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Is Alzheimer's a Metabolic Disease?

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Quick Summary tl;dr

Alzheimer’s disease is not an unknowable mystery. For sure, there are still many unanswered questions and much research remains to be done. But that doesn’t mean we’re completely in the dark about what’s happening inside the Alzheimer’s brain and what to do about it.

To the extent that AD is a metabolic condition, the solution is also a metabolic one: change the way the brain gets energy. Owing to the way a ketogenic diet provides an alternative fuel to the brain—transitioning from dependence on glucose to reliance on ketones—it’s a logical and scientifically sound place to start.

If you'd like to learn more about Alzheimer's disease as "type 3 diabetes" and the potential therapeutic use of ketones and the ketogenic diet, consider exploring my book, The Alzheimer's Antidote: Using a Low-Carb, High-Fat Diet to Fight Alzheimer's Disease, Memory Loss, and Cognitive Decline.

Table of Contents

Whether you’re new to a ketogenic diet or have been following one for a while, you’ve probably heard this way of eating is beneficial for fat loss, diabetes (both type 2 and type 1), metabolic syndrome, PCOS, and more.

But what might come as a surprise is that this low-carb, high-fat way of eating is a promising nutritional intervention for a condition for which there are no effective treatments: Alzheimer’s disease.

What is Alzheimer’s Disease?

Alzheimer’s disease (AD) tops the list people’s most feared illnesses, and for good reason. Except for generally striking people of older age, Alzheimer’s seems to strike indiscriminately. AD affects people of all ethnicities, races, nationalities, faiths, and genders. There’s only one kind thing we can say about AD, and it’s that it doesn’t discriminate: Alzheimer’s is an equal opportunity killer.

However, even though Alzheimer’s disease typically strikes people later in life, it’s no longer a condition that exclusively afflicts elderly people. With a play on words, they used to casually call Alzheimer’s disease “Old Timer’s Disease.” But we’re not talking only about elderly people anymore. AD now affects people ever younger; individuals in their 50s and 60s are being diagnosed with early-onset Alzheimer’s, or the precursor to AD, called “mild cognitive impairment” (MCI). Why is this happening? Why is this frightening form of dementia increasing in incidence, and affecting people at younger ages?

Is Alzheimer's a Metabolic Disease?

Alzheimer’s is a Metabolic Condition

When it comes to conditions such as cardiovascular disease, obesity, type 2 diabetes, infertility, and more, we take it for granted that diet and lifestyle play a role, if not the primary role. No one even questions this anymore.

But for some reason, when it comes to Alzheimer’s, we believe we’re clueless. We feel like we have no idea where it’s coming from, while ignoring the possibility that it might be driven by the same factors behind so many other chronic modern diseases: diets and lifestyles that are a mismatch for healthy human physiology.

In scientific journals, Alzheimer’s disease is regularly referred to as “type 3 diabetes” or “brain insulin resistance” ( 1,  2). Without knowing anything else about the condition, these phrases immediately hint that there’s a connection to glucose and/or insulin in the brain.

Indeed, the primary problem in the Alzheimer’s brain is that neurons in affected regions have lost the capacity to get energy from glucose. Ultimately, Alzheimer’s disease is a metabolic problem; that is, it has to do with the way the brain generates and uses energy.

This condition is complex and multifactorial, but at its heart, AD is an energy crisis in the brain. A fuel shortage. And the brain is an energy hog — it needs constant fuel, and lots of it. The brain accounts for just 2% of a typical adult’s body weight, but it consumes 20-25% of the body’s glucose and oxygen. With such high energy requirements, any disruption in fuel supply to areas responsible for memory processing, learning, and behavior would have catastrophic consequences for cognitive function:

Is Alzheimer's a Metabolic Disease?

“Given the high energy requirement of the brain and its critical dependence on the delivery of a constant supply of fuel, the consequences of leaving such an energy shortfall untreated can be dire. When the brain’s energy supply is insufficient to meet its metabolic needs, the neurons that work hardest, especially those concerned with memory and cognition, are among the first to exhibit functional incapacity (e.g., impairment of memory and cognitive performance)” ( 3).

In keeping with the idea that AD is a brain energy shortage, think about what happens when you’re tired. You get clumsy, right? You move more slowly, and you make mistakes you wouldn’t normally make. Well, what happens when the brain gets tired? It, too, gets clumsy, sluggish, and starts making mistakes. And considering just how much energy the brain needs every second of every day — even when we’re asleep — anything that interferes with fuel use in the brain will have a negative impact on cognition.

What is a Neuron and How Does it Work?

Here’s a simplified look at the basic structure of a neuron:

Is Alzheimer's a Metabolic Disease?

The way neurons communicate with each other is that neurotransmitters and other chemical messages are broadcast out the axon terminals of one neuron and received at the dendrites of other neurons, like a radio station broadcasting a signal. But axon terminals and dendrites don’t actually touch. There’s a tiny bit of space between them, called a synapse, and this is where the communication happens.

Is Alzheimer's a Metabolic Disease?

When a neuron is not receiving or using adequate fuel, in order to conserve energy to keep the cell body alive (the main part of the cell), the neuron sucks the axons and dendrites back in toward the cell body, like a vacuum with a retractable cord.

When the axons and dendrites recede back toward the cell body, the synapse is no longer viable; the space is too big for proper communication to occur. Memory loss and cognitive impairment are the logical outcomes of this. The receding of these crucial structures can be seen via MRI scan (magnetic resonance imaging): doctors can actually see that the physical volume of the brain has shrunk.

Alzheimer’s Takes Years or Even Decades to Develop

The rate at which the brain uses glucose is called the cerebral metabolic rate of glucose (CMRglu). Alzheimer’s patients may have up to a 45% reduction in CMRglu. Reduced brain glucose usage is a universal feature of AD, and some researchers have called this the predominant abnormality in the condition ( 4). A key point here is that this decrease in CMRglu can be measured in people at risk for AD as young as their 30s and 40s ( 5).

Alzheimer’s doesn’t develop overnight. No one wakes up “all of a sudden” with severe AD. Reduced brain glucose metabolism is one of the earliest steps in the disease process, if not the earliest step. However, even if someone in their 30s or 40s is already experiencing a decline in CMRglu, they typically don’t show any signs or symptoms of dementia. At that age, they’re still young and robust, and the brain is able to compensate.

Is Alzheimer's a Metabolic Disease?

Signs and symptoms only emerge when a tipping point has been reached where the “fuel crisis” has been going on for so long, and the resulting damage is so widespread, that the brain can no longer make up for it. But it’s important to understand that signs and symptoms emerge relatively late in the disease process; by the time cognitive problems are noticeable, the pathology has been in place for years, maybe decades ( 6,  7).

This may be part of why the illness has proven so difficult to treat. That damage often accrues silently for so long is also why putting efforts toward potential prevention is so crucial, rather than focusing solely on slowing or stopping the decline once it’s already begun.

What are the Risk Factors for Alzheimer’s Disease?

Advanced Age

Obviously, one of the primary risk factors for developing AD is advanced age. According to the Alzheimer’s Association:

“Of the estimated 5.5 million Americans living with Alzheimer's dementia in 2017, an estimated 5.3 million are age 65 and older and approximately 200,000 individuals are under age 65 and have younger-onset Alzheimer's.”

AD is the sixth leading cause of death in the U.S., and the fifth leading cause of death among people age 65 or older. However, keep in mind that, as I’ve mentioned, it’s likely that the disease only becomes apparent at this older age. The pathological problems driving the disease begin in much younger years.

ApoE4 Gene

Aside from advanced age, there are multiple risk factors for AD. One of the strongest is the ApoE4 gene. This is even sometimes called “the Alzheimer’s gene,” but this is misleading (8).

We have two copies of each gene, one from our mother and one from our father. And it’s true that having one copy of the ApoE4 gene increases risk for AD, and having two copies increases it even more. But not everyone with two copies develops Alzheimer’s, and many people who are afflicted with Alzheimer’s do not carry even one copy! So, this gene is neither required, nor sufficient, to cause AD ( 9).

This being the case, why does ApoE4 increase risk so much?

Like so many modern chronic illnesses that have reached epidemic proportions, Alzheimer’s disease seems to be a mismatch between our evolutionary conditioning and our current diet and lifestyle ( 10,  11).

The ApoE4 gene is strong evidence for this. E4 is believed to be the oldest form of the ApoE gene. (The two other forms of ApoE in humans are E2 and E3.) It’s hypothesized that the E4 variant was forged during our hunter-gatherer times, and it has been selected against in populations with a longer history of grain-based agriculture ( 11,  12).

In other words, human populations with a longer history of consuming grains — that is, a higher carbohydrate diet — have a lower incidence of this gene. So it’s not that the E4 gene, by itself, is harmful. What it means is, people who carry the E4 gene are not well-suited for a high-carb diet, and thus, they suffer the greatest metabolic damage when faced with the modern diet, which is awash in refined sugars and grains.

According to prominent Alzheimer’s researcher Sam Henderson ( 11):

“It should be noted that E4 is not an inherently damaging allele; it is only deleterious in combination with a HC [high-carb] diet (which is deleterious on its own).”

Chronically Elevated Insulin

Beyond genetics, a powerful risk factor for developing AD is chronically elevated insulin, also called hyperinsulinemia. Even for people whose blood glucose is normal, if insulin is chronically elevated, risk is greater for developing AD. ( 13,  14,  15,  16)

For this reason, the phrase “type 3 diabetes” is a bit misleading. Type 2 diabetes is diagnosed solely through glucose measurements, but with regard to AD, it’s not always high glucose causing the problem, but rather, high insulin. The reason this important risk factor is missed in so many people is simply that insulin testing is not a standard part of routine bloodwork, the way fasting blood glucose measurements are.

Even hemoglobin A1c, which is taken to represent a 3-4 month average of blood glucose levels, has become commonplace, but insulin is still rarely measured. If insulin tests were included in routine checkups, people at risk for disorders associated with insulin resistance — such as gout ( 17), hypertension ( 18), PCOS ( 19), benign prostate hyperplasia (BPH) ( 20), and Alzheimer’s — could be identified long before these conditions take root and cause years of worsened health and reduced quality of life.

“Insulin resistance is usually at or near the top of the list of known lifestyle-related factors heightening the risk of declining cognition in the elderly” ( 21).

“An emerging body of evidence suggests that an increased prevalence of insulin abnormalities and insulin resistance in Alzheimer’s disease may contribute to the disease pathophysiology and clinical symptoms” ( 22).

What is the Role of Beta-Amyloid in AD?

If someone in your life is afflicted with Alzheimer’s, or you’re interested in AD research, you’ve no doubt come across the terms beta-amyloid, or amyloid plaques. Amyloid plaques are frequently cited as the cause of Alzheimer’s, but there are problems with this theory. First, though, what is beta-amyloid, and what does it do?

Beta-amyloid (Aβ) is a protein secreted by neurons in response to injury, be it biochemical injury, as in Alzheimer’s, or physical trauma, as is observed in traumatic brain injury ( 22,  23). When these initially protective protein fragments are cleared away efficiently, they’re not a problem. But when they’re left to accumulate — as if the cleanup crew that’s supposed to sweep them away is on strike — they bind to each other and form “plaques.” These plaques block the synapses between neurons, ultimately interfering with neuronal communication. When neurons can’t send signals back and forth, the logical results are declining cognition, memory loss, behavioral changes, and the other problems we observe in AD.

Are Amyloid Plaques the Cause of AD?

So it seems logical that these amyloid plaques could be causing Alzheimer’s. However, many people who lose their lives to AD do not have extensive plaque deposition in the brain, and plenty of people who die from other causes are found upon autopsy to have significant plaque deposition ( 24). Plus, the plaques tend to appear late in the disease process. The first domino to fall — the earliest step in the pathology — is the reduction in the brain’s glucose metabolism. The plaques come much later. Amyloid plaques might be exacerbating cognitive impairment, but they’re not the initial cause.

“A prominent and well-characterized feature of AD is progressive, region-specific declines in the cerebral metabolic rate of glucose (CMRglc) […] Carriers of a common Alzheimer’s susceptibility gene [APOE Ɛ4] have functional brain abnormalities in young adulthood, several decades before possible onset of dementia. Therefore, low regional CMRglc appears to be a very early event in the disease process, well before any clinical signs of dementia are evident, and well before cell loss or plaque deposition is predicted to have occurred” ( 29).

Why Amyloid Proteins Are Neuroprotective

Additionally, amyloid proteins are neuroprotective. They have numerous functions that suggest they play a vital role in neuronal repair and regeneration ( 22). If they were contributing to the disease pathology, then we would expect a drug that reduced secretion of these proteins and formation of the plaques to have a beneficial impact on the illness.

It is noteworthy, then, that every drug developed to target these proteins and plaques has been a failure. They’ve succeeded in that they did reduce secretion of amyloid proteins and plaque formation, but these reductions led to no improvement in the condition. In fact, phase III clinical trials of one such drug were stopped early because in subjects on the drug, cognitive function was declining so much faster than in those on the placebo, and it would have been unethical to continue (25).

The amyloid proteins are initially protective, but it’s true that when they form into plaques, things can go awry. Think of it like a fever: a fever is initially a protective step. It’s your body’s way of raising your core temperature in order to fight off a pathogen inside you, like a virus or bacteria. But if the fever goes too high, then the fever, itself, becomes a problem. It’s a similar situation with amyloid proteins. At relatively low levels, they’re helpful. It’s only when they build up and start linking together that they form plaques and interfere with cellular communication.

The Role of Insulin Degrading Enzyme (IDE)

What’s fascinating about this is, what’s responsible for clearing them away — the cleanup crew I mentioned before — is something called insulin degrading enzyme. This is exactly what it sounds like in plain English: it’s the same enzyme that clears away insulin. (Some enzymes in the body have only one job, but others, like IDE, have multiple jobs.)

The key thing to know here is, IDE favors insulin above everything else. So, whenever there’s a significant amount of insulin to be cleared out of the blood, IDE will always be drawn to it first, leaving all its other jobs — like clearing away amyloid — to be done later.

When someone has healthy insulin levels most of the time, this isn’t a problem. But in someone with chronically high insulin — as is the case for so many people these days — the vast majority of IDE’s attention will be on dealing with all the insulin, and as a result, the amyloid is left build up and cause trouble ( 26,  27).

People With the E4 Gene Produce Less IDE

An interesting tidbit that connects IDE to the ApoE4 gene and the increased risk it confers for AD is that people with the E4 gene produce less IDE than people with other variations of this gene ( 28).

That’s right: they produce less IDE, perhaps suggesting that, as hunter-gatherers presumably with a much lower carbohydrate intake, they may have produced less insulin, and thus have had less need for the enzyme that degrades it.

To Be Continued…

If Alzheimer’s disease results primarily from a fuel shortage in the brain — a shortage occurring because affected neurons are no longer able to use glucose effectively — then if there were some kind of alternative fuel that could nourish these starving cells, perhaps we could slow the progression of this illness, or, if caught early enough, potentially even stop it and undo some of the damage. Next time, we’ll explore exciting research that gives us hope in the otherwise vast darkness that surrounds this condition.

Here’s a sneak peek:

“Two points are clear — (i) AD is at least in part exacerbated by (if not actually caused by) chronic, progressive brain fuel starvation due specifically to brain glucose deficit, and (ii) attempting to treat the cognitive deficit early in AD using ketogenic interventions in clinical trials is safe, ethical, and scientifically well-founded” ( 30).

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Amy Berger, MS, CNS, NTP
Certified Nutrition Specialist and Nutritional Therapy Practitioner

Amy Berger

Amy Berger, MS, CNS, NTP, is a U.S. Air Force veteran, Certified Nutrition Specialist and Nutritional Therapy Practitioner who specializes in using low-carbohydrate nutrition to help people reclaim their vitality through eating delicious foods, and showing them that getting and staying well doesn't require starvation, deprivation, or living at the gym.

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This article was written by Amy Berger, MS, CNS, NTP who is a qualified expert. At KetoDiet we work with a team of health professionals to ensure accurate and up-to-date information. You can find out more on the About us page.

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Evidence-Based articles are based on medical research, and scientific evidence. Our expert authors focus on hard evidence alone and include relevant research references from trusted sources to support their articles. We always aim to deliver relevant, trustworthy and up-to-date information based on trusted evidence and proven research.

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Comments (19)

Do you have a list of your references? I have some friends who love to see the science behind blog posts! Thanks!

Hi Tina, all is referenced in the article - simply click on the numbers and you'll find all the research this article is based on. I hope this helps.

The way to convert your loved ones to Keto is by not talking so much about it but making such interesting and delicious dinners they can't help but start eating Keto.  My own husband didn't join me when I started Keto and I ate the wonderful things I made all by myself and cooked his regular things for him.  In time he asked to try what I had because it looked like a gourmet meal and the smell was awesome.  So now he eats mostly Keto with me on non-work days when he is home but on work days when he takes lunch and doesn't eat supper he eats whatever he packs for lunch and snacks.  I made low carb lemon poppy seed muffins yesterday that he loved and after taking a bite and saying how good it was, the next questions was "is this Keto?"  I love this man and want him to be around a very long time so he's just got to lose that belly and get healthy.  In time!  

Thanks Amy
For such an informative post. Any ideas on how to get a stubborn man to convert to Keto? I am doing it and you would think he would since his family has had so many people pass away from AD. I just can't convince him (but maybe you could) that he needs to at least become grain and sugar-free. To me, it's almost like he is trying to eat all the bad stuff he can, just to spite me! I am his wife, so I don't want to constantly nag, but I need help! I don't want him to end up like his Dad who was diabetic and had AD, his dad's mother, his maternal grandmother and his mother's sister. Any suggestions would be welcome.

Hi Kim,
Unfortunately, the way you convince anyone to change their diet is, you don't. He's a grown man, and he makes his own decisions. The best and fastest way to turn someone OFF from giving this a try is to push it on them or get preachy. The best you can do is live by example, feel and look great, have good energy, and let the way you eat speak for itself. (Or, you could always pick up a copy of my book and leave it sitting around in a place he might see.)  😉   I wish I had a better answer for you, but the truth is, it's very difficult to get someone to do something they're not interested in doing, and when you try too hard, you run the risk of causing a rift and making the likelihood of them ever trying it even lower.

Thank you for sharing this new research with us.
My great grandmother (mom's father's mom) died of Alzheimer’s disease, and it's a terrible thing to watch someone lose their ability to think or even take care of themselves.  I was recently diagnosed diabetic and am following a low carb diet now to help control blood sugar.  If a low carb lifestyle may help prevent future cognitive problems, that gives me even more motivation to stick with it!  

Thank you Amy for this wonderful post. As the son of an AD effected mother, I understand this struggle. She was diagnosed at the age of only 55, but showed signs for degrading mental function and capacity to learn new things. She is now only 62 and in severe dementia and we had to move her to assisted living... Needless to say, I’m scared to death that I may follow her path and leave my young family with the burden and heartache of having to deal with this again. I’m researching numerous ways to improve resistance to brain failure and have implemented a number of them. Whether they will work, I may never know, but worth the effort to potentially work.  My wife and I just started Keto this week. One of the reasons we selected it, as opposed to other diets was the potential relationships to resistance to dementia.  Your blog was a welcome read. Thank you.  
The only part I struggle with about the Keto diet is the reliance on artificial sweeteners and their “associations” with dementia. My mother drank 2 liters of diet soda for as long as I can remember. Sweet and Low (aspartame) in any tea.  She consumed a lot of it for a long period of time. I feel often that this may have been a cause for her early failure. About a year ago I removed all artificial sweeteners from my diet. Even bought genuine sugar gum from Europe since I can’t find it in the US. Don’t let me get started on the FDA. Now though, I’m being encouraged to use artificial sweeteners in order to achieve any level of sweetness in my Keto foods.
Thanks again

Hi Jason,
Try Stevia, it’s all natural, has zero calories and is sweeter than sugar.

Just use Stevia. Artificial sweeteners will raise insulin which will stay circulating in the blood as there is no glucose for it to break down.
Try to stick to meat and veg (not root) with plenty of fat.

Although erithitol sounds artificial it is derived from fruits and vegetables. It is processed, but no more than actual sugar is!

Jason, please don't think you need to use artificial sweeteners to follow the keto diet. There are plenty of natural low-carb or no-carb sweeteners available. Try erythritol which is a natural sugar alcohol that has just a few non-digestible carbs so you don't even have to count them. Stevia is another natural sweetener, as is monk fruit extract. Any of these three are perfect for the keto diet. Good luck!

Thank you for sharing this with us, Jason! This may help: Complete Guide To Sweeteners on a Low-Carb Ketogenic Diet

Hey Jason,
Thanks for reading. I echo what's said below -- that you don't "have to" use artificial sweeteners to follow a low carb diet. They certainly make things easier, but they're not required. You can use stevia, or even very, very small amounts of natural sweetener, like honey or molasses. (Small amounts!) Most of the physicians I know who use low carb and ketogenic diets with their patients have no qualms about artificial sweetener use, but it's an individual decision -- do what you feel is right for you. You also don't absolutely have to stay in ketosis at all times in order to have a fat-based metabolism and remain metabolically healthy, so depending on your individual situation, you might have slightly more "wiggle room with sweetening agents (and carbohydrates in general) than you think you do.

Jason, I also recommend reading Dale Bredesen's book, The End of Alzheimer's, if you haven't already. I think it's a good complement to my own book, The Alzheimer's Antidote. (We didn't mention my book in this post, but you can find it on Amazon.)  

I’m a hairstylist and I have a client who’s  Father part...from Aspartame poisoning.   He, like your Mom, consumed excess amounts of Aspartame.  At autopsy they found it had shrunk his cerebellum.  

Great article, can’t wait for the follow-up!

Thanks for reading!  😊  Coming soon.

Fantastic blog post! Thank you!

Glad it was helpful!