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Introduction to APOE4

APOE, short for Apolipoprotein E, is both a protein and a gene. They go hand in hand, the APOE gene tells the body how to make the ApoE protein.

ApoE Protein. As a protein ApoE is involved in the metabolism of fats (lipids) in the body, oversees the releasing and transporting of lipids between cell types in the brain, and plays a pivotal role in the development, maintenance, and repair of the Central Nervous System (CNS) that regulates multiple important signaling pathways. The ApoE protein comes in different isoforms: ApoE2, ApoE3, ApoE4.

APOE Gene. As a gene, APOE is polymorphic, that is to say a gene with multiple variations called alleles. 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.

Homozygous vs Heterozygous. 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, one came from the mother, the other from the father. When someone says they're homozygous, they're a 4/4, if heterozygous they're either a 2/4 or a 3/4.

The oldest of the alleles. The ApoE ε4 allele is the oldest of the ApoE variants, the apes we evolved from were all 4/4s. Our allele has literally existed 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.

For 96% of human history we were all ApoEε4/4s and the apes we evolved from were 4/4s, the other alleles didn't exist until very recently in evolutionary terms.

How is it different than the other alleles? ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance / glucose metabolism.

Frequency of ε4 is low (light red regions) and high (dark red regions). The gray color indicates that there are no data available for this country. Source:

Global Distribution. Distribution of the alleles vary across the globe. 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).

The APOE4 gene is rare in populations with exposure to agriculture, suggesting that a diet high in grain may have selected against this genotype, (Source:High carbohydrate diets and Alzheimer's disease(Samuel T Henderson, Feb 2004)).

The gene does appear to impact racial/ethnic groups differently. There are populations of dense ε4 carriers who do not experience "typical" APOE4 health concerns. It is difficult to draw definitive conclusions since most research on APOE4 has been conducted on white subjects of European descent. You can read more on these racial/ethnic differences in our wiki Non-white or non-European descent.

Reacting poorly to modern environment. 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, parasites, and walking on dung. In many ways our DNA still thinks we are in the savannah. 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 ε4 allele 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.

In fact, there’s research that bolsters the idea that Alzheimer’s disease and related dementias are diseases of modern environments and lifestyles, with sedentary behavior and exposure to air pollution largely to blame. From this source: Dementia in the Ancient Greco-Roman World Was Minimally Mentioned(Caleb E Finch et al, 25 Jan 2024) analysis of classical Greek and Roman medical texts suggests that severe memory loss was extremely rare as it is in today's Tsimane Amerindians, Indigenous people of the Bolivian Amazon who live an ancient lifestyle. And this paper Could Alzheimer’s disease be a maladaptation of an evolutionary survival pathway mediated by intracerebral fructose and uric acid metabolism?(Richard J. Johnson et al, Mar 2023) suggests that a biological pathway that was essential for early man to survive during times of scarcity is overstimulated by modern diet with detrimental effects leading to Alzheimer's.

Quote from Dr Dale Bredesen, MD, researcher/expert in neurodegenerative diseases, New York Times bestselling author, founder and former CEO of the Buck Institute for Research on Aging, professor at UCLA, and currently Chief Science Officer at Apollo Health.

Alzheimer’s gene or Poor Ager? APOE4 has been nicknamed “the Alzheimer’s Gene” but that is an oversimplified, poor representation. While this allele is the strongest genetic risk factor for the most common form of Alzheimer’s, this is not true for all populations and it is but one risk factor and it is not even the strongest risk factor, aging is the strongest risk factor for Alzheimer’s. The older one becomes, the greater the odds of developing dementia, this is true of all genotypes. But even chronological age isn’t a good measuring stick! There are very healthy, "sharp as a tack" 80 year olds and vice versa. Biological (vs chronological) age is a better measurement. Biological age refers to how old your cells and tissues are based on physiological evidence. Going one step further, the organs of our bodies don't age at the same rate, i.e. the biological age of your muscles and lungs can be different than your brain. In a study involving 5,678 people, researchers at Stanford Medicine worked out the biological ages not of the participants, but of their organs. They did this by studying the proteins in their blood. From this study Organ aging signatures in the plasma proteome track health and disease ((Hamilton Se-Hwee Oh, et al, 6 Dec 2023):

We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20–50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer’s

A better moniker for APOE4 might be “Poor Ager”. Or, in recent years, the term “Antagonistic Pleiotropy Gene” has gained some traction (Source: Short-term memory advantage for brief durations in human APOE ε4 carriers (Nahid Zokaei et al, 11 Jun 2020)). Antagonistic pleiotropy is a theory of aging where pleiotropic genes promote wellness and fitness early in life at the expense of longevity, a front-loaded gene as it were.

Other APOE4 Health concerns. APOE4 does affect many cellular functions and is associated with health issues such as cardiovascular disease, heightened immune response, reduced brain glucose uptake, hyperlipidemia, cerebral vascular issues, plus other concerns that do tend to manifest into ailments later in life. APOE4 is also associated with shortened longevity. (To read more on this, see wiki page: ApoE ε4 and health conditions besides (or maybe contributing to) Alzheimer’s

APOE genotypes can affect many cellular functions such as synaptic integrity, lipid transport, glucose metabolism, Aβ clearance, BBB integrity or mitochondria regulation. Abbreviations: apoE, apolipoprotein E; NFT, neurofibrillary tangle; BBB, blood brain barrier; IL, interleukin; TNF-α, Tumor necrosis factor-α; ROS, reactive oxygen species. Source:

Association with Late Onset aka Sporadic Alzheimer’s and other dementias. The APOEε4 allele is most strongly associated with Late Onset Alzheimer’s disease (LOAD).

Late Onset Alzheimer’s disease (LOAD) is also called Sporadic Alzheimer’s because there is no specific gene that directly causes it. Some ε4s get Alzheimer’s Disease and some live a long, healthy, cognitively intact life (Source: [Cognitive Performance over Time and APOE4 in Non-Demented Oldest-Old (S24.007)(Archana Balasubramanian et al, 23 Apr 2012)]). The other APOE alleles (2s and 3s) also get LOAD, thus this most common form of Alzheimer's is called sporadic. So it seems to reason that the APOEε4 allele isn’t driving LOAD, but it’s the factors to which the APOEε4 allele is particularly susceptible that makes carriers more likely to develop Alzheimer’s and other medical issues, more like being a canary in the coal mine.

APOE4s do develop LOAD earlier than the other alleles. From the paper Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (Tiantian Guo et al, 16 Jul 2020) clinical incidence and average age of AD onset was found to be:

  • 91% at 68 years of age in ε4 homozygous carriers (4/4s)
  • 47% at 76 years of age in ε4 heterozygous carriers (2/4s, 3/4s)
  • 20% at 84 years of age in non-ε4 individuals (2/2s, 2/3s, 3/3s)

The younger onset of Late Onset Alzheimer's Disease should not be confused with what’s known as Early Onset Alzheimer’s Disease (EOAD). Early Onset AD (EOAD) is also known as Familial Alzheimer's Disease (FAD). Early Onset/Familial Alzheimer's Disease is genetically driven (not APOE4) by three gene mutations: Amyloid precursor protein (APP), Presenilin 1 (PSEN1) and Presenilin 2 (PSEN2). EOAD/FAD is the only truly genetically driven AD and it makes up less that 5% of all Alzheimer's cases. Those who develop EOAD usually show symptoms well before the age of 65 and symptoms sometimes begin as early as the 30s or 40s. From outward appearances the symptoms are similar, however, in terms of what goes on inside affected cells, EOAD/FAD is different than LOAD (source: Different Cellular Mechanisms in Familial and Sporadic Alzheimer’s? (ALZFORUM 29 Feb 2024).

Even where Alzheimer's develops in the brain of APOEε4 carriers appears to be different than in non-carriers. The below graphic is from Figure 1 of the paper APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review(Sheina Emrani et al, 4 Nov 2020) where the caption from the paper reads:

"Cognitive and pathological heterogeneity in APOE4+ vs. APOE4− AD patients. A representation of the heterogeneity reported in APOE4+ vs. APOE4− AD patients. APOE4+ AD patients possess relatively more tau accumulation and brain atrophy in their medial temporal lobe, resulting in greater memory impairment, compared to APOE4− AD patients. On the other hand, APOE4− AD patients possess relatively more tau accumulation and brain atrophy in their fronto-parietal lobes, resulting in greater impairment in executive function, visuospatial abilities, and language, compared to APOE4+ AD patients. The level of tau accumulation (brown) represents the levels observed in AD brains during Braak stages V–VI." (Bold font added to highlight the APOE4+ difference.)
APOE4+ AD patients possess relatively more tau accumulation and brain atrophy in their medial temporal lobe, resulting in greater memory impairment, compared to APOE4− AD patients.

The APOEε4 allele is also associated with exacerbating other forms of dementia such as vascular dementia, Lewy-body dementia, and Parkinson’s disease dementia. (You can read more on this in the wiki ApoE ε4 and health conditions besides (or maybe contributing to) Alzheimer’s.

Other genetic factors associated with AD. APOE4 is not the only genetic factor associated with Alzheimer's Disease. According to Alzheimer’s disease risk reduction in clinical practice: a priority in the emerging field of preventive neurology (Kellyann Niotis et al, 10 Jan 2024)

At least 90 distinct genetic loci [a physical site or location within a genome] have been implicated in AD via GWASs, [Genome-wide association studies] and these genes provide evidence of the involvement of specific molecular pathways, including lipid processing and the immune response187 (Fig. 2).

Multifactored Alzheimer's and need for Personalized approach. While Alzheimer's is generally considered one of the diseases under the broader term "dementia", it appears that Alzheimer’s is not one disease. Neurodegenerative disease researcher Dr Dale Bredesen (read more on this wiki page: Bredesen Protocol has identified 6 types of Alzheimer’s. Additionally, this paper Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles ((Betty M. Tijms et al,9 Jan 2024) found that there are five biological variants after examining 1,058 proteins in the cerebrospinal fluid of 419 people with Alzheimer's disease. This suggests different treatments for different types.

Indeed, one size does not fit all, consideration of APOE status is important when addressing treatment of cognitive issues (Source: Alzheimer’s disease risk reduction in clinical practice: a priority in the emerging field of preventive neurology(Niotis et al, 1 Jan 2024)):

APOE ε4 carriers have been found to respond differently than noncarriers to environmental exposures associated with AD risk, as well as cognitive, pharmacological, dietary and exercise-based interventions, and such recommendations should therefore vary accordingly180,181,182 (Table 1).

Certainly, the term “precision medicine”, sometimes referred to as “personalized medicine”, has gained popularity of late. The National Institutes of Health (NIH) defines precision medicine as:

An innovative approach that takes into account individual differences in patients’ genes, environments, and lifestyles.

According to this announcement published by the Alzheimer's Drug Discovery Foundation, Combination therapy and precision medicine Spotlighted as the Gold Standard for the next generation of Alzheimer's treatments in the Journal of Prevention of Alzheimer's Disease (JPAD):

The Journal of Prevention of Alzheimer's Disease (JPAD) with the support of the Alzheimer's Drug Discovery Foundation (ADDF) recently published a comprehensive issue, "The Biology of Aging: Leading The Next Generation of Alzheimer's Drug Development With a Geroscience Focus," which supports the consensus that combination therapy and precision medicine are the future of Alzheimer's treatment.

Unfortunately, with today’s present healthcare system, there's a catch. Healthcare providers and insurers won't offer genetic testing for patients diagnosed with diseases unless there's an approved therapy they could benefit from. Yet, without large-scale testing and the genomic data it yields, researchers can't identify relevant biomarkers and develop targeted treatments. Additionally, most traditional medical doctors are not trained on diet and therapeutic lifestyle interventions.

Dr David Perlmutter is a board-certified neurologist, Fellow of the American College of Nutrition, and five-time New York Times bestselling author. His expertise includes gluten issues, brain health & nutrition, and preventing neurodegenerative disorders.

APOE4 odds for Alzheimer's. Nevertheless, given the strong association with Alzheimer’s, many who learn their APOE4 status want to know their odds for getting Alzheimer’s. It is hard to cite a hard and firm number, different sources cite different percentages. There are also many uncontrollable variables that factor in to the equation such as other genes, gender, age, race, geographic ancestral history, (see wiki page Non-white or non-European descent), environmental exposures, family environmental/trauma history, etc. Additionally, individual, more controllable lifestyle factors such as diet, activity level, stress, and sleep hygiene also contribute. So citing generalized odds are inexact on an individual basis. Suffice it to say, if you live in a modern, western society, your risk as a heterozygote (ε3/4, ε2/4) is elevated, and a homozygote’s risk (ε4/4) is significantly elevated. The good news is there are ways to influence the aging process for the better.

Importance of Diet and Lifestyle. Since Alzheimer's, dementia, and other ailments of age are influenced by many factors besides genes, pursuing a lifestyle that supports health aging is an imperative for APOE4s.

This recent study Association of Lifestyle for BRAin health risk score (LIBRA) and genetic susceptibility with incident dementia and cognitive decline (Jeanne Neuffer et al, 22 May 2024) studied nearly 5200 participants for up to 17 years and found that a combination of lifestyle and other modifiable risk factors is associated with a lower risk of dementia, regardless of genetic susceptibility, including among those most at risk -- APOE4 carriers.

Separately, there’s this study, Association between healthy lifestyle and memory decline in older adults: 10 year, population based, prospective cohort study(Jianping Jia et al, 25 Jan 2023) published in the British Medical Journal (BMJ), which found:

These results support the notion that lifestyle change might counteract the deleterious effect of APOE ε4 on cognitive decline and dementia.

Yet another study, Metabolic syndrome marks early risk for cognitive decline with APOE4 gene variation: A case study(Dawson Brown & Kelly J. Gibas, September 2018):

If APOEE4 is the strongest genetic risk factor for developing late-onset Alzheimer's Disease, then implementing a ketogenic diet and high intensity exercise could essentially turn “off” the effects of this APOE4 gene earlier in life for prevention of future neurodegeneration.

And this study, Apolipoprotein E ε4 magnifies lifestyle risks for dementia: a population-based study (Miia Kivipelto et al, 2008 Mar 4):

Physical inactivity, dietary fat intake, alcohol drinking and smoking at midlife are associated with the risk of dementia and AD, especially among the apoE ε4 carriers. The apoE ε4 carriers may be more vulnerable to environmental factors, and thus, lifestyle interventions may greatly modify dementia risk particularly among the genetically susceptible individuals. (bold font added for emphasis)
23 12 19 Success.jpg

Bottom line. APOE4 is not deterministic. Being a carrier does not mean dementia, cardiovascular disease, or any other ailment is assuredly in your future. It is, however, a significant influencer in the body, therefore it is important for carriers to be extra diligent in lifestyle choices to decelerate the aging process in today's modern environment. These lifestyle choices mostly consist mostly of diet (including timing of feeding to allow the body a chance to work on other processes besides digestion), leading a non-sedendary life, honoring circadian rhythm / concentrating on sleep hygiene, and avoiding chronic stress.

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 SNPedia's page on APOEto 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.

Graphic source: "Advances in the Prevention of Alzheimer's Disease"

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, 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

Other health conditions besides (or maybe contributing to) Alzheimer's

The ε4 variant of the ApoE gene is well known for its association with Alzheimer’s Disease but other conditions have also been linked to it. Discussions in this article include:

Other APOE4 Condition Discussions
High Cholesterol (Hypercholesterolemia) Hypertriglyceridemia Saturated Fat Sensitivity
Cardiovascular Disease (CVD) Heightened Immune response/ Infectious disease susceptibility Slowed brain glucose uptake
Vascular Dementia Lewy Body Dementia & Parkinson's Disease Dementia (synucleinopathies) Cerebral atherosclerosis (AS)
Small Vessel Disease (SVD) Cerebral amyloid angiopathy (CAA) Blood Brain Barrier (BBB) Breakdown/Leakage
Mitochondrial dysfunction susceptibility Impaired Autophagy Gut Microbiota Differences
Sleep Apnea Reduced insulin-degrading enzyme (IDE) Greater Parasite tolerence
Greater pesticide susceptibility Postoperative Cognitive Decline after General Anesthesia Greater incidence of Delirium
Gallstones Decreased Longevity Greater susceptibility for dementia after brain injury
Example Example Example

Main Article: ApoE ε4 and health conditions besides (or maybe contributing to) Alzheimer’s

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

Insulin Resistance

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

Insulin Resistance in the brain

Fructose and Alzheimer's Disease

Fructose is a sugar that can have harmful effects. It is found naturally in sources such as ripe fruit and honey. It is also found in high fructose corn syrup (HFCS), a combination of fructose and glucose, and table sugar (sucrose) also a combination of fructose and glucose. Regardless of source, fructose sends information to the body that times of scarcity are coming. These signals result in physiological changes that were helpful for early human survival, but overstimulation of these adaptations today results in negative health issues. Complicating this, reducing fructose levels in the body is not as simple as avoiding fructose consumption. Under certain circumstances, many of which come from the western diet, the body produces its own (endogenous) fructose, without consuming (exogenous) fructose. Main article: From Fructose to Alzheimer's


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 - Types, Lengths, and Benefits

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.

Main Article: Gut-Brain Connection: Leaky Gut/Leaky Brain, Microbiome (gut bugs)

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

Other related genes

Genetics make a substantial contribution to the risk and age of onset of AD. If you have your genetic data from 23andme or other testing sites, you can read more at Alzpedia, a part of ALZFORUM

Alcohol consumption

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

A deeper dive into ApoE4

APOE4 is more than the “Alzheimer’s gene” nickname that it has been given. While APOE4 is considered the biggest genetic risk factor for Alzheimer’s disease, this is not true across all populations. Additionally, effects of this gene extend beyond Alzheimer’s, to other neurological issues, cardiovascular concerns, aging, infectious diseases, and more.

The studies on APOE4 cover a wide diversity of topics. This deeper dive wiki attempts to be a sort of “library” covering these various areas. It consists mostly of research papers, with a sprinkling of insightful articles, podcasts, etc. all of which include a discussion of ApoE4.

Main article: A deeper dive into ApoE4

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':

Dr Steven Gundry

Dr Steven Gundry Wikipedia Gundry has been referenced often within the 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 and against 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.

On the other hand, Ioannis Delimaris cites a number of studies associating higher protein intake with adverse effects (Delimaris 2013), and Dr. Valter Longo and researchers from Harvard University note modest associations of animal protein intake with cardiovascular mortality and modest inverse associations of plant protein intake with both all-cause and cardiovascular mortality from two large, multi-decade prospective cohort studies (Song 2016).

Main article: Scientific support for a diet higher in protein than the RDA.

Other related topics and deep dives

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

Blood Sugar

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

Circadian Rhythm

Our body follows a 24 hour circadian rhythm. The circadian system is a network of interacting neural and hormonal pathways that drives the sleep-wake cycle, hormonal activity, body temperature, digestion, and immune function. Every organ, even every cell, has its own daily timed circadian rhythms. Being out of sync with one’s circadian rhythms leads to multiple health issues, one of which is Alzheimer's Disease. Circadian rhythm disruption is both a cause and effect of Alzheimer's Disease. Disrupted circadian rhythm encourages conditions that lead to cognitive deficits and that in turn feeds disrupted circadian rhythm which further feeds cell death, oxidative stress and amyloid deposition.

Main article: Circadian Rhythm

Beneficial (and some negative) Plant/Natural Chemicals

Despite the rather current high prevalence of Alzheimer’s Disease, and the projection of cases expected to triple by 2050, only a handful of drugs have been approved by the FDA for treatment. None of these approved drugs can reverse, stop, or even slow down the damage and destruction of neurons. This is in contrast to several scientific studies that have described the use of various medicinal plants and their chemicals for the treatment of Alzheimer’s Disease and other cognitive concerns. Certain chemicals from plants have antioxidant, anti-inflammatory, anti-amyloid, and anticholinesterase properties, the four fundamental pillars identified in the process of Alzheimer’s. Certain plant compounds offer neuroprotective effects which not only act at the level of blocking the progression of Alzheimer’s but also aid in Alzheimer’s prevention. But not all plant chemicals are beneficial, some have negative effects, that's discussed too. Confused when you hear certain terms like polyphenols, adaptogens, flavonoids, resveratrol, lectins, etc.? This page offers a long list of related terms.

Main article: Beneficial (and some negative) Plant/Natural Chemicals

Cannabinoids: CBD, CBN, THC. Also Hemp & Marijuana

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.

Main article: Cannabinoids: CBD, CBN, THC. Also HEMP & Marijuana (Cannabis)

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.

Main article: Coconut Oil, MCT oil, and other Ketone/Cognition Boosters (salts, esters)

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

Vagus Nerve

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


Advance Directive for Dementia

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

"How-To" Get the most out of the website

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 website

What can I eat? Recipes from our members and Recommended food websites/blogs

Abbreviations and acronyms

Searching for a Healthcare Practitioner

A List of ApoE4-Aware Healthcare Practitioners

A List of ApoE4-Aware Health Coaches

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.

A List of ApoE4-Aware Care Facilities

Direct to Consumer Lab Testing Options

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.)

Please note:

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.

Getting your genetic data

Where to buy supplements, olive oil, etc.

ApoE4 Research: What's New And What YOU Can Do

Many Alzheimer's related clinical trials are researching lifestyle or non-drug interventions. Most do not require you to change whatever lifestyle strategies and interventions you are currently using to optimize your health. Do Something Great! Watch a whiteboard video from UsAgainstAlzhiemer's to learn more about clinical trials, and why you should “do something great” and sign up for one. Right now, 80% of studies are delayed because too few people sign up to participate. <ref></ref>
Main Article: ApoE ε4 Alzheimer's Research: What's New and How YOU Can Accelerate Research

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.