Is Alzheimer's a Metabolic 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?

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:

“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:

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.

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.

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).