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How much does ApoE4 increase Alzheimer’s risk?

Alzheimer’s disease is the most notorious 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.1

Needless to say, an Alzheimer’s diagnosis is among the most dreaded anyone can receive, but what causes dementia?

In this post, we discuss the 5 big causes of Alzheimer’s disease, plus the APOE gene, and how much carrying one or two copies of ApoE4 increases the risk for developing Alzheimer’s.

What causes Alzheimer’s disease?

The progression of Alzheimer’s is relatively well understood, with regions of the brain shrinking (displaying atrophy) and the growing 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, with the regions responsible for memory being hardest hit.

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

The nutrition wars on brain health

In nutrition circles, there is heated disagreement as to what causes the limited blood flow to the brain we see in Alzheimer’s Disease.

Plant based advocates characterize the problem as caused by dietary fat and cholesterol causing coronary artery disease which constricts blood flow to all regions of the body, including the brain, and ultimately prevents the brain from using its preferred fuel source: glucose.

By contrast, Paleo circles blame the problem on grains and sugar in the diet, calling Alzheimer’s disease “diabetes 3.” The Paleo view, most vocally advanced by Dr. David Perlmutter, is essentially that insulin resistance, marked by an inability to use the carbohydrate fuel we eat causes Alzheimer’s.

So, who wins?

Neither side can claim victory for all people.

However, as we covered in this post, the plant based community has the better of the science when a higher fat diet causes an uptick in LDL-P, blood pressure and other cardiovascular risk factors. In other words, if you want to answer this question for yourself, have your blood work done. If you inflammatory markers look better eating eggs, wild fish and butter, you have a clue a low glycemic diet could be right for you to protect vascular and brain health. But be cautious – those with the greatest risk of developing dementia, carriers of the ApoE4 genotype, very often have an inflammatory reaction to a high fat diet. These individuals are often healthiest on a largely Vegan diet that adds in healthy animal sources of omega-3 fats.

If you are one of the people, like our Villager or Okinawan diet types are more likely to be, who see a big uptick in cholesterol on a high fat diet, a more plant based diet, subject to your doctor’s advice of course, is likely the better option.

For more, see our ApoE4 case study podcast episode.

Age increases risk for Alzheimer’s

Although the food we eat plays a role, age is the most significant factor related to the development of Alzheimer’s disease. In fact, the risk of developing the disorder doubles every 5 years beyond 65 years of age.

However, approximately 1 in 20 individuals will develop Alzheimer’s before the age of 65, with this form of the disease termed “early onset Alzheimer’s.” This version of dementia 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.

Of course, there are other genetic factors which can predispose people, which we’ll get into below.

Lifestyle and heart disease

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. Major blockages in blood flow to the brain will lead to a stroke, but long term “low grade” reductions are also associated with poor health outcomes.2 The bottom line is heart health plays a big role in protecting the brain, and the big 5 lifestyle contributors to Alzheimer’s listed below all degrade cardiovascular health.

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 / heart health and can be prevented.3

The big ones are:

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

Note: If you participate in daily exercise, it will help improve cognitive function and reduce the formation of amyloid plaques, especially among ApoE4 carriers. 4

The APOE gene and Alzheimer’s

I will now pass the microphone to Aaron, our in-house geneticist, for the technical aspects of APOE.

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 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. 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 the plaques associated with Alzheimer’s.5

APOE ε2, APOE ε3, and APOE ε4

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.56

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.78

How to tell if you have ApoE4

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
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.9

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). 9

The bottom line

Is Alzheimer’s a genetic disease, or can it be controlled by following a healthy lifestyle?


As we learned from Aaron’s section on ApoE4, carrying two copies of ApoE4 increases risk by 19 times. Clearly genetics play a role.

But why would ApoE4 increase risk? Familial hypercholesterolemia and ApoE4 often appear together, with ApoE4 carriers showing a propensity for major upticks in “bad cholesterol” when eating a higher fat diet.10

Some people can eat a high fat diet and see only very small changes in lipids. If this is you and you’re eating a high fat / low carb diet, great. You might not need to change a thing.

By contrast, if you find your body works in the opposite direction, and a diet higher in meat and fat raises blood pressure and bad cholesterol, you could be one of the people who belong on a plant based diet.

The only way to find out is to test. Go see a physician who runs a Boston Heart or Cleveland Heart diagnostic test. Get a full panel. Find out your LDL-P number, Lp(a), homocysteine, TG, uric acid, C-reactive protein, serum TMAO, etc.

Then understand, directionally, why the numbers sit where they do.

For ApoE4 carriers, the plan will likely be more obvious – greater synthesis, lower clearance, and perhaps greater absorption of cholesterol, contribute to bad lipid numbers, which means a largely plant based diet that includes plenty of wild salmon, is likely the best diet for preventing Alzheimer’s. Even these folks may find too much salmon takes their LDL-C to a place they don’t like.

Others may find they need to head in a different direction and that they develop TG LDL-P when eating a diet high in refined carbohydrates.

This is chess, not checkers and there is no substitute for running the appropriate tests (multiple times) and then honoring the results under the supervision of a knowledgeable practitioner.

Dr. Dan Deakter, MD

Dr. Dan Deakter, M.D., serves as the Medical Advisor of Gene Food. He trained in General Surgery at The Albert Einstein School of Medicine in NYC, and is an ABEM certified Emergency Physician. His medical practice is currently focused on improving health span and longevity.

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