Navigating Alzheimers Risk: The Intricacies of ApoE and Beyond

Step into a world where your genes hold sway over your Alzheimer's risk. Did you know that 25% of North Americans carry a gene that could increase their Alzheimer's risk to a staggering 30%? Meet apolipoprotein E (ApoE), a gene with a profound impact on how our brains respond to stressors. In this article, we'll delve into the intricacies of ApoE, exploring its subtypes, the role they play in Alzheimer's disease, and how understanding your ApoE genotype can empower you to take proactive steps toward a healthier brain.
Reading Time: 14 minutes

Written By: Dr Michelle Leary, ND, IFMCP
Director of Functional Medicine at Vida Integrated Health

Step into a world where your genes hold sway over your Alzheimer’s risk. Did you know that 25% of North Americans carry a gene that could increase their Alzheimer’s risk to a staggering 30%? Meet apolipoprotein E (ApoE), a gene with a profound impact on how our brains respond to stressors. In this article, we’ll delve into the intricacies of ApoE, exploring its subtypes, the role they play in Alzheimer’s disease, and how understanding your ApoE genotype can empower you to take proactive steps toward a healthier brain.


Unveiling ApoE: The Architect of Brain Defense

The story of ApoE unfolds into three distinctive subtypes. To appreciate these subtypes, let’s take a moment to revisit the intricacies of gene inheritance. In our genetic blueprint, we inherit two sets of genes, one from our mother and one from our father. Some genes wield a potent influence on disease risk, known as autosomal dominant genes, but these are relatively rare, particularly if they lead to a severe pathological outcome, as evolution would have mitigated their prevalence.

On the other hand, certain genes exert a more subtle impact, influencing risks such as allergies, asthma, B vitamin activation, and even conditions like acne and autoimmune disorders. ApoE doesn’t fall into the deterministic category, yet it occupies a significant space that can heighten the risk of Alzheimer’s disease if one carries the at-risk subtype. ApoE, a genetic maestro orchestrating our brain’s defense mechanisms, comes in three subtypes: ApoE2, ApoE3, and ApoE4. Your unique combination of these subtypes significantly influences your Alzheimer’s risk. The combinations can vary, allowing for either identical subtypes or a mix, depending on the copies inherited from both parents.


ApoE3: The Average Guardian

ApoE3/E3, the most prevalent genotype, confers an average 9% risk of Alzheimer’s. Approximately 50-70% of North Americans fall into this category (Wu et al, 2016).

However, being average in health may not be ideal, urging us to explore personalized approaches to brain health.

ApoE2: The Rare Protector

ApoE2 carriers, a fortunate minority at less than 1%, enjoy a significantly reduced risk of Alzheimer’s (Wu et al, 2016).

Understanding your genetic rarity could be a game-changer in your quest for cognitive well-being.

ApoE4: The Risky Trailblazer

– ApoE3/E4, where one parent contributes the risk-increasing ApoE4, raises the stakes to approximately 30%.

– The ApoE4/E4, a mere 5 to 9% of the population, faces over a 50% lifetime risk of Alzheimer’s, making them the most vulnerable group.

The silver lining in this scenario is that there’s encouraging news: there are practical, preventive, and lifestyle-focused measures available now that could potentially be life-saving over the course of years to decades (Toups et al., 2022).


Unlocking the Genetic Code: ApoE4’s Influence on Alzheimer’s Risk

ApoE4, while historically advantageous against infections, poses challenges in the modern era. This genotype, tied to poor clearance of amyloid protein, plays a central role in Alzheimer’s development. When exposed to inflammatory stimuli, infections, or even food intolerances, ApoE4 carriers struggle to clear amyloid beta, leading to its accumulation in the brain.


What is Amyloid Protein?

Alright, imagine your brain as a busy city. There are different buildings (cells) and roads (neurons) connecting them, helping information to flow smoothly. Now, think of amyloid protein as a kind of construction material.

Amyloid protein is something that your brain makes naturally. It’s like the bricks your body uses to build structures in this bustling city of your mind. But, just like in any city, sometimes there can be too many bricks lying around.


The Protective Purpose of Amyloid Protein

Now, let’s imagine there’s an invader in this city – let’s call him Mr. Trouble (diseases, infections, and inflammation). When Mr. Trouble shows up, your brain wants to protect itself. This is where amyloid protein becomes a superhero.

Amyloid protein, like a shield, is produced by your brain to defend against Mr. Trouble. When the city (your brain) is under attack, more and more of this protective shield is created to keep the bad guy away. So, in a way, amyloid protein is like the brain’s own superhero suit, ready to fight off any threats. This is important for survival.


The Twist in the Tale: Alzheimer’s Disease

But, here’s where the story takes a turn. In some situations, especially if the city is under attack for a long time, too much of this shield (amyloid protein) starts piling up. Imagine if you kept building walls and walls, even when there was no more danger. The city would get cramped, right?

In the case of Alzheimer’s disease, too much amyloid protein can build up in the brain. Instead of being helpful, it starts to cause problems. It’s like having too many shields, and they start to get in the way of the normal workings of the city.


Why Does Amyloid Protein Play a Role in Alzheimer’s Disease Risk?

Now, the tricky part is that not everyone’s brain responds the same way to these situations. Some people’s brains are really good at cleaning up the extra shields (amyloid protein), while others may struggle.

If your brain has a specific type of gene called Apolipoprotein E4 (ApoE4), it might not be as good at cleaning up the extra shields. So, in people with this gene, the protective shields can pile up more easily, leading to a higher risk of problems like Alzheimer’s disease.

In a nutshell, while amyloid protein is like a superhero shield protecting your brain, having too much of it, especially if your genes are a certain way, might lead to trouble and increase the risk of Alzheimer’s disease.


Amyloid Protein – A deeper dive

Now that you get the concept of amyloid protein, how does ApoE4 influence the risk of Alzheimer’s disease? It plays a crucial role in the brain’s self-defense mechanism by generating extra amyloid protein. So why can’t we create a medication to help block extra amyloid protein deposition, you might ask? Unfortunately, despite substantial research investments (in the billions) and the pursuit of a “silver bullet” cure, pharmacological interventions have shown zero success in treating or reversing Alzheimer’s disease. The prevailing approach is akin to chemotherapy for terminally ill cancer patients – not curative but potentially buying time.

This is where physician-scientist Dale Bredeson, MD, a practicing neurologist, stepped in. Recognizing the complexity of Alzheimer’s disease and the various factors influencing amyloid protein, he developed RECODE and PRECODE programs. These initiatives are designed to assist clinicians and patients in identifying modifiable risk factors to reduce amyloid protein accumulation in the brain.

Individuals carrying the ApoE4 gene are predisposed to inefficiently clear amyloid protein after its deposition. This trait, evolutionarily advantageous over 200,000 years ago for resisting infections. In our modern era, where antivirals, antifungals, and antibiotics are prevalent, the benefits of this genetic influence are diminished.

When exposed to inflammatory stimuli, microbial infections, gut pathogens, or even food intolerances, individuals produce inflammatory proteins. These proteins circulate in the bloodstream and can accumulate in the brain. Another critical piece to consider is metabolic dysfunction, which contributes to the cumulative inflammatory effects on the brain. With conditions like “diabesity” affecting over 11% of the US population, the impact on the brain becomes substantial (Norwitz et al., 2021). Furthermore, less conventional forms of diseases, such as heavy metal exposure (Huat et al., 2019), chemical toxicity from mercury amalgams, contaminated seafood and water, and pesticide exposure like round-up (glyphosate) (Winstone et al., 2022), add to the complexity. In cases of chronic exposure to these environmental factors, the brain becomes immersed in a toxin-laden environment that amyloid protein attempts to shield against but struggles to fully protect from.

The concept of “leaky brain” and “leaky gut” involves disruptions in the integrity of the blood-brain barrier and the gut barrier, respectively, and their potential role in diseases such as Alzheimer’s. In Alzheimer’s disease, it is hypothesized that a compromised blood-brain barrier allows the entry of inflammatory substances into the brain, contributing to neuroinflammation and the accumulation of amyloid-beta plaques. Concurrently, a “leaky gut” scenario involves increased permeability of the intestinal barrier, allowing the passage of harmful substances, including bacteria and their byproducts, into the bloodstream. These substances may trigger systemic inflammation, affecting the brain through various mechanisms. The intricate crosstalk between the gut and the brain, known as the gut-brain axis, is increasingly recognized as a crucial factor in neurodegenerative diseases. Understanding and addressing these barriers’ integrity could unveil potential therapeutic avenues for Alzheimer’s and related conditions by targeting the underlying inflammatory processes associated with the leaky brain and gut phenomenon.

Intestinal and blood-brain barrier cross-talk highlights the connection between the brain and the gut. ApoE4 carriers struggle to efficiently clear amyloid beta, leading to faster accumulation compared to ApoE2 or ApoE3 carriers (O’Brien RJ, Wong PC., 2011). These amyloid protein segments aim to protect the brain from disease-causing stimuli. In chronic conditions, this protein continues to build up in the brain, potentially causing neurons to die over time and the brain to shrink, culminating in an Alzheimer’s disease diagnosis.


Does having an ApoE3 or ApoE2 genotype protect you from getting AD?

The straightforward answer is no. However, having an ApoE3 or ApoE2 genotype indicates that your brain’s ability to clear amyloid beta, a key player in AD, is superior to an ApoE4 carrier. Think of it like having a slightly larger bucket for inflammatory triggers, reducing risk but not eliminating it. Even ApoE2, with its “XL bucket,” can overflow. Alzheimer’s risk is a complex interplay of factors, including elusive ones like psycho-social influences—life purpose, meaningful relationships, and mental health (Ren et al., 2023).

Now, ApoE3 is the marker of the average person. But let me tell you, as a physician with nearly a decade of experience in the United States, aiming for average health in this country is not ideal. Proactively caring for your brain health should start as early as adulthood. While many of us didn’t give much thought to our health in our 20s, realizing the proximity of mid-life brings a new perspective. The good news is that it’s never too late to start. Your present actions will shape your brain’s tomorrow. We are dynamic organisms capable of regeneration, even in the brain—contrary to the prior belief that it couldn’t heal once damaged. Dale Bredeson’s groundbreaking work showcases the reversal of late-stage Alzheimer’s disease and the complete cessation of symptoms in those with mild cognitive decline (Toups et al., 2022, Bredeson, 2017).


Unlocking the Potential: The Ketogenic Diet for ApoE4 Carriers

For individuals carrying the ApoE4 gene, a ketogenic diet emerges as a potential ally in the quest for Alzheimer’s disease prevention. The ketogenic diet is characterized by a low-carbohydrate, high-fat intake, prompting the body to enter a state of ketosis where it primarily utilizes ketones for energy. This dietary approach holds promise for ApoE4 carriers due to its influence on metabolic pathways and brain health. Research suggests that a ketogenic diet may aid in reducing inflammation, a crucial factor in Alzheimer’s risk for ApoE4 carriers. By promoting the production of ketones, this diet offers an alternative energy source for the brain (besides glucose), potentially circumventing the challenges associated with the inefficient clearance of amyloid beta, a hallmark of Alzheimer’s in ApoE4 carriers.


Navigating the Nutritional Landscape: Foods to Avoid and Embrace

When it comes to Alzheimer’s disease prevention for ApoE4 carriers, dietary choices play a pivotal role. To safeguard brain health, certain foods are best avoided. High-carbohydrate, processed foods, and those with added sugars should be minimized, as they contribute to inflammation and may exacerbate the risk for Alzheimer’s.

Some foods can especially augment the vascular health of the brain and help with antioxidant and free radical balance. Nitric oxide, a signaling molecule, plays a multifaceted role in vascular regulation and neurotransmission. While its production is essential for maintaining healthy blood flow and cognitive function, an imbalance can contribute to oxidative stress and inflammation, key players in Alzheimer’s pathology. Nitric oxide-stimulating foods, such as leafy greens and beets, can potentially support proper vascular function. Antioxidants, found abundantly in fruits, vegetables, and nuts, act as a counterbalance by neutralizing harmful free radicals generated during nitric oxide synthesis. This delicate equilibrium underscores the importance of a well-rounded, antioxidant-rich diet in potentially modulating Alzheimer’s disease risk by addressing the intricate dynamics of nitric oxide regulation in the brain.


  • Leafy Greens: Spinach, kale, and Swiss chard are rich in nitrates, serving as precursors to nitric oxide, and contain antioxidants like vitamins A and C.
  • Beets: High in nitrates, beets can boost nitric oxide levels and provide antioxidants, including betalains.
  • Berries: Blueberries, strawberries, and raspberries are antioxidant powerhouses with compounds like anthocyanins and vitamin C.
  • Dark Chocolate: Cocoa contains flavonoids that stimulate nitric oxide production and acts as an antioxidant.
  • Citrus Fruits: Oranges, grapefruits, and lemons are loaded with vitamin C, a potent antioxidant.
  • Nuts: Almonds and walnuts contain arginine, a precursor to nitric oxide, along with vitamin E.
  • Garlic: Garlic promotes nitric oxide synthesis and possesses antioxidant properties.
  • Pomegranates: Pomegranate seeds are rich in antioxidants like punicalagins and anthocyanins, supporting nitric oxide production.
  • Green Tea: With catechins as antioxidants, green tea also aids in nitric oxide synthesis.
  • Turmeric: Curcumin, the active compound in turmeric, has antioxidant and anti-inflammatory effects, potentially impacting nitric oxide pathways.


Unveiling the Triad: Cardiorespiratory Fitness, Zone 2 Training, and Lean Tissue Mass in Alzheimer’s Prevention

In the quest to thwart Alzheimer’s disease, the symbiotic relationship between cardiorespiratory fitness, Zone two training, and the preservation of lean tissue mass emerges as a formidable trio. Cardiorespiratory fitness, often measured by VO2 max, reflects the body’s ability to utilize oxygen during physical activity—a metric intricately tied to brain health. Engaging in Zone two training, characterized by moderate intensity, becomes pivotal. This zone not only optimizes fat metabolism but also enhances mitochondrial function, a key player in brain health. Beyond aerobic capacity, the preservation of lean tissue mass, achieved through resistance training, serves as a protective shield. Lean tissue acts as a metabolic powerhouse, influencing insulin sensitivity and overall systemic health, both critical components in Alzheimer’s prevention.


Navigating the Ideal VO2 Max at 65: A Blueprint for Health Maintenance

As we age, maintaining an ideal VO2 max becomes a compass for sustaining health, particularly at 65. This measure signifies the maximum amount of oxygen the body can utilize during intense exercise. For health maintenance, a VO2 max around 30 ml/kg/min is often considered optimal at this age. This range aligns with the preservation of cardiovascular and cognitive function. It’s not just about the quantity of years but the quality, and a robust VO2 max at 65 can be indicative of a well-maintained cardiovascular system, contributing to Alzheimer’s prevention.


Centenarian Decathlon: A Testament to Longevity and Health by Peter Attia, MD

The Centenarian Decathlon, a concept championed by Peter Attia, MD, embodies the epitome of aging with vitality. Dr. Attia’s work underscores the significance of not just lifespan but healthspan—the duration of life spent in good health. By intertwining cardiorespiratory fitness, Zone 2 training, and the preservation of lean tissue mass, individuals can aspire to not only live longer but thrive in their later years. The Centenarian Decathlon serves as an inspiration, illustrating that the pursuit of optimal health is a marathon, not a sprint, and a strategic combination of physical fitness elements is the key to unlocking the doors to longevity and cognitive well-being.


Supplements to Support Cognitive Health

First on the list is phosphatidylserine, a phospholipid crucial for maintaining neuronal structure and function. Studies suggest that phosphatidylserine supplementation may enhance cognitive performance, reduce age-related cognitive decline, and support neurotransmitter activity, offering potential benefits for ApoE4 carriers.

Curcumin, the active compound in turmeric, is another promising supplement. Known for its anti-inflammatory and antioxidant properties, curcumin has demonstrated neuroprotective effects. It may inhibit the formation of beta-amyloid plaques, a hallmark of Alzheimer’s disease, and reduce neuroinflammation. Research indicates that curcumin could modulate pathways implicated in the progression of Alzheimer’s, making it a valuable supplement for ApoE4 carriers aiming to address the genetic risk.

Omega-3 fatty acids, particularly DHA and EPA found in fish oil, can be instrumental for ApoE4 carriers due to their anti-inflammatory effects. These fatty acids are integral to brain structure and function, and studies suggest that they may reduce the risk of cognitive decline. Additionally, Coenzyme Q10 (CoQ10) serves as an essential antioxidant and plays a role in mitochondrial function. As ApoE4 carriers may have compromised mitochondrial efficiency, CoQ10 supplementation could potentially support energy production and protect against oxidative stress. Lastly, vitamin D, with its anti-inflammatory properties, is essential for overall brain health and may contribute to reducing Alzheimer’s risk in ApoE4 carriers. The science supporting these supplements underscores their potential to address specific aspects of Alzheimer’s pathology and promote cognitive resilience in individuals with the ApoE4 genotype. Nevertheless, personalized healthcare guidance is crucial for optimizing supplement regimens based on individual health conditions and needs.


Hormones and Their Role in Alzheimer’s Disease Prevention

Hormone optimization, particularly with estrogen, progesterone, testosterone, and pregnenolone, plays a significant role in addressing Alzheimer’s disease risk, especially in individuals with an ApoE4 genotype. These hormones are crucial for various aspects of brain health, and their decline or imbalance may contribute to the pathogenesis of Alzheimer’s disease.

Estrogen, primarily known as a female sex hormone, exerts neuroprotective effects. It influences synaptic plasticity, enhances neurotransmitter activity, and has antioxidant properties. In women, the decline in estrogen during menopause has been associated with an increased risk of Alzheimer’s. For ApoE4 carriers, hormone replacement therapy (HRT) involving estrogen may be considered to mitigate this risk, although the decision should be made on an individual basis, weighing potential risks and benefits.

Progesterone, another female sex hormone, complements the effects of estrogen and has neuroprotective properties. It may modulate inflammation, reduce beta-amyloid deposition, and promote neurogenesis. Hormone optimization, either through natural means or supplementation, could be beneficial for maintaining cognitive function in ApoE4 carriers.

Testosterone, predominantly considered a male hormone, is also present in females at lower levels. It plays a role in synaptic plasticity, neuronal survival, and has anti-inflammatory effects. Testosterone decline with age may contribute to cognitive decline, and optimizing testosterone levels through hormone replacement therapy may be considered in individuals with ApoE4 genotype.

Pregnenolone, often referred to as the “mother of all hormones,” serves as a precursor to various hormones, including estrogen and testosterone. It has neuroprotective properties, influences neurotransmitter activity, and may enhance cognitive function. Hormone optimization involving pregnenolone may be a consideration for ApoE4 carriers to support overall brain health.

However, it’s crucial to note that hormone optimization should be approached with caution and personalized to each individual’s health profile. The decision to pursue hormone replacement therapy should involve thorough consultation with a healthcare professional who can assess the individual’s specific health status, risks, and potential benefits. Additionally, ongoing monitoring and adjustments to hormone therapy may be necessary to ensure optimal outcomes and minimize potential risks.


Crafting a Personalized Approach: Individual Considerations for Alzheimer’s Prevention

While the ketogenic diet, exercise and lean tissue building, hormone optimization, and targeted supplements show promise in Alzheimer’s prevention for ApoE4 carriers, it is essential to recognize the value of a personalized approach. Each individual’s response to interventions can vary, and consulting with a healthcare professional, particularly one versed in the nuances of neurodegenerative conditions, is crucial. Factors such as overall health, lifestyle, and genetic makeup should be taken into account when crafting a strategy for Alzheimer’s prevention. By combining dietary modifications with comprehensive lifestyle changes, individuals carrying the ApoE4 gene can embark on a holistic journey towards optimizing brain health and potentially mitigating Alzheimer’s risk.




“Diabetes by the Numbers.” Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/health-equity/diabetes-by-the-numbers.html#:~:text=37.3%20million%20people%20have%20diabetes,not%20know%20they%20have%20it. Accessed November 5, 2023.

O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci. 2011;34:185-204. doi: 10.1146/annurev-neuro-061010-113613. PMID: 21456963; PMCID: PMC3174086.

Toups K, Hathaway A, Gordon D, Chung H, Raji C, Boyd A, Hill BD, Hausman-Cohen S, Attarha M, Chwa WJ, Jarrett M, Bredesen DE. Precision Medicine Approach to Alzheimer’s Disease: Successful Pilot Project. J Alzheimers Dis. 2022;88(4):1411-1421. doi: 10.3233/JAD-215707. PMID: 35811518; PMCID: PMC9484109.

Wu L, Zhao L. ApoE2 and Alzheimer’s disease: time to take a closer look. Neural Regen Res. 2016 Mar;11(3):412-3. doi: 10.4103/1673-5374.179044. PMID: 27127474; PMCID: PMC4829000.

Norwitz NG, Saif N, Ariza IE, Isaacson RS. Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers. Nutrients. 2021 Apr 19;13(4):1362. doi: 10.3390/nu13041362. PMID: 33921683; PMCID: PMC8073598.

O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci. 2011;34:185-204. doi: 10.1146/annurev-neuro-061010-113613. PMID: 21456963; PMCID: PMC3174086.

Huat TJ, Camats-Perna J, Newcombe EA, Valmas N, Kitazawa M, Medeiros R. Metal Toxicity Links to Alzheimer’s Disease and Neuroinflammation. J Mol Biol. 2019 Apr 19;431(9):1843-1868. doi: 10.1016/j.jmb.2019.01.018. Epub 2019 Jan 18. PMID: 30664867; PMCID: PMC6475603.

Winstone JK, Pathak KV, Winslow W, Piras IS, White J, Sharma R, Huentelman MJ, Pirrotte P, Velazquez R. Glyphosate infiltrates the brain and increases pro-inflammatory cytokine TNFα: implications for neurodegenerative disorders. J Neuroinflammation. 2022 Jul 28;19(1):193. doi: 10.1186/s12974-022-02544-5. PMID: 35897073; PMCID: PMC9331154.

Bredesen D. The End of Alzheimer’s. Avery; 2017.

Ren Y, Savadlou A, Park S, Siska P, Epp JR, Sargin D. The impact of loneliness and social isolation on the development of cognitive decline and Alzheimer’s Disease. Front Neuroendocrinol. 2023 Apr;69:101061. doi: 10.1016/j.yfrne.2023.101061. Epub 2023 Feb 8. PMID: 36758770.

Want to schedule and appointment but unsure about your coverage? Easily find out by using our contact us form. We will check your coverage and send you the results!

Contact Us

Related Articles

© 2022 Vida Integrated Health. All Rights Reserved.
This website uses cookies for Marketing Purposes. To learn more, see our Privacy Policy.