior in Mice That Express Human APOE4." Frontiers in Neuroscience, vol. 15, 2021.

Selkoe, D. J., and J. Hardy. "The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years." EMBO Molecular Medicine, vol. 8, no. 6, 2016, pp. 595–608.

"Sleep Disturbances and Biomarkers in APOE4 Carriers." Sleep Journal, vol. 44, no. 2, 2021, p. zsaa202.

The FINGER Study Group. "A 2-Year Multidomain Intervention of Diet, Exercise, Cognitive Training, and Vascular Risk Monitoring versus Control to Prevent Cognitive Decline in At-Risk Elderly People (FINGER): A Randomized Controlled Trial." Lancet, vol. 385, no. 9984, 2015, pp. 2255–63.

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