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Can diet reduce the risk of Alzheimer’s in APOE4 carriers?

Article at a Glance
  • Alzheimer’s may be considered a “disease of old age,” but there are other risk factors, including genetics and lifestyle, that come into play in our chances of developing a dementia-related illness. The APOE genotype is a key indicator of how likely we may be to get Alzheimer’s disease.
  • After getting a DNA test, you’ll find out what APOE genotype you have. APOE ε4 carriers have the highest risk of developing Alzheimer’s.
  • Although we can’t change our genetics, there are things we can do to slow down the progression of or even prevent Alzheimer’s and dementia. Nutritional therapy focuses on avoiding saturated fat and taking in enough polyunsaturated fats, along with cutting out alcohol and not smoking. Getting more exercise helps our brain stay healthy, too.
  • Some studies suggest that Mediterranean diet is the best choice for those looking to prevent or reduce the progression of Alzheimer’s. Eating foods rich in antioxidants, including tea, also may assist some APOE genotypes, along with supplementing with nutrients such as NAD, curcumin, grape seed extract, and niacin.
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Alzheimer’s disease is the most common form of dementia, with dementia being defined as “a series of conditions occurring when nerve cells or neurons in the brain die or no longer function as they should.”  These changes will impair a person’s ability to carry out basic daily life activities, and even more, Alzheimer’s will also affect one’s memory, behavior, and the ability to think clearly. (R) Needless to say, an Alzheimer’s diagnosis is devastating news for any family, but are there nutritional interventions that can either prevent Alzheimer’s, or slow its march to improve quality of life once a diagnosis has been made?

In this post, we discuss the causes of Alzheimer’s disease, brain function as it relates to the APOE gene, and using nutrition to enhance our brain health.

What causes Alzheimer’s disease?

The pathology of Alzheimer’s is relatively well understood, with regions of the brain shrinking (displaying atrophy) which significantly affects the structure and function of the brain. Other common features include the formation of amyloid plaques, protein rich deposits which impair neuronal activity. Neurofibre tangle formation, alterations in levels of the neurotransmitter acetylcholine, and vascular changes in the brain limiting blood flow are also hallmarks of the progression of the disease.

Over time these structural changes spread throughout the brain leading to the debilitating symptoms associated with the disease, with the areas responsible for memory often the first and hardest hit.

What we don’t know is why this happens in some people, but not others, but there are several risk factors.

In nutrition circles, there is heated disagreement as to what causes this limited blood flow to the brain. Plant based advocates characterize the problem as caused by dietary fat and cholesterol, while Paleo circles blame the problem on grains and sugar in the diet. As we will see, the plant based community has the better science at this point in the debate, and especially for those carrying one or two APOE4 alleles, although there is nuance based on recent studies.

Age

Although the food we eat plays a role, age is the most significant factor related to the development of Alzheimer’s disease with the risk of developing the disorder doubling every 5 years beyond 65 years of age. However, approximately 1 in 2o individuals will develop Alzheimer’s before the age of 65, with this form of the disease termed early onset Alzheimer’s. This variant has a very strong genetic element through three different genes (APP, PSEN1 and PSEN2) and affected families are often well aware of the familial risk. There are other genetic factors which can predispose people, which we’ll get into below.

Lifestyle

A major focus in recent years has been the link between cardiovascular diseases and the onset of Alzheimer’s/dementia. The brain is an incredibly resource intensive organ needing a continuous supply of oxygen and other nutrients to function correctly. Acute alterations in this flow will lead to a stroke, but long term reductions are also associated with poor health outcomes. (R) Therefore, maintaining good cardiovascular health is something everyone can work on to lessen their risk of developing Alzheimer’s.

It has been estimated that at as many as one third of Alzheimer’s cases world wide are caused by 5 risk factors, most of which are tied to lifestyle and can be prevented. (R) The big ones are:

  1. smoking
  2. hypertension
  3. obesity
  4. diabetes;
  5. and physical inactivity

If you participate in daily exercise, it will help improve cognitive function and reduce the formation of amyloid plaques, especially among APOE4 carriers. (R)

Genetics

The genetic basis of early onset Alzheimer’s is controlled relatively tightly with a strong familial association. However, there is another genetic polymorphism which has been shown to correlate with Alzheimer’s risk in the general population, APOE.

APOE isoforms and Alzheimer’s

APOE encodes for the most prevalent of the brain’s lipoproteins, apolipoprotein E. These proteins function to transport lipids throughout the body, as lipids are normally insoluble in water (think of the fat droplets that form in your sink when washing a pan), and are therefore difficult for cells to absorb. These lipids are essential for proper cell growth and maintenance, and the brain, as a major site of cell development, requires a steady supply. Interestingly, APOE also functions to clear the beta-amyloid protein — Aβ — in the brain, which is a component of plaques associated with Alzheimer’s. (R)

Now not all APOE is identical, there are actually three distinct forms which can be produced termed APOE ε2, APOE ε3, and APOE ε4 (from now on we’ll just say APOE2, 3 or 4). These isoforms are important as they have been shown to carry differing risk for the development of Alzheimer’s and also the resulting rate of cognitive decline. (RR)

The APOE3 form is the most frequent in all populations and is considered to be the neutral form. Interestingly, APOE2 is protective for the development and progression of Alzheimer’s, although it is relatively rare, and is associated with an increased risk for some cardiovascular disorders. Conversely, E4 is associated with an increased risk for Alzheimer’s disease, a more severe progression and also an increased risk of developing other neurological disorders.

It is however important to note that there is not a 100% association with any of these isoforms. Carrying the APOE4 isoform does not mean you will develop Alzheimer’s, rather that you are at an increased risk compared to the general population, and there are lifestyle changes you can make to reduce this risk. (RR)

Identifying your APOE isoform

There are two SNPs which can be used to identify your APOE isoform C526CT or rs7412 and T388C or rs429358. The combinations and which isoform they produce (and the percentage occurrence in the population) are shown in the table below.

T388C - rs429358
TC
C526T - rs7412C3 (79%)4 (14%)
T2 (7%)Unknown as so rare.

It is important to remember that the above table gives you your isoform for a single allele, you will however carry two copies so it’s important to work this out for both variants as the risk varies widely as you can see in the table below. (R)

APOE risk

APOE Genotype2:33:32:43:44:4
Odds Ratio0.311.14.419.3

As you can see those carrying two copies of APOE3 have a neutral risk of 1.

A single APOE4 allele increases this risk up to 4.4, and two copies of APOE4 increase this to 19.3!

The protective effect of the APOE2 allele can also be seen, a single copy of APOE2 reduces the risk down to 0.3, and can mitigate for an APOE4 allele, effectively keeping the risk neutral (1.1). (R)

Eating right for your APOE genotype

So now you know your APOE genotype, what can you do with this information?

Several strategies have been proposed to help prevent, slow the onset or progression of Alzheimer’s disease. Nutrition is among these widely investigated approaches, suggesting an interaction between genes and nutrients in the development of the disease; hence, nutritional therapy is aimed to target specific nutrients depending on the APOE genotype you have inherited. (R)

Usually, those with the APOE4 genotype have hypercholesterolemia (high cholesterol), which in turn can boost the production and accumulation of the toxic amyloid plaques that lead to dementia. (RRR)

If you inherited the APOE4 genotype, you should take special care to follow a heart healthy diet avoiding saturated fats and other foods that promote alterations in LDL:HDL cholesterol ratios, as changes in this ratio are associated with increased APOE expression in the brain. (R) In practical terms, this means eating Vegan at least 3-4 days a week and completely avoiding butter, ice cream, fatty meats and supplements like MCT oil. Note, that MCT oil has actually shown promise in some studies for treating dementia, but like fish oil, doesn’t appear to help APOE4 carriers. (R)

Niacin has also been proven to balance LDL:HDL ratios in multiple studies. Researchers suggest that avoiding excess saturated fat and taking in enough Omega 3 PUFAS may decrease the risk or postpone the onset of dementia for this group. (RR)

Mediterranean diet and Alzheimer’s

However, while APOE4 carriers should avoid the Bulletproof diet, and other diets high in saturated fat, it is important to keep in mind that avoiding saturated fat does not necessarily mean cutting out all fat. Publicly funded research by the NIH has shown that a group following a Mediterranean diet had a slower build up of the amyloid plaques that cause Alzheimer’s than did a group eating a standard Western diet high in refined sugar, red meat, and saturated fat. (R) The Mediterranean diet is essentially a plant based diet plus a few servings a week of fish, and occasional goat or sheep cheese and small servings of high quality lean poultry. However, not everyone agrees that APOE4 carriers should eat poultry. Dr. David Gundry, author of The Plant Paradox, recommends that APOE4 carriers remove poultry entirely from their diets. (R)

This balanced approach to regulating cholesterol levels and lipid intakes may explain why the traditional Mediterranean diet is associated with a reduced incidence of Alzheimer’s disease (as well as several other disorders). (RR) For example, in another small study, patients with Alzheimer’s following a Mediterranean diet improved survival almost 5 times compared to those on a normal Western diet. (R)

But once again, due to a lack of understanding about the exact causes of Alzheimer’s we can’t home in on exactly why this diet is beneficial.

Foods rich in flavonoids and polyphenolic compounds — like fruits, vegetables, red wine, and tea — are also thought to have a protective role due to their antioxidant and anti-inflammatory activity. Vitamins from the B family and vitamin D will exert a benefit, too. (R)

However, it is important to note that these recommendations seem to address Alzheimer’s prevention broadly. Dietary interventions can be more difficult for APOE4 carriers. (R)

Does Vitamin E slow Alzheimer’s progression?

Increased oxidative stress is said to be a risk factor for Alzheimer’s disease, which has led researchers to look at antioxidants, like Vitamin E in the treatment of Alzheimer’s, but not necessarily prevention. After promise in mouse models, some trials have looked at high dose Vitamin E for Alzheimer’s patients, however, the results have been mixed.  Having said that, it appears the pro Vitamin E camp may be winning out. The Alzheimer’s Disease Cooperative Study Group (ADCS) supports the use of high dose Vitamin E with Vitamin C for the treatment of the disease. This recommendation is based on this large clinical trial. To quote the study:

Over the mean (SD) follow-up of 2.27 (1.22) years, participants receiving alpha tocopherol had slower decline than those receiving placebo as measured by the ADCS-ADL. The change translates into a delay in clinical progression of 19% per year compared with placebo (approximately 6.2 months over the follow-up period). Caregiver time increased least in the alpha tocopherol group.

Can fish oil help with APOE4?

You may have read about some clinical trials that show the omega 3 fatty acids found in fish oil demonstrate promise for easing dementia symptoms. This is true. (R) Interestingly, there is some speculation in the literature that the rise of Alzheimer’s has mirrored the corresponding increase in omega 6 ratios to omega 3 ratios. However, no benefit was found in APOE4 carriers who took fish oil supplements.

Nutrients to support APOE4

NutrientMechanismStudy
NADImproves DNA repair in the brain(R)
CurcuminReduces beta amyloid plaques(R)
Grape seed extractIncreases NAD production(R)
NiacinNiacin deficiency linked to dementia, supports LDL:HDL ratio(R)

Final thoughts

Early onset Alzheimer’s has a strong genetic risk element, with many individuals already aware of the elevated risk. However, with the advent of genetic testing individuals are now able to identify that they may be of elevated risk, due to their APOE4 carrier status. Although it is just that, an elevated risk, not a diagnosis it is understandable that those with an APOE4 allele would like to make lifestyle changes to protect against disease development, or severity.

Unfortunately given our relatively poor understanding of what triggers disease onset only relatively broad nutritional advice can be given, with a focus on maintaining cardiovascular health and LDL:HDL ratios, which for the APOE4 carrier means avoiding saturated fat and cholesterol in the diet.

Janeth Santiago Rios

Janeth Santiago Rios is a dietitian-nutritionist from Colombia with an MSc in Nutrition and Metabolism from Barcelona and Rovira i Virgili University. Janeth is passionate about healthy eating, plant-based diets, and helping others improve their quality of life through nutrition.

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6 Comments

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  1. Bo says:

    I am in my 50s and have APO e3/e4.
    I don’t have, and never have had, high cholesterol. Saturated fat has not been a problem for me, and I seem to do better on it than on other kinds of fats. I don’t go overboard at all with it, and I don’t eat much red meat because I just don’t like it (although it’s healthy for me and I need the iron and protein), but I think probably eating more saturated fat would be healthier (for me in my particular case) and I would not want to go 4 days a week without it, on a vegan type of diet. Maybe that’s because I already was a vegetarian for 12 years in mid-life – and getting away from that diet (stopping eating a number of grains that I discovered were causing me digestive issues and join pain, eating a tiny bit more meat protein every day) has helped my health.
    A couple of years ago, when I first learned about my APO e4 allele and looked into the suggestions at the time, I tried NAD, curcumin, grape seed extract, and niacin:
    * Taking one “half” dose of a high-quality, recommended NAD gave me an astonishingly-bad 2-day splitting headache and wiped me out — I vowed never to try it again.
    * I took a small amount of curcumin (1 500 mg capsule daily) for a few months and even though it helped a lot in several ways — improved my mood, increased my positive dreaming while sleeping, dramatically improved my joint pain — it caused a lot of unwelcome side effects and I had to stop taking it.
    * Taking a small dose of grape seed extract must have revved up my male hormones (I am female) and it quickly made bristly, thick facial hair grow on my chin and upper lip. (I later learned that it’s known to be a beard-booster.) When I stopped taking it, the beardy growth slowly subsided on my face.
    * I used to take a small dose of niacinamide as my form of niacin supplement (for decades), but I several years ago I learned that there are quite a number of issues with niacinamide and I decided to avoid it, so I tried a couple of other newer “trendy” forms of niacin and I didn’t do well AT ALL with them, then I switched to nicotinic acid (just “plain” niacin), which I can barely tolerate in terms of the flush effects even though I’ve taken it consistently for several years — I get flushing on doses as low as 16 mg (yes, sixteen milligrams). I have to buy it in 100 mg tablets so I can cut them into 6 pieces to get 16 mg each, because I can’t fiddle with tipping out a few bits of powder from the nicotinic acid capsules that often have 500 mg or more in them. Other than the flushing, it seems that this tiny dose of niacin I do okay with, and I probably feel better on it than I felt on the niacinamide, but it’s very subtle.
    However, I seem to have a HUGE sensitivity to the niacinamide that is in an increasing array of topical products (like face wash, face lotion, skin lotion) and when I have a bit of skin contact with one of those products, it will cause me a red skin rash and feeling of heat (on that area of skin that was touched by the niacinamide-containing toiletry) that lasts for an hour. There isn’t much on the internet about niacin topical sensitivity, but I did find a few mentions on the internet and apparently it’s more common than one would think. From these different experiences, I conclude that I probably am sensitive to niacin internally and externally, but I don’t want to go without niacin entirely as a supplement because I take a small dose of many of the other B vitamins 5 days a week, and I don’t want my Bs to be imbalanced (which I experienced about 10 years ago when I was taking a highly-rated supplement that had a very unbalanced ratio of Bs and it caused me problems until I figured it out).
    Therefore, the main nutrients that are recommended to help APOE e4 people I don’t tolerate very well.
    There is a website and discussion group for APOE e4 people – I haven’t visited it in about a year, but it had good info at that time.
    When I found out this was one of my alleles (through 23andme that I did 7 years ago), I concentrated on researching other issues that were more pressing to my health for the first few years, and I only stumbled on the APOE e4 result a couple of years ago. After I realized that this is an important thing to know about my health and what it might involve down the road, I mentioned it to my doctors (all MDs – GP, endocrinologist, neurosurgeon) and the first 2 told me they’ve never heard of APOE e4 and they couldn’t address it, the third didn’t say whether or not they had heard of it specifically but replied, “We are all going to get Alzheimers, so it doesn’t matter and there isn’t anything you can do about it, aside from living a healthy life” (um………….). I switched endocrinologists and thankfully the new one had heard of APOE e4 and understood the significance of it, but after 2 visits to that person (which were dealing with more pressing health issues), my insurance company changed and I lost ALL my doctors. I don’t have high hopes to find new ones that know much about it or care (I live in an area of the US that isn’t entirely backwards but it isn’t at all forwards.)
    It’s amazing that a lot of MDs haven’t even heard of APOE e4 and don’t care to find out more about it when a thoughtful, educated, responsible patient brings it up as an important genetic finding. Whatever — I’ve had to self-diagnose and fight for treatment for some other major things in the last 10 years; it’s ridiculous.

  2. Lee says:

    I have read a lot of articles on apoe4 since finding out I have one allele for it and would like to minimize my risk. I am 66 years and still working full time in IT. Besides eating as much unprocessed food as possible one thing that strikes me is that in western society we eat too much and too often. I’ve done intermittent fasting off and on for a few years,but after reading Dr Bredesen’s book, I try and have a 12 hr fast every day and every 2-3 weeks I do a 20-24 hr water fast which I find rather exhilarating. Occ go for 48 hrs.
    I believe I got the allele from my mother’s side, but there is no documented Alzheimer’s on either side of the family.
    I also uploaded my raw 23&me data to get a full report. Interestingly there were a couple markers for increased cognitive ability so hoping my epigenetics and genetics work for me.

  3. gerald says:

    thank you for this article, as a APOE 3.4, I am looking to change my diet. I have worked out every day for the last 40 years both resistance trainng and running. No smoking, no hypertension, no diabetes and have the same waist size from high school. I have been eating a low carb diet with lots of saturated fat.
    2 things I will need to change
    1. Go vegetarian with whey protein to prevent muscle loss
    2. Stop 2 supplements that I take, fish oil and MCT oil. I already to take the ones you recommend.

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