APOE, short for Apolipoprotein E, is both a protein and a gene. As a protein ApoE is involved in the metabolism of fats (lipids) in the body and comes in different isoforms: ApoE2, ApoE3, ApoE4. As a gene it is polymorphic, that is to say a gene with multiple variations called alleles. They go hand in hand, the ApoE gene tells the body how to make the ApoE protein. To distinguish the allele from the protein the lower case Greek letter epsilon “ε" is sometimes added. The three ApoE alleles are: ApoE ε2, ApoE ε3, and ApoE ε4.
Everyone gets one allele from their mother and another from their father. For example, when someone says they are a 3/4, that means one ApoE ε3, and one ApoE ε4. When someone says they're homozygous, they're a 4/4, if heterozygous they're either a 2/4 or a 3/4.
The ApoE ε4 allele is the oldest of the ApoE variants, having existed literally since the dawn of man. For 96% of human history, we were all ApoE4 homozygotes (ε4/4s). The other alleles showed up “recently” in evolutionary terms. ApoE3 appeared 220,000 years ago, it now dominates in numbers, and 80,000 years ago ApoE2 appeared.
From APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics (Mohammed Amir Husain et al, 17 Feb 2021)
- The world-wide frequency of human APOE alleles varies considerably. APOE3 is the most common among all human populations and its frequency ranges from 85% (Asia) to 69% (Africa) (Singh et al., 2006). APOE4 allele frequency varies considerably in native populations of Central Africa (40%), Oceania (37%), and Australia (26%) (Corbo and Scacchi, 1999). The distribution across Europe and Asia follows an apparent gradient from north to south, with low APOE4 allele frequencies in the Mediterranean or South China and higher frequencies in northern regions (up to 25%) (Egert et al., 2012). APOE2 is the least common allele with a global prevalence of 7.3% and is absent in many indigenous people without any clear regional pattern (Corbo and Scacchi, 1999; Singh et al., 2006).
It’s theorized that the ε4 allele was quite beneficial in allowing early man to survive through variable food availability and inflammatory conditions like wounds and walking on dung. But in today’s world of plentiful, industrially produced, artificially sweetened, processed food, environmental insults, artificial lighting, high stress, low sleep, sedentary lifestyle, and other factors, the gene doesn’t seem to be responding well. In our modern environment, the ε4 allele of the gene confers a higher risk for Alzheimer's disease and other medical conditions.
These pages have been created in order to organize information about how to prevent and address health problems related to the APOE-ε4 allele. We try our best to aim these at the non-scientist, but the nature of this disease requires some scientific references and terminology to back up these approaches. We've created a list of abbreviations and acronyms to help you in your reading. For simplicity, we often refer to the APOE-ε4 allele as ApoE4 or E4 and Alzheimer's Disease as AD.
If you want to check your E4 status
Before you get tested, we encourage you to read our post Thinking About Testing? Always good to go in with an informed view of what the results might mean for you.
Many labs can test your APOE status. Search the Web to find the most up-to-date options for testing.
You can also look at the raw genetic data from a company such as 23andMe and look up your results for rs429358 and rs7412. These are referred to as SNPs, which represent variations in your DNA. Once you look up your values for these SNPs, go to this page at snpedia to help you convert the results into your APOE status.
Just found out you're an E4 carrier?
- If you are new here, we encourage you to read our Welcome Page. Many of our members are E4 carriers and grappled with many of the same questions you might have today.
- For the quickest set of preventive strategies, we put together this summary list, and the steps are related to improving brain health as well as overall health.
- For a great overview about E4, please check out our primer on our forums. It is authored by a member physician who carries two copies of the APOE-ε4 allele, and it offers accessible science background and prioritized, sensible preventative measures.
Note: We know it can be devastating to find out your E4 status, given the inevitable decline with advanced Alzheimer's and the current lack of effective pharmaceutical treatments for it. But we have created ApoE4.Info to help search, organize, and share what we do know about prevention and addressing the early symptoms of AD. As you read through these pages and the forum, you will come to see that there is so much you can do for yourself and your loved ones.
What you need to know about E4 and...
Risk of developing Alzheimer's disease
Many new members want a sense of their lifetime risk. This study (Emmanuelle Genin, et al.) looked at 7,351 cases and 10,132 controls and reported:
"At the age of 85 the LTR [long term risk] of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers..." So, part of your risk is also based on gender - women are more at risk than men.
Although being an E4 carrier increases the risk, the number one risk factor for AD is not E4, but aging! According to Genome-Wide Association Study of Brain Connectivity Changes for Alzheimer’s Disease (Samar S. M. Elsheikh, et al Jan 2020) the effects of ApoE4 account for only 27.3% of the overall disease heritability. Research shows that Alzheimer’s takes a long time to develop and is influenced by numerous factors that can increase risk or provide protection, of which ApoE4 is only one factor. There are many modifiable risks that you can control.
Decreasing the Population Risk of Dementia: A 2014 study by a team of U.K. and USA authors reviewed the “Potential for Primary Prevention of Alzheimer’s Disease.” Seven potentially modifiable risk factors having consistent evidence were: diabetes, midlife hypertension, midlife obesity, physical inactivity (sedentary), smoking, depression and educational attainment (curiously diet is not separately identified). Considering that the risk factors were not independent they accounted for nearly 30% of Alzheimer’s cases with physical inactivity being the largest proportion in the UK, USA, and Europe. “Risk factors associated with the onset and progression of Alzheimer’s disease: A systematic review of the evidence,” by Mona Hersi, et al, was published in the Journal of Neuro Toxicology, https://doi.org/10.1016/j.neuro.2017.03.006). Ninety three primary reviews of studies on risk factors covering four hundred and thirty two studies published between 2010-2012 were evaluated. “Highlights are: Inherited or “familial” cases of Alzheimer's account for less than 5% of all cases, Several factors including age, head injuries, smoking, lower social engagement, sedentary lifestyle, and the APOE e4 gene are associated with increased risk, Several factors including statins, light to moderate alcohol intake, physical and cognitive activities and APOE e2 gene are associated with decreased risk. A number of risk factors are potentially modifiable and may be targeted for prevention.
A 24 expert paper in the medical journal Lancet looked at the global burden of dementia and made recommendations about strategies to reduce number of individuals affected. Nonmodifiable risk factors account for 65% of dementia, including a 7% contribution for ApoE𝟄4. Modifiable factors include:
Early Life (<18)
Low Education RR 1.59 PAF 8%
Middle Life (18-65)
Hypertension RR 1.6 PAF 2% Hearing Loss RR 1.9 PAF 9% Obesity RR 1.6 PAF 1%
Later Life (>65)
Smoking RR 1.6 PAF 5% Depression RR 1.9 PAF 4% Physical activity RR 1.4 PAF 3% Social Isolation RR 1.6 PAF 2% Diabetes RR 1.5 PAF 1%
RR is relative risk, PAF is population attributable fraction
Although low educational achievement doesn’t have a particularly high relative risk it is very common globally and thus has a higher impact on the population. Although hearing loss wasn’t considered a risk factor it is associated with dementia and is quite common. Some of the factors that those of us in the west may concentrate on may contribute less to the population burden of dementia.
Livingston et al Lancet 2017; 390: 2673-734 (Available free online with registration)
A graphic can be seen at http://www.thelancet.com/infographics/dementia2017.
Other health conditions besides Alzheimer's
The ε4 variant of the ApoE gene is famous for its association with Alzheimer’s Disease but other conditions have also been linked to it: other forms of dementia, other brain disorders, high cholesterol, cardiovascular disease, infectious disease susceptibility, and gallstones.
Of non-white or non-European descent
Minorities are underrepresented in health studies, most research on APOE-ε4 and Alzheimer’s has been conducted on white subjects of European descent. Further compounding this situation is that much of the research conducted on health conditions that affect ApoE4s: Alzheimer’s, Cardiovascular disease, shortened longevity, etc. often do not stratify by APOE status much less racial/ethnic status. One would think genes are color blind, and yet there are differences in non-European ApoE4s. So what to believe? This wiki is dedicated to sharing what research is available.
Main Article: Non-white or non-European descent
If there is just one strategy an ApoEε4 can pursue, it should be reducing Insulin resistance. Insulin Resistance (IR) is the root of many health concerns, particularly those to which ApoEε4s are susceptible. Insulin Resistance is very common, it’s been estimated 50% of the US population has it. IR develops slowly (over decades), silently, and typically goes undiagnosed. Insulin resistance (IR) does not equal Type 2 Diabetes (T2D), although T2D is one of the possible end points of insulin resistance. A person can have what is conventionally thought of as good blood glucose (blood sugar) levels, feel that they’re healthy, but be insulin resistant. Understanding insulin resistance and the strategies to improve insulin sensitivity is vital to ApoEε4 health. Studies have shown that everybody who has Alzheimer’s Disease has insulin resistance in the brain whether or not insulin resistance exists elsewhere in the body.
Insulin Resistance in the brain
- The brain needs a lot of fuel, more than any other organ in the body, and it needs it 24 hours a day. Insulin is critical to providing the brain with the adequate amount of energy it needs. There is a clear connection between insulin resistance and Alzheimer’s Disease. The term Type 3 Diabetes was coined over 10 years ago to describe Alzheimer’s Disease and the moniker still persists today, having only been reinforced with further research.
Main Articles: Insulin Resistance and
Getting a good night's rest is a critical component of brain health. Good sleep helps remove amyloid beta (Aβ) and reduces oxidative stress. Sleep deprivation increase plaque formation and Aβ aggregation. There is some limited evidence that supplemental melatonin is effective in slowing the progression of MCI and Alzheimer's.
Main article: Sleep
Exercise is good for the brain as well as the body. Exercise in some form or another is probably more critical for ApoE4s than other genotypes.
Main article: Exercise - Types, Lengths, and Benefits
The four pillars to prevent/reverse cognitive decline are: Diet, Exercise, Sleep and reducing Stress. The body’s response to stress provides protective measures when the stress is short lived, but modern western lifestyle subjects us to multiple and constant stressors. Constant stress over the long term is damaging to the entire body, not just the brain and ApoE4s seem to be even more susceptible to the negative effects of stress.
Main article: Stress
Mitochondria produce energy for our bodies, particularly the energy hungry brain. Mitochondria also contribute to potentially harmful oxidative stress. When the balance between producing beneficial energy and damaging oxidative stress is disrupted, mitochondria become damaged and can enter a downward spiral of degraded energy production resulting in even greater damaging effects. Mitochondrial dysfunction is a major determinant in how we age, is a key factor in a myriad of diseases, and in particular is one of the earliest and most prominent features of Alzheimer’s Disease.
Main article: Mitochondria
Ketosis and Ketogenic diet
The brain typically gets its energy from glucose (blood sugar), but ketone bodies (ketones) are the brain's main reserve fuel when glucose supply is compromised. Since the uptake of glucose is compromised in Alzheimer’s, a number of ApoE4s have adopted strategies to encourage “metabolic flexibility” which allows the body to easily switch between glucose to ketones to fuel the brain in order to regain or maintain cognitive ability. But ketosis has medical benefits beyond just providing an source of energy for the brain, it also reduces inflammation. Ketosis is one of the strategies recommended by Dr Bredesen who has reversed cognitive decline. See also Bredesen Protocol.
Main article: Ketosis and Ketogenic Diet
Fats, Omega-3 &-6, DHA and more
A common diet recommended for ApoE ε4s is the Mediterranean diet because it is high in monounsaturated fats. Another commonly recommended diet is a high fat diet Ketosis_and_Ketogenic_Diet. We know to stay away from unhealthy fats, and saturated fats are said to be ill-advised for ApoE ε4s, but which fats truly are unhealthy?
Additionally, there’s the Omega-3 (also written as ω-3) and Omega-6 (also written as ω-6) factor. Research has shown that polyunsaturated fats high in Omega-3s especially DHA, are critical contributors to cell structure and function in the nervous system suggesting supplementation may slow early memory decline in ε4 carriers. Then there are Omega-6s which are inflammatory, something ApoE ε4s already have a susceptibility towards.
All these factors to consider when trying to follow a healthy diet, and all these terms: Saturated, Polyunsaturated, Omega-3s, Omega-6, DHA,… it can make a head spin. This article attempts to provide understandable background information on dietary fats as well as opportunities and pitfalls that ApoE ε4 should be aware of to maximize healthy fat intake.
Main article: Fats, Omega -3(ω-3) & -6(ω-6), DHA and More
Cholesterol, Lipids and Treatments, including statins
"This is a horrendously complex topic...GLYCAEMIC CONTROL TRUMPS LIPIDS, EVERY TIME. (Read Insulin Resistance for info on glycemic control). You have been dealt a hand of cards. You need to play them cleverly. IR (Insulin Resistance) is far more damaging than a high LDL, but LDL still matters. We are on a seesaw trying to balance these two. The balance point will be different in everyone." - Stavia, as posted in the Primer. E4s are at higher risk of cardiovascular disease, yet cholesterol is an important component in brain health. How do we resolve the two?
Main Article: Cholesterol, Lipids and Treatments, including statins
Gut-Brain Connection: Leaky Gut/Leaky Brain, Microbiome (gut bugs)
Health of the gut plays an important role in the health of the brain. Inflammatory lifestyle and dietary habits can lead to a disrupted gut microbiome and a “leaky gut.” Leaky gut, in turn, can lead to “leaky brain” which triggers neuroinflammation. Additionally, research shows that there is a difference in microbiota diversity and abundance for ApoE4s.
Hormone Replacement Therapy
Information coming soon...
MTHFR gene, methylation and homocysteine
There may be an increased risk of carrying both ApoE4 and MTHFR variants. This provides an overview of methylation, methylation genes such as MTHR, and hacking methylation problems including high homocysteine.
Main article: Methylation
Correlative studies have shown that regular consumption of a small amount of alcohol is linked to a number of health benefits, especially cardiovascular benefits, which are correlated with reduced risk of dementia. But the studies are not all consistent, and many researchers speculate that there are too many confounding factors to be able to adequately isolate the effect of alcohol consumption.
More importantly, when the results are stratified by APOE variant, most studies show that even small amounts of alcohol cause harm to ε4-carriers.
Main article: Alcohol consumption
Recommended lab tests and all about biomarkers
From our threads and the research, we've distilled out some important lab testing to start with in order to understand your overall health and give a sense of where to start treatment. We've also included descriptions of various biomarkers and their relevance to ApoE4 carriers.
Common lab tests list is coming... in the meantime, there's a summary of key tests for ReCode Protocol Taken from Dr Bredesen's book The End of Alzheimer's in the Bredesen Protocol write-up.
Main article: Biomarkers
The Bredesen Protocol (ReCODE)™ explained for laypeople
Dr. Dale Bredesen Dr. Bredesen has created a protocol that involves multiple interventions to address specific components of AD pathology that research has identified to date. Each intervention is measured and tweaked over time by using blood tests, cognitive evaluations, and other markers of overall health improvements. His analogy is to think of AD as a leaky roof - there are as many as 36 leaks in in the AD roof that need to be addressed to stop the problem. Not every patient will have the same leaks, and the protocol is customized based on the patient’s genetics, current health, and lifestyle.
Main article: Bredesen Protocol.
Here is a summary of Bredesen's book, The End of Alzheimers': http://soler7.com/IFAQ/TheEndOfAlzheimers.html
Dr Steven Gundry
Dr Steven Gundry Wikipedia Gundry has been referenced often within the ApoE4.info forums. He is not an “Alzheimer’s doctor”; he is a cardiothoracic surgeon who, in 2002, changed the direction of his career from surgically repairing the damage of disease to a functional medicine approach of helping patients repair their own bodies with food and supplementation. Shortly after this career change, Dr Gundry began testing for ApoE4 status among the many blood tests on his patients. He has followed thousands of patients with one or two ApoE4 alleles, testing blood markers every three months and advising diet/supplementation accordingly to maintain healthy cholesterol levels, inflammatory markers, cognitive ability, etc. For his specific recommendations for ApoE4s see Dr Steven Gundry’s protocol.
Main article: Dr Gundry's Protocol.
Scientific support for a high protein diet
Individual differences aside (though very important), some forum members find the literature and concepts supporting a higher protein, higher leucine diet in the absolute sense to be more persuasive than the epidemiological studies used to underpin low protein recommendations. Caveats can include implementing higher protein in a way that avoids chronic stimulation of mTOR and choosing traditionally raised meat, eggs and dairy. From this perspective, Don Layman and other long-time protein metabolism researchers have 1) presented a cogent case supporting near lifelong higher protein intakes that should be considered when formulating a personal protocol, and 2) established that the need for protein above the RDA will apply one way or another to nearly everyone if not everyone. Animals are preferred for a number of reasons, but plant proteins can be combined to support protein metabolism in vegetarians and vegans.
Main article: Scientific support for a diet higher in protein than the RDA.
BDNF Brain Derived Neurotrophic Factor
Brain Derived Neurotrophic Factor is produced by neurons and regulates synaptic transmission in the hippocampus. It promotes neurogenesis and nerve growth. Because it plays a critical role in neuronal survival, synaptic plasticity, and memory, BDNF reduction may contribute to synaptic and cellular loss and memory deficits characteristic of Alzheimer’s Disease. BDNF might also explain some of the increased risk of AD in women.
Main article: BDNF
There is substantial evidence that controlling blood sugar (also known as blood glucose) levels can have a great impact on the risk of developing dementia.
Main article: Blood Sugar
Cannabinoids, Cannabidiol (CBD), THC, HEMP, Marijuana, Cannabis
Products from cannabis plants (both hemp and marijuana) offer many health benefits of interest to ApoE4 carriers and can enhance a program addressing lifestyle strategies. From decreasing Amyloid-beta plaque, offering neuroprotection, aiding in generating new neurons, lowering inflammation, assisting with insulin sensitivity, helping with stress, improving sleep and helping maintain hormonal balance.
Coffee (and caffeine)
Much evidence exists that coffee consumption, and caffeine in general (tea will be considered separately), seems to offer some protection against many forms of dementia, including Alzheimer's, regardless of ApoE status.
Main article: Coffee (and caffeine)
Coconut Oil, MCT oil, and other Ketone/Cognition Boosters (salts, esters)
Ketones are a source of fuel for the body, especially the brain. With certain dietary/lifestyle approaches the body can make its own ketones but there are also products that can be consumed for rapid conversion to ketones in the body to aid brain function: coconut oil, MCT oil, salts, esters etc. There are positive and negative aspects to using these products as well as particular considerations for ApoE ε4s.
Inflammation and LPS (lipopolysaccharides)
Inflammation plays an important role in the pathology of AD. Inflammation can be beneficial, but when left unchecked, inflammation becomes detrimental. “Lipopolysaccharides (LPS), also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals” (Wikipedia). The Wikipedia page also reports that humans are much more sensitive to LPS than other animals. Lipopolysaccharides are known to induce inflammatory responses and are often used to induce central nervous system inflammation in mouse studies.
Main article: Inflammation & LPS
Oxalates, a potential problem for Keto, Paleo and vegan diets
Most people have heard of oxalates because of their connection to kidney stones. Or perhaps with regards to spinach, because the calcium in spinach is bound by oxalates, and not considered a good source of calcium. Here's some background on what makes oxalates so toxic to humans and why they might be the missing link to improving your health.
Main article: Oxalates
Resveratrol treatment has been shown to reduce neuronal inflammation and improve cognitive performance by mitigating reactive oxygen species, inhibiting pro-inflammatory molecules such as cyclooxygenase-1, or COX1, and inhibiting beta-amyloid plaque formation and aggregation.
Main article: Resveratrol
Sirtuins are crucial cellular proteins that hold sway over a broad range of physiological processes, including circadian regulation, anti-inflammatory activity, metabolic adaptations, and neurological protection. As such, they present a promising therapeutic strategy to ameliorate age-related diseases and extend healthspan. The focus of current sirtuin-related research is centered on the use of NAD+ supplementation or sirtuin-activating compounds such as resveratrol to boost sirtuin activity to revert the disease process and promote healthy aging.
Main article: Sirtuins
Thiamine, sometimes spelled thiamin, is also known as vitamin B1. Preliminary evidence suggests that it could help improve the brain's mitochondrial activity by helping optimize its glucose metabolism. Glucose metabolism is compromised in ApoE4 individuals.
Main article: Thiamine
Turmeric and curcumin
There is evidence that tumeric and in particular one of its components, curcumin, might protect against Alzheimer's and other forms of dementia.
Main article: Turmeric and curcumin
The vagus nerve is a primary carrier of information describing the state of the body to the brain, and also transmits information from the brain back to the body. In 2000, neurosurgeon Kevin Tracey published the results of an experiment where anti-inflammatory drugs in the brain blocked inflammation in the spleen and other organs. He concluded that the brain used the vagus nerve to return the immune system to a place of homeostasis. Researchers are looking to see how the vagus nerve might be used to treat a variety of diseases including cardiovascular disease, autoimmune disease, and Alzheimer's, along with how stimulating the nerve might lead to better health.
Main article: Vagus Nerve
Standard advance directives don't adequately address medical scenarios faced by dementia patients; at the same time, these patients may no longer have the executive functioning necessary to think such decisions through when the need occurs. Consequently, countless Alzheimer's and other dementia patients are not necessarily given the care they would desire at different stages of the disease, while caregivers can suffer deep anxiety trying to guess what their loved one with dementia would want. This section provides a free dementia advance directive form you can fill out and add to your other end-of-life papers. It also provides links to online discussions of the issues that people may want to consider.
Main Article: Advance Directive for Dementia
A "How-To" guide for new and not-so-new members. We hope you will browse this user-friendly guide. It includes screenshots and step-by-step directions for such useful actions as posting on the site, using quotes to notify members of a response to their post, using hyperlinks to articles or other forum topics, subscribing to a favorite topic, and using Private Messages. Link to the Guide: "How-To" Get the most out of the ApoE4.info website
What can I eat? Recipes from our members and Recommended food websites/blogs
Health coaching is a client-centered process in which the client determines their own path and the coach provides the support and encouragement to make positive and lasting lifestyle changes. Coaches guide the client to create a vision for their health and help them set goals to achieve that vision. Coaches can supply information and education, work with clients to explore options, brainstorm, prioritize, set goals, help them stay accountable, explore barriers, and celebrate successes. For improving or preventing cognitive decline, health coaches can support clients as they learn about healthier lifestyle options and work to improve their diet, exercise, sleep, relaxation, social engagement or any other habits to reach their health goals. Note: coaches will most likely will not be physicians, physician assistants, or nurse practitioners, so will not be ordering or interpreting lab tests, or prescribing medicine.
ApoE4.Info members often find that their health insurance (including Medicare) does not cover certain tests that they deem not "medically necessary". You can check with your insurance company to determine if they cover the tests you plan to request. For example, a lipid profile or Vitamin D test may be considered medically warranted for certain populations.
If the tests you want aren't covered by insurance, or you don't have a practitioner who will order them, you can use a Direct-to-Consumer Lab Testing company. You decide which tests to order and the results are sent only to you.
Lab result tracking and sharing
The 'ApoE4.Info Biomarker Targets, Ranges and Labs' spreadsheet includes biomarker targets recommended by noted doctors/researchers and lab companies, including Dr. Bredesen's ReCode recommendations. To use it as a base to track your own results, open the sheet and choose File / Make a copy. (If you only see the Download option, click the Sign in button in the upper right corner, and log in using your Google account.)
1) While you are signed into Google and using the spreadsheet in the same browser, your Google ID will show to others in the upper right corner of the spreadsheet. Neither ApoE4 nor those who contribute to this spreadsheet will be responsible for your identity becoming known in this way.
2) If you copy or download this spreadsheet for your own use, entries in the master spreadsheet are likely to change over time and will not be reflected in your own version.
You can also add your results to the public Community Test Results spreadsheet if you would like to share them with others.
About This Wiki
These wiki pages are a compilation of information posted to forum threads and research done by individual members. It has not been reviewed by any scientific committee, and represents the nature of the ongoing forum discussions.
And given the pace and disagreements in research, you might find information that is outdated, incorrect, or not relevant. Because we are all volunteers here, the Board has opted for a wiki format, and as new information or even disagreements pop up, it encourages people to edit the wiki directly.
If you'd like to edit the wiki to add to a topic, feel free to jump in. If you do edit, just know that your first edit will be moderated and then you'll be given permission to do further edits without moderation.
Please consider sharing what you know, because we're all experts in something, and your knowledge might just help a fellow E4 traveler.