By Julie Gregory, Chief Health Liaison for Apollo Health

The Ancestral ApoE4 Gene: Friend or Foe? takes a deep dive into the history and mechanisms of ApoE4. As an ApoE4 homozygote and founder of ApoE4.Info, who devoted the past ten years to learning all that I can about the gene, I’m excited to take the next step by examining the ApoE4 mechanisms that can lead to pathology and discussing ways that we can manage and harness them to extend our healthspan. I firmly believe that ApoE4 can be your friend and that even non-ApoE4 carriers can improve their overall health and cognition by following our approach.

First, it’s important to keep in mind that the ApoE4 allele is NOT deterministic. Many with the gene never go on to develop Alzheimer’s and many without the gene do. While you may be at risk genetically, the great news is that you have control over how your genes are expressed. Indeed, the science behind epigenetics — the study of how your behaviors and environment can cause changes that affect the way your genes work — is very real.

Statistics suggest that one copy of ApoE4 can increase your risk of developing Alzheimer’s two to threefold, whereas two copies can increase your risk eight to twelvefold as well as increase your risk for coronary artery disease in a dose-dependent fashion. Fortunately, you now have the tools to greatly reduce that risk by adopting the Bredesen Protocol and practicing the Bredesen Seven. Because Dr. Bredesen has worked with many ApoE4 carriers who’ve been able to reverse symptoms in the early stages (like me), we’re adding further proof of the validity of this approach and the power of epigenetics. In fact, a sub-group analysis of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) demonstrated that ApoE4 carriers made better and faster cognitive improvements compared to non-ApoE4 carriers.   

If you carry a copy or two of ApoE4, you are in rare company. Somewhere around 25% of the world’s population carries a single copy, whereas less than 2% carry two copies. We all get one APOE copy (commonly ApoE2, 3, 4) from each of our parents. ApoE4 is the ancestral or original version of the APOE gene. Over time, other common variations (alleles) of the gene have emerged — E3 (which is thought to be neutral) and more recently E2 (which is thought to be protective.) ApoE4 wouldn’t still be in circulation if it didn’t offer some advantages. Unfortunately, with our modern lifestyle, it also can confer disadvantages. Our job is to try to harness the benefits while minimizing the disadvantages.

Prior to the groundbreaking work from Drs. Bredesen and Ram Rao (our principal research scientist), it was thought that this gene was just involved in carrying lipids. We now know that it is a transcription factor, which also influences the expression of many other genes. This is more good news for ApoE4 carriers, because it further confirms that our epigenetic practices can help to exert control over how our “risky” gene is expressed.

In ApoE4 Positive: Now What?, Apollo Health subscribers can read about the specific mechanisms that lead to ApoE4 pathology along with a detailed list of strategies to turn each potential deficit into a benefit. The great news is that there’s tremendous overlap between all of the recommendations, even those activating different mechanisms and for different body systems including the brain and heart. A decade ago, I was told that I would have to choose between my brain and heart when trying to reverse my cognitive decline. Researchers were beginning to understand that ketosis could benefit the brain but were convinced that the dietary approach would lead to heart disease. It made no sense to me that an ancestral gene could have such different requirements. Indeed, we’re finally arriving at a consensus on how to increase our overall healthspan and turn a gene that was once associated with antagonistic pleiotrophy (which promotes wellness and fitness early in life at the expense of longevity) into a modern-day benefit. Below see my top five strategies for ApoE4 carriers to protect our brains, hearts, overall health, and increase longevity.


Top Five Strategies for ApoE4 Carriers

  • Maintain metabolic health. Maintaining metabolic health is key as it will protect your brain by providing fundamental fuel while also protecting against heart disease. While you may initially need to use supplements or medications to help support the transition to metabolic health, the optimal method involves aligning with ApoE4 ancestors by using the KetoFLEX 12/3 Lifestyle.
  • Use the modified KetoFLEX 12/3 Lifestyle. The KetoFLEX 12/3 Lifestyle, which combines our plant-rich KetoFLEX 12/3™ diet with exercise and fasting on a foundation of quality sleep, will help to optimize your metabolism and fuel your brain, while also protecting your heart. This approach will naturally lead to the creation of endogenous ketosis. To better align with our ancestral gene, ApoE4 carriers may want to modify this approach by slowly extending their daily fast to 16+ hours and increasing daily exercise rather than relying heavily upon higher amounts of dietary fat. Early man fasted for long periods when food was scarce and moved throughout the day to find food. This modification works beautifully as long as you can maintain a healthy weight with strong muscles. When increasing healthy fats, limit saturated fat and instead use high polyphenol EVOO, avocados, nuts, seeds, and low mercury wild-caught fatty fish.
  • Reduce Inflammation. Because the ApoE4 gene is pro-inflammatory, it’s vital to adopt frontline strategies to reduce inflammation.
    • Avoid inflammatory foods. This includes any that are processed or refined with inflammatory industrialized oils, all sugars, simple carbohydrates, conventional dairy, and grains. None of these foods are aligned with the ancestral ApoE4 allele.
    • Prevent leaky gut. Avoid the foods above along with any that cause sensitivities or allergies. Additionally avoid alcohol and smoking, while also minimizing stress. Use prebiotic fiber, small amounts of resistant starch (as tolerated), and probiotic foods to optimize the microbiome and overall gut health, as well as pastured bone broth several times per week.
    • Optimize metabolic health. The ancestral formula to achieve this goal is described above in the modified KetoFLEX 12/3 Lifestyle.
    • Maintain good oral health. You can do this by increasing professional cleanings to 3x per year, avoiding gum disease, considering an oral care probiotic, and proactively addressing cold sores (HSV-1) with a preventative regimen.
    • Exercise ancestrally. Early man was constantly on the move searching for food, interspersed with periods of more intense exercise during a hunt. We can do our best to mimic an ancestral exercise plan by avoiding a sedentary lifestyle, moving throughout the day, and including at least 30 minutes of daily aerobic exercise, preferably outdoors, with strength training 3 to 4 times per week. 
    • Manage stress. Chronic unresolved stress increases cortisol, which in turn elevates inflammation. Use any or all of the strategies that we regularly discuss including mindfulness, meditation, breathing breaks, gratitude, the Dynamic Neural Retraining System, along with HeartMath to measure your progress.
    • Consider low-dose naltrexone. Low-dose naltrexone (LDN) can safely upregulate endorphins naturally reducing inflammation throughout the body and helping to modulate immunity. This is also used to treat a variety of conditions and is typically prescribed by a functional physician. You can see Dr. Bredesen hosting a Facebook Live entitled Low-Dose Naltrexone(LDN): Why it Works so Well.
  • Identify and address potential Alzheimer’s contributors. This is fundamental for not only reducing inflammation but for addressing all potential brain insults which can lead to increased Aβ and tau aggregation and reduced clearance. We can do this by following the Bredesen Protocol® and the Bredesen Seven.
  • Work to reduce Aβ and tau aggregation and promote clearance. Research has revealed specific strategies that can help to do both. This is fundamental for also avoiding cerebral amyloid angiopathy (CAA), well-known to be associated with ApoE4, in which Aβ accumulates in arteries of the brain and can lead to hemorrhagic stroke. See CAA: Notes from the Frontlines for a list of additional strategies to avoid this condition. 
    • Sleep Quality restorative sleep has been shown to help reduce Aβ and tau by upregulating the glymphatic system. Side sleeping also helps to promote clearance.
    • Curcumin Research shows that curcumin prevents Aβ and tau aggregation and can cross the blood-brain barrier to protect neurons from various toxic insults of aging. It’s important to use a supplement brand that is bioavailable. Dr. Bredesen recommends 1 gram taken once or twice daily.
    • Extra Virgin Olive Oil A recent clinical trial showed that extra virgin olive oil (EVOO) not only helped to promote Aβ and tau clearance, but also enhanced the blood-brain blood barrier function, and actually improved cognition. Always try to use the highest polyphenol content that you can tolerate. These can be quite peppery and even cause a small amount of burning in your throat but can be delicious once you become acclimated.
    • Fasting A long daily fast is a primary component of the plant-rich KetoFLEX 12/3 diet. Everyone is encouraged to fast for a minimum of 12 hours daily, with at least three hours before bedtime. ApoE4 carriers are encouraged to extend this daily fast to 16+ hours — only if they can maintain a healthy weight with strong muscles. This helps to promote autophagy, a natural cellular process that helps to prevent Aβ and tau aggregation and helps to promote their clearance.
    • Aerobic exercise Aerobic exercise confers many neuroprotective benefits including increased cerebral blood flow, upregulated brain-derived neurotrophic factor (BDNF), and reduced Aβ plaques and tau aggregation. As a part of exercising ancestrally (described above), ApoE4 carriers should target a minimum of 30 minutes of aerobic exercise daily, preferably outdoors to glean the additional benefits of spending time in nature.

An explosion of ApoE4 research lends truth to the adage Knowledge is Power. As recently as a decade ago, researchers and physicians didn’t recommend that patients learned their APOE status because they believed that “nothing could be done” for ApoE4 carriers. Sadly, those who’ve not kept up with more recent developments are still providing this antiquated advice. You now have the power in your hands to lead a long, healthy, and productive life by understanding and aligning with your ancestral gene. To learn more, read The End of Alzheimer’s Program or consider a free 30-day trial of PreCODE (for prevention) or ReCODE (for reversal).

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