APOE4 Gene: What You Need to Know About This Alzheimer's Risk Factor

The day I received my genetic test results, I wasn’t nervous at all. It was simply a free test I’d been gifted as a perk for appearing on a podcast and only took it as a fun experiment. Assuming I’d find nothing interesting since I considered myself a healthy person, I was shocked to discover I actually carried two copies of the APOE4 allele, which puts me at the highest risk for Alzheimer’s disease. 

As a registered dietitian nutritionist, I actually knew a bit about the APOE gene and how the APOE4 variant has been connected to the development of Alzheimer’s disease. But the thought of carrying the APOE4 variant myself was daunting. I knew I had to dive into the vast world of APOE and Alzheimer’s research to learn more. 

It felt overwhelming at first, but through my research, I began to discover that APOE4 is not necessarily a one-way ticket to chronic disease. I learned that it doesn’t have to be a hopeless experience—in fact, it can be an empowering one. 

After all, even if the cards aren't stacked in your favor, you have the power to be proactive. You can choose to take control of your health, and make lifestyle changes that help you build a strong foundation of health. 

So, come on this journey with me as I explore the connection between the APOE4 gene and Alzheimer’s and arm you with strategies that can reduce the risk for Alzheimer’s and other chronic conditions connected to APOE4.

Understanding the APOE Gene Family

Before I began to think about how to make lifestyle changes to prevent risk, I first had to learn more about the APOE gene itself and the differences between each variant. The APOE gene (short for apolipoprotein E gene) and its variants encode for a protein called apolipoprotein E, which acts as a transporter of fats and cholesterol throughout various tissues and organs. 

Every human gets two copies of the APOE gene—from your mother and one from your father. There are three main variants of the APOE allele, and while these variants may differ by only two amino acids in their protein sequence, they hold profound implications for our health. Here’s a quick overview:

APOE2

• Appears to be associated with a lower risk of developing Alzheimer's disease.
• Least common variant — only five percent of the general population has it. 
• This APOE genotype may also be protective against cardiovascular disease. 

APOE3

• Considered to be the most neutral APOE variant.
• Is not strongly associated with either increased or decreased risk of developing neurodegenerative disorders.
• Known to be the most common allele of the APOE gene.

APOE4

• Most well-known for its connection to Alzheimer's disease. 
• Linked to an increased risk of cardiovascular disease.
• May also be attributed to higher cholesterol and triglyceride levels. 
• About 15 to 20 percent of people have this allele, and only two to five percent of those people carry two copies. 

What is APOE4 and Why Does it Matter?

Next was a deep dive into what I'd just discovered—what did the two copies of the APOE4 gene really mean for me? Since I had no family history of Alzheimer's, the leading associated risk, I wanted to learn what other indicators could have suggested it.

But then it hit me—my family tree was full of cardiovascular issues and other neurodegenerative diseases. So what is APOE4, and why is it so connected to your risk for chronic disease? 

The APOE protein plays a central role in lipid metabolism—the process by which the body handles fats and cholesterol. It serves as the main cholesterol carrier in the brain, moving cholesterol in the body to give neurons the energy they need.

APOE-ε4 is a genetic variant of the APOE gene that has been linked to a higher risk of conditions such as:

• Cardiovascular disease
• Heart attack
• Stroke
• Alzheimer’s disease
• Other neurological disorders 

In fact, APOE4 is the strongest risk factor for Alzheimer’s besides age. Those who inherit one allele of the APOE4 gene from either parent are one to two times more at risk for developing Alzheimer’s, and those who inherit two alleles, like me, are 10 to 15 times more at risk.

After my discovery, I had a conversation with podcaster and health writer Max Lugavere about APOE4 and the health implications it can have. Check it out here:

So, why does this gene variant even exist in the first place? Neuroscience researchers believe that APOE4, despite its association with Alzheimer's risk, may have once conferred an evolutionary advantage. 

Researchers believe that in early human history, the APOE4 variant played a role in survival and was likely the original allele, as it led to a strong inflammatory response and was protective against infection. However, as human lifestyles and diets have evolved over time, the protective and inflammatory aspects of the APOE4 gene have become less advantageous.

The Link Between Alzheimer’s and APOE4

While research still isn’t conclusive, one prevailing hypothesis about the link between APOE4 and Alzheimer’s suggests that APOE4 is involved in the formation and clearance of amyloid-beta plaques. These are brain abnormalities characteristic to Alzheimer's. 

Studies suggest that APOE4 disrupts the distribution of lipids in the brain, affecting the structure and function of synapses, which are the connections between neurons essential for learning and memory. This can lead to worsened cognitive function.

“I usually explain this as being a less efficient energy transporter overall, as it seems to inefficiently move lipids and glucose in and out of the brain.” —Kara Collier, RDN, LDN, CNSC

APOE4 may also impact the blood-brain barrier, and may lead to higher levels of neuroinflammation in the brain, which has been shown to contribute to the onset and progression of Alzheimer’s. 

This gene variant has also been linked to less efficient neuronal repair and glucose dysregulation in the brain, which can lead to issues for regulating insulin and glucose levels. In spite of all these findings, however, research on the exact causes and the link between APOE4 and Alzheimer’s is ongoing. 

Other Factors Associated with Alzheimer’s

Even with all the research available,  it’s important to remember that the APOE4 gene is not a predetermined sentence of Alzheimer's disease. Genetics are just one piece of the puzzle. 

Lifestyle factors, such as diet, exercise, cognitive stimulation, and social engagement, also play essential roles in influencing Alzheimer's risk and the development of late-onset Alzheimer's disease. 

Strategies to Reduce Your Risk of Alzheimer’s Disease

While the stats around APOE4 and Alzheimer’s can be alarming, it’s important to keep in mind that some people with two copies of the APOE4 variant never get Alzheimer’s. Unfortunately, since we’re still learning about the causes of Alzheimer’s, I believe it’s important to be proactive and take steps to reduce your risk in any way you can.

Genetic risk factors for disease may load the gun, but it’s your lifestyle habits that actually pull the trigger. Michael Greicius, MD, MPH, is associate professor of neurology and neurological sciences and director of the Stanford Center for Memory Disorders. In an interview with Stanford associates, he explains that not everyone with APOE4 will develop Alzheimer's. Having another gene variant for the klotho protein may be protective.

That’s why optimizing your metabolic health and reducing inflammation are two of the most important things you can do. To make sure you’re proactive about your health, I always suggest monitoring specific labs and biometrics on a regular basis.

“Beyond the basic labs I believe everyone should monitor annually, someone with APOE4 should monitor hsCRP, apoB, vitamin D, and homocysteine.”—Kara Collier, RDN, LDN, CNSC

Other important actions you can take are to:

• Stay on top of your weight
• Monitor your glucose data with a CGM
• Watch your blood pressure levels

With this in mind, here are some of the top strategies and lifestyle habits I learned through my journey, that may help reduce your risk for Alzheimer’s: 

1) Improve Your Metabolic Health

Poor metabolic health markers can be risk factors for developing Alzheimer's disease. These factors can include:

• High blood pressure
• High HDL cholesterol levels or triglyceride levels
• Insulin resistance

It can be challenging to improve your metabolic health, but implementing certain lifestyle changes may actually reduce the risk of developing Alzheimer's disease. Unfortunately, APOE4 can make maintaining good metabolic health slightly more difficult, so you need to be even more diligent about it than someone who isn't a carrier. 

2) Get Plenty of Exercise

Exercise might be one of the most powerful tools against risk factors for Alzheimer’s and other chronic diseases. Appropriate types and amounts of exercise can benefit people with APOE4 in particular, as it’s been shown to reduce amyloid plaque formation and increase overall vascular health.

This can reduce the risk for Alzheimer’s by 45 percent. Exercise is also proven to:

• Improve cardiovascular health
• Possess anti-inflammatory effects 
• Protect brain cells from damage caused by oxidative stress
• Improve insulin sensitivity and glucose regulation

The best exercise routine is a combination of endurance training and strength training. Here are some upper body and lower body routines to follow. 

3) Optimize Your Diet

Interestingly, there’s a strong connection between diet and Alzheimer’s. Working as a registered dietitian, I’ve seen firsthand how nutrition can have an impact on your body’s insulin sensitivity, glucose metabolism, inflammation, brain health and myriad other factors that affect Alzheimer’s risk. 

For people carrying APOE4, fat intake and balancing your omega 3:6 ratio is particularly important. You’ll want to focus on consuming monounsaturated fats and getting plenty of omega 3 in your diet. Whole food sources of saturated fats can also be beneficial, though it’s important to monitor your lipid labs to make sure they don’t start to skew in the wrong direction. 

Here are a few additional tips to help create a balanced and healthy diet:

• Prioritize high quality protein in your diet
• Find your carbohydrate threshold using a continuous glucose monitor (CGM) and professional nutritionist guidance
• Fill in the rest of your daily calories with quality fats (focused on monounsaturated fats and omega-3 fatty acids sources)
• Consider taking a high quality omega 3 fish oil supplement 
• Minimize sources of dietary inflammation from processed foods, refined grains, sugar, and processed seed oils
• Maximize your intake of nutrient-dense whole foods

Consider Following an Alzheimer’s-Friendly Diet 

For some people, following a specific diet may be beneficial–though what works for each individual can vary. My personal approach is a combination of a few things. 

“I follow a Mediterranean focused diet, though I consume a higher amount of saturated fat sources from whole foods, like grass fed beef. I also aim to eat a personalized low-carb (but not keto) diet made up of low-glycemic foods, which I adjust based on my CGM data.” - Kara Collier, RDN, LDN, CNSC

Here are three popular diets I’ve found to be potentially beneficial for Alzheimer’s-related risk factors.

• A low-glycemic diet, which focuses on how foods affect your blood sugar, can be beneficial to those with APOE4.
• The ketogenic diet, which may also reduce inflammation, oxidative stress, and other metabolic issues that contribute to Alzheimer’s. 
• The Mediterranean diet, which may reduce the risk of cognitive impairment and Alzheimer’s.

Whether you follow a specific diet or not, focusing on nutrient-rich foods and reducing your intake of added sugars, simple carbohydrates is key. Working with a registered dietitian or nutritionist can be a great way to get focused, personalized suggestions for your diet. 

4) Reduce or Eliminate Alcohol Consumption

Excessive alcohol consumption can have negative cognitive effects for anyone, including damaged brain cells, memory problems, and altered emotional recognition. Research also shows that alcohol consumption, in any amount, can increase the risk of Alzheimer’s disease in those with APOE4 gene. 

To reduce your risk of Alzheimer's, follow guidelines for moderate alcohol consumption or consider abstaining from alcohol altogether. 

5) Engage Your Brain

Engaging in continuous learning and cognitive activities can reduce the risk of Alzheimer's disease and support brain health. Research shows that keeping the brain active and engaged promotes neuroplasticity, delays cognitive decline associated with aging, and supports overall brain health. 

To keep your brain active and continuously challenge it through all stages of life, I recommend these tips:

• Reading
• Writing
• Learning a new language
• Solving puzzles
• Learning new skills
• Participating in hobbies that require mental effort

6) Prioritize Sleep and Manage Stress

Healthy sleep is an important factor in reducing the risk of Alzheimer's disease and supporting brain health, especially for those with APOE4. Chronic sleep problems can also increase amyloid plaque deposits, a hallmark of Alzheimer’s disease, which can even further disrupt sleep. 

At the same time, chronically high stress levels can also increase inflammation and impact your body’s insulin sensitivity. Stress can negatively impact all areas of your health–including cardiovascular and neurological health. Taking steps to manage stress effectively is essential for anyone who carries APOE4.

8) Consider Outside Sources of Inflammation

Finally, there are many other outside sources of inflammation that go beyond your diet and are often overlooked as a result. These factors can sneak up on you and contribute to health issues without you even realizing it. 

Here are some of the most common outside causes of inflammation in the body that I recommend keeping an eye on:

• Dental health
• Environmental toxins like water quality, air quality, cleaning products, cooking products, and cosmetics
• Smoking and vaping
• Dysbiosis

Takeaways from a Registered Dietitian Nutritionist

Discovering that I carry the APOE4 gene was a turning point in my life. It really brought home the importance of proactively improving my metabolic health to reduce the risk of Alzheimer's and other chronic conditions related to APOE4.

As the VP of Health at Nutrisense, a big part of my role is understanding the impact of lifestyle habits on our overall health. My particular expertise in the field of nutrition has given me a unique vantage point to explore the relationship between the APOE4 gene, lifestyle habits, metabolic health, and Alzheimer’s disease. 

For that reason, I feel it’s my responsibility to pass on my knowledge and personal experience to others. For more tips on glucose regulaton, implementing healthy lifestyle habits, and improving longevity, follow me on Instagram here.

Whether you’ve discovered you have the APOE4 gene, or just want to be proactive about your health, here are some strategies I use:

• Be proactive about your health by visiting your doctor frequently and staying on top of health screenings related to metabolic and cognitive health. 
• Focus on the fundamentals of health. Advice on the internet may point you to supplements that claim to reduce your risk of dementia, but what good are supplements if you aren’t focusing on fundamental nutrition, healthy amounts of exercise, and supporting your metabolic health?
• Vet your healthcare provider by asking some specific questions. Your average primary care provider may not have done adequate research on APOE and its variants, so be wary of any doctor that isn’t a specialist who claims to know everything about the subject.

At Nutrisense, we believe that personalized insights and data-driven decisions can empower individuals to make meaningful changes that lead to a healthier, more fulfilling life. 

While I already had some understanding of the science behind APOE4, confronting its presence in my own genetic makeup brought a sense of urgency to my mission at Nutrisense–empowering individuals to take control of their health through real-time metabolic insights. I encourage everyone reading to take charge of their health and seek to understand how your choices impact your metabolic and cognitive well-being.