Reevaluating the APOE4 Gene: Is It a New Genetic Form of Alzheimer’s Disease?

June 03, 2024

The APOE4 gene variant has long been known to be connected to Alzheimer's disease.  Recognized as a “risk gene,” it increases the likelihood of developing Alzheimer's.  Each person can carry up to two copies of APOE4.  Carrying one copy may increase risk up to 3-4 times, and carrying two copies may increase risk up to 10-15 times, but in either case, the majority of evidence indicates that carrying APOE4 does not guarantee a person will suffer from Alzheimer’s disease.1  However, a recently published research article in the journal Nature Medicine dove deeper into historical data on APOE4, and what they conclude is that having two copies of APOE4 (being an “APOE4 homozygote”) may be more than just a risk factor.  The study suggests that being an APOE4 homozygote represents a new genetic form of Alzheimer’s disease, similar to other dominantly genetic conditions, like having Down’s syndrome or having cystic fibrosis.2  But what does this really mean? 

This new research received attention in the media, and it was certainly alarming to many who carry APOE4.  So, before we dive in, let us remind you that carrying two copies of APOE4 does not guarantee an Alzheimer's diagnosis.  While the risk is higher, it's not a certainty.  Proactive lifestyle and nutrition modifications can reduce your risk of neurodegenerative disease and general age-related cognitive decline, and there are some that are specifically very important for APOE4 carriers, which we’ll summarize in this also. 

Thomas Holland MD, from Rush University Medical Center, and NeuroReserve Medical Advisor says "Being a carrier of APOE4, regardless of if it's one or two copies, confers an increased risk of developing Alzheimer's disease.  This does not mean you will develop Alzheimer’s disease.  Gene-lifestyle interactions play a role. While we don't fully understand these factors, we know that some lifestyle factors that have been associated with decreased risk regardless of APOE4 status include a brain healthy diet, regular exercise, and avoiding alcohol.  These all play a large role for APOE4 carriers, and we strongly encourage these behaviors in our clinical practice and research." 

The good news is that the latest research into APOE4 brings greater awareness to it and creates more opportunities for dialogue and education about it among physicians, researchers, and the general public. 

A Refresher on the APOE Gene 

We've discussed APOE4 in detail previously here, but let's have a quick refresher on what the APOE gene is and how it can impact your risk of Alzheimer's. 

APOE is the strongest and most prevalent genetic risk factor for Alzheimer's disease.  The APOE gene contains the code to make a protein called apolipoprotein E, which moves fat throughout the body.  Each person carries two copies of the APOE gene, one from each parent.  The gene comes in three forms: APOE2, APOE3, and APOE4, resulting in six possible combinations: e2/e2, e2/e3, e2/e4, e3/e3, e3/e4, and e4/e4. 

The APOE2 form may decrease the risk of Alzheimer's disease.  APOE3, the most common form, is associated with an average risk.  APOE4 is linked to an increased risk, as mentioned, with one copy raising the risk 3-4 times and two copies increasing it up to 15 times.3 

Get your FREE e-guide "Living with APOE4: Strategies for Reducing Genetic Risk" with recipes, simple tips, and more.  

Understanding the Biological Impacts of APOE4 

APOE4 brings with it some unique biological impacts, including how our bodies process fats and cholesterols, neuroinflammation, blood brain barrier aging, insulin resistance, and amyloid beta “plaque” buildup in the brain.  (You can learn more by visiting our previous article here.) 

Those biological impacts can leave clues in our blood and other parts of our body, called biological markers.  The recent Nature Medicine article focused primarily on the biological markers of APOE4 in the brain and cerebrospinal fluid (CSF, which is the fluid in the spinal cord and brain).  Biological markers are typically obtained through lab tests to measure substances in the body or analyze genetic material.  However, diagnosing Alzheimer's disease involves more than just biological tests; it also requires clinical assessments of symptoms, cognitive tests, and medical history.  It's important to remember this difference between biological markers and fully diagnosed disease.  

Analyzing Major Insights from the Nature Study on APOE4 

A few major findings from the Nature Medicine article are that people who carry two copies of APOE4 start showing biological markers of Alzheimer’s disease at an earlier age than non-carriers, starting as early as age 55.  Also, it showed that by the time APOE4 double carriers turned 65 years old, almost all had abnormal levels of amyloid beta in their cerebrospinal fluid, and the vast majority (75%) had detectable levels of amyloid beta plaques in the brain through brain imaging scans.2  You may recall, amyloid beta plaques are a pathological “hallmark” of Alzheimer’s disease, though it is also not uncommon for people to have such plaques in their brain but not show any cognitive symptoms. 

Regarding cognitive symptoms, another finding from the study is that people who carry two copies of APOE4 tend to be diagnosed earlier than non-carriers (i.e. people who carry two copies of APOE3), on average around 65 years old in showing cognitive symptoms.  However, it is important to note that this age of onset has a range with some showing symptom earlier, while others show symptoms later.

The question is:  What can cause these biological markers and cognitive symptoms to be delayed a little, by a lot, or even delayed indefinitely? 

NeuroReserve Medical Advisor Dr. Annie Fenn shares her perspectives about this new study in an article which will be publicly released later this month.  We’ll link it here when it releases. 

Are Double APOE4 Carriers Guaranteed an Alzheimer's Diagnosis? 

The short answer is no.  The Nature Medicine study provides great new evidence that gives us a better idea regarding the sequence of when biological markers and symptoms may occur for APOE4 carriers.  However, as we mentioned earlier, developing Alzheimer's involves many factors, and APOE4 carriers can take advantage of those other factors to bend the trajectory in their favor.  As an APOE4 carrier, it's crucial to consider how proactive you are about reducing your risk.  Lifestyle and nutrition are significant areas you can manage to influence your risk. 

Get your FREE e-guide "Living with APOE4: Strategies for Reducing Genetic Risk" with recipes, simple tips, and more.  

How to Proactively Lower Risk:  Areas That Are Particularly Important for APOE4 Carriers 

Certain dietary and lifestyle factors have a bigger effect on APOE4 carriers vs non-carriers, presenting a bigger opportunity for positive impact.  

Exercise: Physical activity is very helpful for APOE4 carriers.  A 21-year study showed that midlife physical activity reduces the risk of Alzheimer's in APOE4 carriers.  It found that amyloid beta shares a sequence with insulin and binds to insulin receptors, increasing insulin resistance.  Higher insulin resistance is linked to reduced Alzheimer's-related brain function.  Physical activity decreases insulin resistance and lowers chronic inflammation, countering the harmful effects of amyloid beta.4 

Managing Health Factors: The APOE4 gene doesn't impact your brain in isolation; it also interacts with other health issues.  It’s particularly important for APOE4 carriers to manage hypertension and diabetes, as these may exacerbate the effects of APOE4.  Also, a study found that better cardiovascular health is linked to a lower risk of dementia for both APOE4 carriers and non-carriers.  Interestingly, women were significantly impacted by their cardiovascular health status in relation to dementia risk, even in the presence of APOE4.  So, taking good care of the heart is often good for the brain.5, 6 

Restricting Alcohol Intake:  APOE4 carriers must be especially careful about their alcohol consumption.  Even moderate drinking can raise low-density lipoprotein (LDL) levels, often referred to as "bad" cholesterol.  Elevated LDL levels can increase the risk of Alzheimer's disease by contributing to the buildup of harmful plaques in the brain.  Higher alcohol intake can lead to greater cognitive decline and an earlier onset of Alzheimer's.  To protect brain health, APOE4 carriers should limit alcohol as much as possible.7 

Sleep: Sleep is the most precious time for your brain, as it's during sleep that our brain can clear out and fight back against amyloid beta buildup.  Research suggests that older adults who sleep longer at night tend to have lower levels of amyloid beta buildup in their brains.  Making sure you have good sleep habits, checking for underlying sleep disorders, and aiming for 7-8 hours of sleep each night are non-negotiables for APOE4 carriers.  It's important to note that getting 7-8 hours of continuous sleep is the key.  Daytime naps have been associated with increased buildup of amyloid beta in the brain.5   

Avoid Air Pollution if Possible:  Keeping the air fresh around APOE4 carriers may be important.  There’s early and growing evidence of this, and in one study of people who had prolonged exposure to the debris from the September 11, 2001 World Trade Center attack, APOE4 carriers had higher risk of mild cognitive impairment.6 

Nutrition: APOE4 carriers may benefit from specific nutrients that their brains either struggle to obtain in adequate amounts or that help offset the impact of APOE4.  Here are a few that are recommended by researchers at Weill Cornell Medical Center for APOE4 carriers:8   

  • B-vitamins:  B-vitamin supplementation, especially B12, can improve homocysteine levels.  Elevated homocysteine levels are associated with Alzheimer's disease, particularly when linked with APOE4 status.  Lowering these levels is usually recommended as it can decrease APOE4 gene expression, which is important for cholesterol transport in the brain.  B-vitamin complex supplementation slowed brain atrophy, especially in individuals with high homocysteine and omega-3 levels.  B-vitamins also work well with DHA, as they help support brain health by aiding DHA transport and utilization. 
  • Omega-3's (DHA):  Research indicates that people with Alzheimer's disease typically have reduced levels of DHA in their brains, while diets high in DHA-rich fish (like salmon, mackeral, and sardines) are associated with lower rates of Alzheimer's.  DHA possesses anti-inflammatory properties and enhances the function of microglia, especially significant for APOE4 carriers who might need elevated DHA intake to counter increased metabolism and possible challenges in delivering DHA to the brain.  
  • Quercetin: This nutrient is an antioxidant found in onions and capers, has been shown to reduce the activity of MMP-9, an enzyme found in elevated amounts in the brains of Alzheimer’s sufferers. 

You can explore more APOE4 specific nutrient recommendations by downloading our FREE e-guide on “Living with APOE4: Strategies to Reduce Risk”, click here to get the guide.  

The Mediterranean dietary pattern includes the nutrients mentioned, plus others known to protect the brain and more.  Studies have shown that higher adherence to the Mediterranean diet is associated with a lower risk of dementia, even for APOE4 carriers.  Specifically, participants who ate the Mediterranean way most consistently had a 23% lower risk of developing dementia compared to those who ate it the least consistently.9

NeuroReserve Medical Advisor, Dr. Annie Fenn and founder of the Brain Health Kitchen, a cooking school dedicated to providing recipes that may help reduce the risk of Alzheimer's, will be publicly releasing her 21 Things You Can Do to Reduce the Risk of APOE4 later this month, which we’ll be linking here later this month.  

Completely overhauling your diet overnight can be challenging, especially when trying to adjust in various areas.  While you're making progress with your diet, consider supplementing for the areas where you fall short.  Our brain health supplement, RELEVATE, contains 17 vital nutrients from the Mediterranean and MIND diets, helping keep your brain sharp and strong.  Formulated to work together, these nutrients help your brain stays covered nutritionally, even when you struggle with your diet.  You can use code: APOE4 for $20 OFF your first order, plus 10% OFF for all future orders. 

For June, Alzheimer's and Brain Awareness Month, we have a special offer featuring Dr. Annie Fenn's "Brain Health Kitchen Cookbook." This cookbook focuses on reducing the risk of Alzheimer's through diet, with over 100 recipes and science breakdowns, making it relevant for anyone looking to maintain brain health.  Additionally, the offer includes 3 bottles of RELEVATE and a stainless steel RTIC tumbler for hydration, which is super important for the brain. Learn more about this limited offer here.  

The Takeaway: 

It's encouraging to see ongoing research delving into various factors related to Alzheimer's disease, reflecting a growing focus on this critical area.  However, it's vital to view each study not in isolation but as part of a larger body of evidence.  For people who carry two copies of APOE4, you should not interpret such findings as grounds for fear but rather as motivation to take proactive steps.  There's still ample room to support brain health and change our individual risk.  So, rather than being alarmed and anxious, let this information inspire steady action and a commitment to lifelong brain health. 

For more tips and recipes for APOE4, download our free e-guide here.  By downloading our guide, you’ll automatically be entered into a $700 giveaway for a GenoRisk™ Alzheimer’s at-home test from ADxHealth which evaluates 31 genetic variants genetic test including APOE status, 3 bottles of RELEVATE, and a copy of the Brain Health Kitchen Cookbook 

References

  1. M. Di Battista, A., M. Heinsinger, N., & William Rebeck, G. (2016). Alzheimer’s Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function. Current Alzheimer Research, 13(11), 1200. https://doi.org/10.2174/1567205013666160401115127
  2. Fortea, J., et al. (2024). APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease. Nature Medicine 2024 30:5, 30(5), 1284–1291. https://doi.org/10.1038/s41591-024-02931-w
  3. Alzheimer’s: Is it in your genes? - Mayo Clinic. (n.d.). Retrieved September 11, 2023, from https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-genes/art-20046552
  4. Jeon, S. Y., et al. (2020). Midlife Lifestyle Activities Moderate APOE ε4 Effect on in vivo Alzheimer’s Disease Pathologies. Frontiers in Aging Neuroscience, 12, 507310. https://doi.org/10.3389/FNAGI.2020.00042/BIBTEX\
  5. Lee, M., et al. (2022). Education and Cardiovascular Health as Effect Modifiers of APOE ε4 on Dementia: The Atherosclerosis Risk in Communities Study. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 77(6), 1199. https://doi.org/10.1093/GERONA/GLAB299.
  6. Berkowitz, C. L., Mosconi, L., Rahman, A., Scheyer, O., Hristov, H., & Isaacson, R. S. (2018). Clinical Application of APOE in Alzheimer’s Prevention: A Precision Medicine Approach. The Journal of Prevention of Alzheimer’s Disease, 5(4), 245–252. https://doi.org/10.14283/JPAD.2018.35/METRICS
  7. Angelopoulou, Efthalia et al. “APOE Genotype and Alzheimer's Disease: The Influence of Lifestyle and Environmental Factors.” ACS chemical neuroscience vol. 12,15 (2021): 2749-2764. doi:10.1021/acschemneuro.1c00295
  8. Norwitz, N. G., Saif, N., Ariza, I. E., & Isaacson, R. S. (2021). Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers. Nutrients, 13(4). https://doi.org/10.3390/NU13041362
  9. Shannon, et al. (2023). Mediterranean diet adherence is associated with lower dementia risk, independent of genetic predisposition: findings from the UK Biobank prospective cohort study. BMC Medicine, 21(1), 1–13. https://doi.org/10.1186/S12916-023-02772-3/FIGURES/3
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