The APOE4 gene is the most well-studied gene in relation to Alzheimer’s disease. People who carry one copy of the APOE4 gene are at an increased risk of Alzheimer’s disease and heart disease. People with two copies of the gene (known as APOE4/4) are at an even higher risk. The APOE4 gene is an ancient genetic variation. Many hunter gather peoples carry this variation. It is thought to have been a dominant variation in pre-agrarian societies. Yet, these people did not get Alzheimer’s disease or heart disease. We also know from recent studies of existing hunter gatherer peoples who carry the APOE4 gene that they do not get Alzheimer’s disease and they have clean arteries. This clearly indicates that lifestyle strongly interacts with the APOE4 gene to prevent or cause Alzheimer’s disease. It also indicates that adopting the diet of our ancestors, matched to the needs of our genes, offers considerable hope for preventing heart disease and Alzheimer’s disease.

In May 2015 a major discovery about the APOE4 gene was published in the Journal of Neuroscience. The authors of the article discovered for the first time that the APOE4 gene decreases brain synapses. This disrupts cognition and memory before the formation of amyloid plaques and tangles. This disruption is caused by the APOE4 gene increasing the activity of enzymes known as histone deacetylases or HDACs. This interaction interferes with the DNA responsible for the formation and maintenance of brain synapses. In addition, when HDAC activity is increased by APOE4, brain-derived neurotrophic factor (BDNF) is decreased, which further disrupts the maintenance of brain synapses. Therefore, the authors suggest that future pharmaceutical treatment for APOE4 carriers should focus on inhibiting histone deacetylases (HDACs) and increasing brain-derived neurotrophic factor (BDNF) in order to preserve brain synapses. The authors do not offer any other solutions, nor any dietary or lifestyle advice.

This finding is tremendously exciting. If the study is correct then the aim for APOE4 carriers must be to inhibit HDACs and increase BDNF. This should help the formation and preservation of brain synapses. Doing so would halt the development of amyloid plaques and tangles, thus preventing Alzheimer’s disease and age related cognitive decline.

Fortunately, there is excellent evidence in other studies that convincingly show how HDACs activity can be reduced by food, and how BDNF can be increased by diet and exercise. Such a diet has the secondary effect of increasing good gut bacteria, which in turn helps mental health, and improves vascular health and lipid levels, which benefits the heart and brain, and affords anticancer protection.

It should be noted that HDACs over expression is indicated in a number of other diseases aside from Alzheimer’s disease. It has an established role in the formation of numerous type of cancers, as well as multiple sclerosis, schizophrenia, and depression. Therefore, inhibiting HDACs has the notable side effect of reducing the risk of cancer. At the time of writing fifteen HDACs inhibiting drugs are undergoing clinical trials to treat cancer.

There is little to no risk in inhibiting HDACs through diet. The food recommendations outlined below are uncontroversial and are widely held to be anticancer, and good for heart and brain health. None of the recommendations are known by either tradition, history, or science to cause harm.

These findings indicate there are eight main targets for APOE4 carriers (and for the general population):

1. Encourage excellent vascular and lipid health, with an emphasis on low LDL cholesterol.
2. Decrease HDACs.
3. Increase BDNF.
4. Maintain optimal blood glucose levels.
5. Reduce inflammation to a minimum.
6. Minimize homocysteine. Protein recycle and reduce IGF-1 through fasting.
7. Maintain good gut bacteria.

(This article does not consider the interaction of dietary fat with the APOE4 gene.)

How to inhibit HDACs and lower your risk of heart disease and Alzheimer’s disease

There are a number of studies on food and HDACs inhibition. Perhaps the best overview is a 2014 study in the journal Nutrients titled “The Role of Dietary Histone Deacetylases (HDACs) Inhibitors in Health and Disease.” This study outlines in some depth the different types of food that inhibit HDACs.

Eating a diet rich in various types of flavonoids inhibits HDACs. This dietary intervention is as effective as current pharmaceutical interventions. Therefore, the first step is to increase or optimize intake of flavonoid and polyphenol food. Specific flavonoid and polyphenol foods for HDACs inhibition include olive oil, green tea, apples, citrus, berries, and grapes.

Cacao is a native drink of the Kuna Indians. It is one the very richest sources of flavonoids and therefore should inhibit HDACs. Tens of studies have shown its beneficial effect upon the brain and cognition. In one astonishing study, people in their sixties with cognitive decline were given cacao everyday for nine weeks. At the end of the study their cognitive performance matched people in their thirties and forties. MRI scans revealed that cacao did this not through stimulation but through forcing more blood into the brain. Kuna Indians typically consume five cups of cacao per day. This much is too much for most people. The cognitive benefits found in numerous studies can be had from one cup of cacao (note cacao not cocoa) per day (or possibly every other day) made with one 3 – 5g teaspoon of cacao. More than one cup per day may produce adverse effects in people without Kuna Indian ancestry.

The point about cacao is to show how flavonoids powerfully help with cognition. It doesn’t mean that cacao is obligatory to drink for good health (although you may if you like it). It does mean that diets should be rich in flavonoids, preferably from in season foods native to your lands.

Next, ensure regular consumption of cruciferous vegetables, especially broccoli.

Then, increase the short-chain fatty acid butyrate. Butyrate has multiple effects: it inhibits HDACs while simultaneously increasing good gut bacteria and lowering the LDL-c. Therefore, butyrate is good for the heart, the gut, and the brain. Butyrate is generated by bacteria in the colon when dietary fiber is eaten. Oats have been shown to simultaneously increase butyrate, inhibit HDACs, lower LDL-c, and increase good bacteria. European unprocessed cheese increases butyrate and lowers LDL-c. Roquefort is especially beneficial, though other unstudied traditional cheeses probably increase butyrate just as much. A word of caution is necessary here. The current weight of medical evidence shows that APOE4 carriers do not respond well to saturated fats. The French who get the most help from cheese eat about 30g a day. Therefore, APOE4 carriers only need minimal amounts of blue or traditional cheese, which need not be eaten daily. Due to the regulations on cheese by the United States FDA any cheese available for sale in America is not worth eating, and is most likely harmful. Finally, exercise increases butyrate and benefits good gut bacteria. Natural yogurt massively interacts with good bacteria and gene expression to improve mental health and has some mild butyrate increasing qualities. It also lowers inflammation. For people who can tolerate dairy products natural yogurt is an important dietary addition.

Eat one brazil nut a day or two brazil nuts every few days. Brazil nuts inhibit HDACs. Just one brazil nut a day increases verbal fluency and benefits cognition in older people with cognitive impairment. That’s right: just one brazil nut a day. With brazil nuts more is not better: regular consumption of more than two brazil nuts per day is enough to cause selenium toxicity.

Feverfew and basil

Many herbs are touted as having anticancer effects. Two ancient herbs stand out. The first is feverfew. Feverfew has been used since the ancient Greeks and by early European herbalists. It was known as medieval aspirin, then subsequently found to inhibit platelets. It is also an important HDACs inhibitor. There is no current evidence (beyond HDACs inhibition) that it prevents Alzheimer’s disease. However, it is known to act on multiple pathways in the brain including the vasculature of the brain, it is the most effective natural remedy for preventing (not alleviating) migraines. It is a potent anti-inflammatory, anticancer herb rich in flavonoids. The recommended dose is two or three whole leaves in water. The leaves are better than a supplement as there are multiple compounds in the herb. Caution is needed if taking multiple blood-thinning medications or platelet inhibiting herbs and supplements.

Ursolic acid found in Holy Basil (also known as Tulsi, especially in India) is a potent HDACs inhibitor. Holy Basil protects against the heavy metals and chemicals/pesticides that APOE4 carriers are known to be susceptible to. It protects against physical and mental stress, which also interact with the APOE4 gene to elevate Alzheimer’s disease risk. Holy Basil enhances memory and cognitive function, and is anti-inflammatory. It increases lean muscle and decreases white fat. In Ayurveda it is considered to be queen of all herbs and is known as the ‘incomparable one’ and ‘elixir of life’.
Turmeric. There is little to add to the known benefits of turmeric for APOE4 carriers save to mention that it can now list HDACs inhibition among its many talents.

Increase BDNF

As mentioned above the APOE4 gene elevates HDACs and decreases beneficial brain-derived neurotropic factors (BDNF). Therefore, APOE4 carriers must elevate BDNF. The two most effective ways to do this are exercise and fasting. Both exercise and fasting additionally increase the proliferation of good gut bacteria. Everyone should have a minimum of 12 hours every day or night without food, and two days a week of more than 12 hours (up to 24 hours) brings further benefit.

Increase fiber

A fiber rich diet is essential for good gut bacteria and the production of butyrate, which in turn inhibits HDACs. The average western diet just about provides 20g of fiber per day. It is estimated that our ancestors ate 150g of fiber per day. Some extremely beneficial foods include brewers yeast (6g of fiber per 30g); ground flaxseed (8g per 30g); oats (6g per 50g); and oat bran (40g per 50g). The lack of fiber is the main problem with low carbohydrate diets. In the short-term low carbohydrate diets reduce weight. After one year this benefit disappears. Long-term there is good evidence that a low carb diet invokes a pro-inflammatory state, especially as there is a natural tendency for low carbers to resort to a meat heavy diet. One of the main problems of a low carbohydrate diet is the lack of variety and fiber. This damages gut bacteria.


Carbohydrates are currently the most contentious macro-nutrient. There is a consensus that carbohydrates from vegetables are beneficial. Moderate fruit consumption is also beneficial, with berries especially useful for preventing cognitive decline and protecting against cancer. Any further discussion of starch and grain based carbohydrates must consider both history and the AMY1 gene. History because large populations in Asia have thrived on rice without age-related cognitive decline. The AMY1 gene because it is responsible for producing the enzyme amylase that breaks down starch. The AMY1 gene is a copy number variation: people can have anywhere from 2 to 15+ copies of the gene. The more copies of the gene the more able a person is able to break down and thrive on starchy carbohydrates. Asian populations tend to have high number of AMY1 copies, which explains why they thrive on rice and starch. Moreover, when rice is eaten with chopsticks the production of insulin dramatically declines. Those people with less than five copies of the AMY1 gene are up to 800 times more likely to be obese than people with more than ten AMY1 copies, and are unable to adequately digest starchy carbohydrates. This leads to insulin production and obesity. Hunter-gather populations tend to have low copy numbers of AMY1 suggesting that a Paleo type diet is more appropriate for them. This explains why Australian Aborigines thrive when they return to their native diet. People with low copy numbers of the AMY1 gene are still able to digest non-starch carbohydrates such as fruit, honey, and dairy (providing they carry the lactase enzyme. The Masai are a case in point here).

Northern and western Europeans are an interesting case. While northern Europeans ate carbohydrates it is not clear how much starch was eaten. Potatoes are a new world food, rice is from Asia, and yams were unknown. This raises the question of what carbohydrates northern Europeans should eat. Europeans who carry the A allele of the MCM6 gene have historically eaten dairy products and should be fine when consuming dairy, providing they can tolerate casein. Berries, apples, pears, plums, and local fruit are also fine to eat. However, arguably the grain without peer for northern Europeans is oats and oat bran. Oats are gluten free, balance blood glucose levels, and crucially lower LDL cholesterol. In addition, oats act upon gut bacteria in a remarkable way. Oats contain both soluble and non-digestible fiber, both of these forms of prebiotic fiber feeds the growth of good gut bacteria and produces butyrate. Professor Zhao of China uses oats in his clinic to repopulate the gut bacteria of obese people. For preventing Alzheimer’s disease oats and oat bran (which contains 7x more fiber than oats) are the best grain for northern Europeans to eat. For northern Europeans who are not gluten intolerant rye and barley are good choices. In contrast, many, but not all, Asian populations are mostly fine eating rice (in moderate amounts), millet, and their traditional grains. While non-hunter-gatherer African populations thrive on tubers and legumes, both of which have been shown to improve gut bacteria in people of African heritage in as little as two weeks.

The two main vitamins to consider are vitamin D and the B group of vitamins including folic acid.

It is not necessarily important to take a vitamin D supplement. What is important is to maintain vitamin D levels between 70 – 110 nmol/L. This can be done through diet, exposure to sunlight, or supplementation.

The B group of vitamins with folic acid / folate are important for lowering homocysteine, which is linked to heart disease, dementia, and Alzheimer’s disease. Phosphatidyl choline interacts with this group of vitamins to further lower homocysteine, and independently protects against cognitive decline.

The upshot is that knowing your APOE genotype, and whether you carry the APOE4 variation offers tremendous hope and opportunity. It is not a death sentence. It does not mean a slow and inevitable cognitive decline. It means that diet and exercise can be personalized for people carrying this genetic variation. This ensures that Alzheimer’s disease is prevented, as is heart disease, and that they have the clean arteries that their ancestors once had.