Alzheimer's Disease: New Genetic Culprit Found

alzheimers risk

Story at-a-glance -

  • The gene thought to be most strongly associated with Alzheimer’s disease is the apolipoprotein E4 (APoE4) gene, but new research suggests TOMM40 is also a key player
  • A TOMM40 variant may actually be more influential than APoE4 in declines in immediate memory, i.e., the ability to hold onto new information
  • TOMM40 appears to play a role in memory decline independent of the APoE gene, particularly the decline of verbal learning after age 60
  • It’s estimated that genetics account for less than 5 percent of Alzheimer’s cases, and even if you have the aforementioned “Alzheimer’s genes,” it does not mean your fate is set in stone; many lifestyle changes can significantly lower your risk

By Dr. Mercola

The gene thought to be most strongly associated with Alzheimer's disease is the apolipoprotein E4 (APoE4) gene. Everyone inherits a form of APOE from their parents (it may be type e2, e3 or e4). If you inherit one copy of APoE4, it increases your risk of developing Alzheimer's, while inheriting two copies increases the risk even more — but is not a guarantee that you'll develop the disease. Research published in the journal PLOS One, however, suggests a different gene, known as TOMM40, is also a key player.1

APoE4 is thought to increase Alzheimer's risk by influencing the buildup of amyloid plaque in the brain, which is a hallmark of the disease. The featured research revealed a TOMM40 variant may actually be more influential than APoE4 in declines in immediate memory, i.e., the ability to hold onto new information, according to the study's first author, Thalida Em Arpawong, a postdoctoral fellow in the department of psychology at the University of Southern California.2

The study involved testing more than 30,000 participants for immediate and delayed recall by reading a list of 10 nouns and then asking participants to recall them immediately and five minutes later. A large discrepancy in the test results of each test can be a sign of dementia, including Alzheimer's. They then examined genetic data to see if there was a link between any genetic variants and the memory test results. Medical News Today reported:3

"Only TOMM40 was found to be strongly associated with a decline in immediate and delayed recall. The results also showed an association with the 'traditional' genetic culprit, APoE4, but the link was not as strong. Additionally, the analysis revealed that the e3 variant of the ApoE gene was also associated with a low memory score, when found in conjunction with the TOMM40 gene."

As noted by the study's senior author, USC psychology professor Carol A. Prescott, TOMM40 appears to play a role in memory decline independent of the APoE gene, particularly the decline of verbal learning after age 60. Further, she suggested memory problems attributed to APoE4 in other studies may actually be due to TOMM40 or a combination of the two, stating, "the causes of memory decline are even more complicated than we thought before."4

Genetics Account for Less Than 5 Percent of Alzheimer's Cases

An estimated 75 million Americans have the single allele for ApoE4. Those who are ApoE4 positive have a 30 percent lifetime risk of developing the disease. Approximately 7 million have two copies of the gene, which puts them at a 50 percent lifetime risk.

It's unknown how many Americans have the TOMM40 gene or others that may affect risk. It can be unsettling to hear that having a certain gene may predispose you to a disease like Alzheimer's, but keep in mind it's estimated that genetics account for less than 5 percent of Alzheimer's cases.5

Further, even if you have the aforementioned genes, it does not mean your fate is set in stone. Dr. David Perlmutter, a board-certified neurologist and author of The New York Times best seller "The Grain Brain Whole Life Plan: Boost Brain Performance, Lose Weight, and Achieve Optimal Health," explains:

"To be clear, no one inherits Alzheimer's. Some of us who have relatives [with] Alzheimer's … are at increased risk. We certainly know there are some genes, the apoliprotein E (ApoE) 3, 2 and 4 genes that are playing a role in carrying the ApoE-4 allele. It does increase a person's risk.

But this is not a determinant that you will or won't get the disease. It does indicate that you have a higher risk for that disease. But the beauty of what we are talking about is you can offset that risk. You can change your destiny."

In short, yes, there are certain genes that may be linked to Alzheimer's risk, some of which are likely yet to be discovered. But there are dozens of other factors that are also involved; genetics is only one small piece of the puzzle. For instance, research presented at the 2014 Alzheimer's Association International Conference (AAIC) revealed Alzheimer's patients with TDP-43, an infectious protein, were 10 times more likely to have been cognitively impaired at death than those without.6

Mounting research also suggests Alzheimer's disease is intricately connected to insulin resistance; even mild elevation of blood sugar is associated with an elevated risk for dementia.7 Diabetes and heart disease also elevate your risk, as all three conditions are rooted in insulin resistance. Arterial stiffness (atherosclerosis) is even associated with the buildup of beta-amyloid plaque in your brain.8

As such, according to Perlmutter, your diet is by far the greatest contributing risk factor. To prevent Alzheimer's, you need to focus on a diet that powers your brain and body with healthy fats, not net carbs (total carbohydrates minus fiber), i.e., a ketogenic diet.

A Ketogenic Diet for Brain Health

A ketogenic diet calls for minimizing carbohydrates and replacing them with healthy fats and adequate amounts of high-quality protein. I recommend a cyclical or targeted ketogenic diet for everyone, where you increase carbs and protein once you are able to burn fat for fuel on the two to three days a week you are strength training. I believe this is healthy for most individuals, whether they have a chronic health problem or not.

I say that because the ketogenic diet will help you optimize your health by converting from burning carbohydrates for energy to burning fat as your primary source of fuel. You can learn more about this approach to improving your mitochondrial function, which is also at the heart of Alzheimer's disease, in my book, "Fat for Fuel."

One of the most common side effects of being a sugar-burner is that you end up with insulin and leptin resistance, which it at the root of most chronic disease. Keep in mind that adopting the ketogenic diet along with intermittent fasting may further boost your results, especially if you have the ApoE4 gene.

Why Intermittent Fasting Is Critical If You Have the ApoE4 Gene

Interestingly, ApoE4 is actually a rather useful gene, as it helps your body survive famine. However, lack of food is a rare situation in most developed nations — most suffer health problems from an overabundance of food — but as soon as I heard this, I suspected having this gene could be a strong clinical indication that you absolutely need to do intermittent fasting or longer fasts on a regular basis in order to avoid Alzheimer's.

Dr. Dale Bredesen, director of neurodegenerative disease research at the University of California, Los Angeles (UCLA) School of Medicine, and author of "The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline," confirms my suspicion. For ApoE4-positive patients, 14 to 16 hours of daily fasting is recommended. He continues:

"This is absolutely the case. I think it's a very interesting point. ApoE is such a remarkably interesting gene … [It's] is a fat-carrying molecule … What does that have to do with Alzheimer's disease? Why do you start with ApoE4 and end up with Alzheimer's? We started looking at this. It turned out, surprisingly, that ApoE actually enters the nucleus. It binds to the promoters of 1,700 different genes. It literally reprograms your cell toward a more inflammatory state.

In fact, if you look at the groups of genes, you couldn't tell a better story about Alzheimer's. It binds to things related to neurotrophic support … ApoE has a big impact … The ApoE4 was the primordial gene that appeared between 5 and 7 million years ago … For 96 percent of all of evolution of hominids, we've all been ApoE4 double positive … ApoE3 appeared 220,000 years ago. ApoE2 appeared 80,000 years ago.

Interestingly, ApoE4 prepares you to change niches. When we moved from in-the-trees arboreal ancestors to walking on the savannah, stepping on dung, puncturing our feet, eating raw meat filled with microbes, we needed a pro-inflammatory gene. In fact, if you look at the genes that are different between simians and hominids, a surprising number of these are pro-inflammatory.

It also allows you to eat fat, absorb it better and go longer without eating. If you take people who are ApoE4-positive and -negative and starve them, the ones who are negative will tend to die earlier. Therefore, it's not that it's better or worse. It's different. It gives you some advantages. It gives you some disadvantages.

Therefore, you can learn to live your life slightly differently that is of advantage to you. My argument is that if you do the right things, Alzheimer's disease should be a very rare illness …"

150 Factors May Contribute to Alzheimer's Disease

Dr. Dale Bredesen's ReCODE protocol evaluates 150 factors, including biochemistry, genetics and historical imaging, known to contribute to Alzheimer's disease. This identifies your disease subtype or combination of subtypes so an effective treatment protocol can be devised.

For instance, Bredesen states that type 1 Alzheimer's is "inflammatory" or "hot," and patients present predominantly inflammatory symptoms. Type 2 is atrophic or "cold," with patients presenting an atrophic response. In type 3, or toxic "vile" Alzheimer's, patients have toxic exposures. There's also a mixed type, type 1.5, which is referred to as "sweet" and is a subtype that involves both inflammation and atrophy processes, due to insulin resistance and glucose-induced inflammation.

An algorithm is used to determine a percentage for each subtype based on the variables evaluated, and an individualized treatment protocol is created. For example, if you have insulin resistance, you want to improve your insulin sensitivity. If you have inflammation, then you'll work on removing the source of the pro-inflammatory effect.

Oftentimes you'll need to eliminate toxins and/or address leaky gut or a suboptimal gut microbiome. Interestingly, they also place great focus on the rhinosinal microbiome, the microbes residing in your nose and sinuses.

Further, as mentioned, restoring mitochondrial function is a cornerstone of successful Alzheimer's treatment, and one of the most powerful ways to optimize mitochondrial function is cyclical ketosis. Bredesen also recommends the following Alzheimer's screening test so you can evaluate your risk and then get on an appropriate program for prevention or, if you're already symptomatic, reversal:

Test Recommended range


40 to 60 ng/mL


Less than 16 U/L for men and less than 9 U/L for women

25-hydroxy vitamin D

40 to 60 ng/mL. You can get test here.

High-sensitivity CRP

Less than 0.9 mg/L (the lower the better)

Fasting Insulin

Less than 4.5 uIU/ml (the lower the better)

Omega-3 index and omega 6:3 ratio

Omega-3 index should be above 8 percent and your omega 6-to-3 ratio between 0.5 and 3.0. You can get the omega-3 index test here.

TNF alpha

Less than 6.0


Less than 2.0 microunits/mL

Free T3

3.2 to 4.2 pg/mL

Reverse T3

Less than 20 ng/mL

Free T4

1.3 to 1.8 ng/mL

Serum copper and zinc ratio

0.8 to 1.2

Serum selenium

110 to 150 ng/mL


5.0 to 5.5 μm

Vitamin E (alpha tocopherol)

12 to 20 mcg/mL

Body mass index (which you can calculate yourself)

18 to 25

ApoE4 (DNA test)

See how many alleles you have: 0, 1 or 2

Vitamin B12

500 to 1,500

Hemoglobin A1c

Less than 5.5 (the lower the better)


4.4 to 10.8 mcmol/L

You CAN Prevent, and Possibly Reverse, Alzheimer's

It's often said that Alzheimer's disease is incurable and there's no known cause. A more accurate statement would be that there are many causes, and, if you address the specific factors causing the cognitive decline, as Bredesen says, "There a tremendous amount you can do."

Alzheimer's disease has grown to be one of the most pressing and tragic public health issues facing the U.S. With the number of people affected expected to triple by 2050, the Alzheimer's Association estimates that by mid-century someone in the U.S will develop Alzheimer's disease every 33 seconds.9

However, by getting to the root of the disease, it may be possible to change that. In addition to the dietary strategies and intermittent fasting already discussed, Bredesen recommends, exercise to increase brain-derived neurotropic factor (BDNF), stress reduction, optimizing your sleep, which is critical for cognitive function, and nutritional support. Important nutrients include animal-based omega-3 fats, magnesium, vitamin D and fiber.

There are other exciting treatment strategies in the works as well, including photobiomodulation, in which stimulation of the brain with near-infrared light has been found to boost cognition and reduce symptoms of Alzheimer's, including more advanced stages of the disease. Dr. Lew Lim has developed a device called the Vielight, which employs light emitting diodes at these frequencies. Alzheimer's patients using the device for 20 minutes a day report remarkably positive results.

Electromagnetic exposures from wireless technologies are a crucial component that needs to be addressed, as this type of radiation activates the voltage-gated calcium channels (VGCCs) in your cells, and the greatest density of VGCCs are in your brain, the pacemaker of your heart and male testes.

It is my belief that excessive microwave exposure and glyphosate, which disrupts the blood-brain barrier, and at the root mitochondrial dysfunction, are among the most significant factors contributing to Alzheimer's. Getting back to genetics, you may or may not be among those who have an "Alzheimer's gene," so to speak, but it doesn't change the fact that you do have control over many factors that can cut your Alzheimer's risk considerably.

If you are genetically predisposed to the disease, it's even more important for you to take proactive steps to lower your risk, but, really, everyone could benefit from doing so. To learn more, be sure to pick up a copy of Bredesen's "The End of Alzheimer's: The First Program to Prevent and Reverse Cognitive Decline," which details all the different evaluations recommended in his ReCODE Protocol.

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