Ketogenic Diet and Alzheimer’s Disease

Estimated reading time: 30 minutes

Author’s note: As a Licensed Mental Health Counselor with 16 years of private practice experience, I’ve spent the last six years transitioning individuals with mental illness and neurological disorders onto a ketogenic diet. It took me a long time to write this article, and I am not sure why. I think, as someone who suffered from cognitive impairment in my personal health history, this post felt emotional and difficult to be objective about. I didn’t have Alzheimer’s disease (thank goodness), but I did have the cognitive impairment of someone with Stage 1 Alzheimer’s disease. Also, as a mental health counselor, I sit with patients who are watching their loved ones slip away from them due to this illness. The research is much farther ahead on this topic than it was in September 2021 when I began this blog. So much so that I feel quite confident in the strong assertion I have made in the creation of the title “The Ketogenic Diet: An Unrivaled Approach to Combating Alzheimer’s Disease.” And now, something deep in my gut tells me it is time. I write this blog article in the hopes that someone (like you) will find it and learn of a powerful way to markedly slow or stop the disease progression of this illness for themselves or someone they love.

Introduction

I am not going to go into what Alzheimer’s disease is or its prevalence rates. If you are visiting this post, you are likely here to learn about better treatment options, and time is of the essence. Neurodegenerative processes like dementia are time-sensitive conditions. The longer you wait to treat underlying causes, the more damage is done. Nonetheless, it’s important first to get a handle on existing treatments and their shortcomings. This knowledge will allow you to contrast them with the potential advantages of the ketogenic diet to you or your loved ones.

Current treatment options for Alzheimer’s are nothing short of bleak. Currently approved medications – typically cholinesterase inhibitors and NMDA receptor antagonists – mainly aim to manage the symptoms rather than address the underlying disease mechanisms driving the neurodegenerative process.

Cholinesterase inhibitors such as Donepezil (Aricept), Rivastigmine (Exelon), and Galantamine (Razadyne). These drugs work by slowing down the breakdown of acetylcholine, a neurotransmitter involved in memory and cognition, which is often depleted in Alzheimer’s patients. Common side effects can include nausea, vomiting, and diarrhea.

NMDA receptor antagonists like Memantine (Namenda). This drug works by regulating the activity of glutamate, another neurotransmitter that plays a role in memory and learning. Overactivity of glutamate can cause cellular damage, which Memantine attempts to help to prevent. Potential side effects include dizziness, headaches, and confusion.

While these medications can provide temporary relief for some symptoms like memory disturbances and confusion, they often fall woefully short in halting or even slowing the disease’s progression. Moreover, these drugs come with a litany of potential side effects, ranging from nausea and diarrhea to serious heart rhythm disturbances.

But what about the promise of anti-amyloid beta (Aβ) drugs? These have been promised as the cure, and if we hold out a little bit longer, this miracle drug is going to fix Alzheimer’s disease. Right?

These drugs compromise long-term brain health. So why in the world would we be using this for Alzheimer’s disease? And why are neurologists not providing adequate informed consent to patients about the limitations and dangers of using drugs to attempt to treat the symptoms of Alzheimer’s disease? In our bid to temporarily ease the symptoms, we may inadvertently exacerbate the overall disease trajectory.

In the following sections, we’ll delve deeper into the pathological processes underlying Alzheimer’s disease and explore how a ketogenic diet might interact with these mechanisms – and why you have the absolute right to know about it as a potential treatment for you or someone you love.

Central to Alzheimer’s pathology is a phenomenon known as brain hypometabolism. Let me explain better what that term means.

Brain hypometabolism refers to a state of reduced metabolic activity in the brain, characterized by a decreased uptake and utilization of glucose – the primary energy source for brain cells. This disastrous metabolic slowdown is not just a mere lack of energy, although that would be devastating enough. It triggers a cascade of detrimental effects that impair neuronal function and disrupts communication between brain cells.

Neurons are highly energy-dependent; even a slight energy deficit can significantly impact their ability to function. Without the ability to utilize glucose for fuel, they become less efficient at transmitting signals, and their ability to form new connections, essential for learning and memory, is compromised. Over time, sustained hypometabolism can lead to the loss of neurons and a subsequent reduction in brain volume (shrinkage of the brain), both of which contribute to cognitive decline and the emergence of symptoms associated with conditions like Alzheimer’s Disease. Hence, brain hypometabolism represents a key factor in the pathogenesis of various neurodegenerative disorders.

Let me be very clear in case that last sentence didn’t hit home for you.

This is not a matter of debate or contention in the scientific community. Brain imaging studies have consistently shown reduced glucose uptake in certain areas of the Alzheimer’s brain. Numerous peer-reviewed studies have linked this diminished metabolic activity to the cognitive decline and memory loss that characterizes Alzheimer’s Disease.

It’s not a hypothetical link or mere correlation but a firmly established aspect of the disease’s pathology. Hence, brain hypometabolism is not a side effect or an outcome of Alzheimer’s; it’s a core part of the disease process itself.

Faced with this irrefutable evidence, targeting brain hypometabolism emerges as an essential, arguably paramount strategy in grappling with Alzheimer’s Disease. Yet, despite its core role in the disease’s progression, brain hypometabolism remains unaddressed by current medications or standard-of-care treatments for Alzheimer’s Disease.

Hypometabolic Brain Structure in AD

As previously mentioned, in AD, this metabolic impairment is particularly evident in specific brain regions critical for memory and cognitive functions. Two regions frequently implicated are the parietal lobe and the posterior cingulate cortex.

The parietal lobe, located near the back of the brain, is responsible for various tasks, including spatial navigation, attention, and language processing. Its impairment can lead to difficulties in performing these tasks, manifesting as getting lost easily, struggling to maintain attention, or having trouble with reading or understanding speech.

The posterior cingulate cortex, found in the middle of the brain, plays a vital role in memory retrieval and cognitive control. Dysfunction in this area can contribute to difficulties in recalling information and making decisions, which are hallmark symptoms of AD.

As the ability of these regions to effectively utilize glucose diminishes, so too does their ability to perform these critical tasks, contributing significantly to the cognitive decline seen in AD.

But I do not want to give you the impression that it is just a couple of areas of the brain that become hypometabolic in Alzheimer’s disease.

In Alzheimer’s Disease, brain hypometabolism isn’t confined to a single area, but rather, it manifests in a progressive manner, affecting various regions over time. While it’s true that the parietal lobe and the posterior cingulate cortex are among the earliest and most severely affected, as the disease progresses, other areas of the brain also experience reduced glucose uptake and utilization.

Notably, the frontal lobe, the seat of our executive functions like decision-making, problem-solving, and emotional control, eventually becomes hypometabolic in the later stages of the disease. This metabolic decline in the frontal lobe can lead to behavioral changes, impaired judgment, and difficulties in carrying out routine tasks.

But the problem of brain hypometabolism doesn’t just stop there.

In Alzheimer’s Disease, brain hypometabolism insidiously spreads beyond the initially affected areas, gradually engulfing virtually the entire cerebral cortex, the brain’s outermost layer tasked with higher-order functions. Of particular significance is the temporal lobe, home to the hippocampus—the brain’s memory epicenter. As metabolic activity dwindles in these regions, symptoms associated with Alzheimer’s, such as memory loss, become increasingly apparent. The pervasiveness of this metabolic disruption underscores the critical importance of combating this issue head-on.

According to a publication from the National Center for Biotechnology Information (NCBI) database, researchers have observed a reduction in glucose utilization in specific regions of the brain, indicating brain hypometabolism. This phenomenon occurs at least 15 years (possibly 30) before severe enough manifestation of symptoms associated with Alzheimer’s disease. While there is potential for utilizing brain imaging and spinal fluid analysis to evaluate the risk of Alzheimer’s disease over a decade or more before the typical manifestation of symptoms, including mild cognitive impairment, don’t expect your doctor to offer this level of testing anytime soon. Currently, the medical establishment does not take your early cognitive symptoms seriously enough to offer them.

Luckily we have the ketogenic diet—literally a metabolic brain therapy.

Inducing a state of ketosis shifts the body’s energy source from glucose to fatty acids, which are broken down into ketone bodies, like beta-hydroxybutyrate and acetoacetate.

Two of these ketones, beta-hydroxybutyrate and acetoacetate, are ridiculously efficient at bypassing dysfunctional glucose metabolism in the brain. They can be swiftly and efficiently taken up by brain cells for fuel, thereby reinvigorating the brain’s energy supply.

Is all this feeling theoretical? No worries. I encourage you to watch this video of a brain literally lighting back up with energy after an infusion of just one of these ketone bodies in a research study.

But you’ve been told brains need glucose! What is going to happen to me or my loved one if we cut carbs that low? Your brain makes all the glucose your body needs through gluconeogenesis, which provides it in just the right amount and schedule. In fact, eating too many carbohydrates may have helped create the problem of brain hypometabolism to begin with.

When you or your loved one restricts your carbohydrate intake for a long enough period, the body will use both the dietary fat you eat and the fat it burns off the body to produce ketones. If someone is malnourished or has a lower weight, it just means we increase dietary fat intake to keep the energy up and minimize the potential for any weight loss.

Since we are talking about brain metabolism and brain energy, I need you to know that ketogenic diets do not just rescue brain energy by providing an alternative fuel source. They are also molecular signaling bodies.

And as that applies to energy, you should know that they turn gene pathways on that allow more mitochondria (power plants of the cells) to be created and also allows the existing powerhouses (mitochondria) to work more efficiently and function better. As you can imagine, this has a lot of beneficial downstream and healing effects for the struggling Alzheimer’s brain struggling with energy production.

And my goodness, wouldn’t just this one effect of ketogenic diets being able to correct brain hypometabolism be such a godsend? Wouldn’t just this one effect be a better treatment all by itself than all the medications we currently use as a standard of care? Yes! It absolutely would. And I would leave this article at that and send you on your way toward your healing (or that of your loved ones). But there are actually additional effects that a ketogenic diet provides that are so instrumental in slowing or stopping Alzheimer’s disease progression. I want you to know them all.

Keep reading.

Oxidative Stress in Alzheimer’s Disease: Utilizing Ketogenic Power

Considering impairment of mitochondrial function is a driver of oxidative stress (OS), it should come as no surprise that oxidative stress is part of what drives the disease process in Alzheimer’s disease (AD).

For those new to this term, oxidative stress describes the imbalance that occurs in our bodies between harmful molecules called reactive oxygen species (ROS) and our ability to defend against them. You can’t be alive and not make ROS, as they are a normal part of metabolism, but in the Alzheimer’s brain, oxidative stress goes off the charts, and the brain’s inability to combat it drives disease progression, causing damage to our neurons, proteins, and DNA. This damage is what we refer to as oxidative stress. But what does oxidative stress look like when it is happening in the brain? It looks like lipid peroxidation and protein misfolding.

Oxidative Stress Drivers in Alzheimer’s

Lipid peroxidation is one of the most common outcomes of oxidative stress. It is super destructive to neurons because their plasma membranes contain high amounts of polyunsaturated fatty acids. Polyunsaturated fatty acids are susceptible to oxidation. This process changes the properties of the cell membrane, affecting its fluidity, permeability, and the function of membrane-bound proteins. This tanks crucial neuronal functions and the ability of neurons to communicate with one another.

Protein oxidation leads to the alteration of protein structure and function. This can disrupt enzyme activity and receptor function, inhibiting neurons’ normal biochemical and metabolic processes.

And what do we see in the Alzheimer’s brain, struggling with huge amounts of oxidative stress?

Oxidative stress can exacerbate amyloid-beta production and accumulation. This peptide can induce oxidative stress by itself, creating a vicious cycle of damage. Moreover, oxidatively damaged proteins and lipids are prone to form aggregates, which can exacerbate the formation of amyloid-beta plaques.

The role of oxidative stress is also evident in the hyperphosphorylation of tau, another characteristic of Alzheimer’s. Under conditions of oxidative stress, there is increased activation of several kinases (enzymes that add phosphate groups to other proteins), which can lead to tau hyperphosphorylation. Hyperphosphorylated tau is more prone to aggregation, leading to the formation of neurofibrillary tangles, another hallmark of AD.

Additionally, oxidative stress can lead to neuronal death in AD through a process called apoptosis or programmed cell death. Chronic exposure to oxidative stress can trigger this pathway, leading to the loss of neurons and the worsening of cognitive symptoms.

Let me say that again, in another way, in case that didn’t hit home for you.

Oxidative stress doesn’t merely play a bystander role in Alzheimer’s disease. This is not merely an associational connection found in the scientific literature. Oxidative stress in the Alzheimer’s brain is a powerful and insidious force actively driving the disease’s development and progression. Its unchecked reign triggers and accelerates the brain’s decline, relentlessly exacerbating the degeneration that hallmarks Alzheimer’s disease.

Unchecked oxidative stress drives neurochemical events leading to the formation of Alzheimer’s characteristic hallmarks: amyloid-beta plaques and tau tangles.

Why is oxidative stress unchecked in the Alzheimer’s brain? Because the medications we develop for the disease do not go far enough back in the causational chain to give us anything to hope for. They don’t fix brain energy. They don’t address the cascade of oxidative stress that comes in many cases of Alzheimer’s disease from a crisis of brain energy.

Luckily, we have the ketogenic diet at our disposal to help battle oxidative stress in the Alzheimer’s disease brain.

But what are the mechanisms by which the ketogenic diet accomplishes this?

Ketogenic Diets Reduce Oxidative Stress

First, increasing brain energy and improving mitochondrial number and function which is a part of the ketogenic diet, is a huge boon to fighting oxidative stress. Neurons need the energy to do the basic functioning and housekeeping of cells! How good are you at doing your chores or work when you don’t have energy? Not so good? Things pile up, and stuff is barely accomplished or not done well? Exactly. Your brain needs the rescue of energy that occurs on a ketogenic diet to keep oxidative stress in check and manage the balance between oxidative stress and ROS in the brain.

β-hydroxybutyrate (BHB), a primary ketone body produced during ketosis, has been found to possess antioxidant properties. A reduction in ROS is achieved by enhancing the efficiency of the electron transport chain in mitochondria, reducing electron leakage and, subsequently the formation of ROS. By lowering the overall ROS production, BHB can indirectly reduce the burden of oxidative stress.

But the ketogenic diet has other powerful ways in which it helps reduce oxidative stress. Ketogenic diets have been shown to be able to increase a powerful endogenous (made in our body) antioxidant known as glutathione (GSH).

The increase in glutathione production we see on a ketogenic diet is likely because ketosis promotes the production of NADPH, a coenzyme that plays a vital role in the regeneration of glutathione. When cells have an adequate supply of NADPH, they can more efficiently convert oxidized glutathione (GSSG) back into its reduced, active form (GSH), thereby maintaining a robust antioxidant defense.

By supporting the production and regeneration of glutathione, BHB helps maintain a pool of active, reduced glutathione ready to neutralize ROS and reduces oxidative stress by exhibiting its own independent antioxidant properties. This symbiotic relationship between BHB and glutathione serves to reinforce the antioxidant defenses, particularly important in the brain where oxidative stress can have devastating effects.

Why wouldn’t we use the ketogenic diet as a first-line defense against the ravages of oxidative stress? Why wouldn’t this be a powerful treatment of choice, particularly within the context of the devastatingly insufficient effects on Alzheimer’s disease progression being offered as our current standard of care?

Wouldn’t a rescue of brain energy through an alternative fuel source, increased mitochondrial biogenesis, and improved antioxidant properties to reduce oxidative stress be enough to nominate this metabolic therapy for the brain as treatment of the year for dementias? It would. But believe it or not, there are more pleiotropic effects of a ketogenic diet that you will want to know about.

Neurotransmitter Imbalance in Alzheimer’s: The Keto Effect

Medications that intervene solely at the neurotransmitter balance and function level are, quite frankly, missing the forest for the trees. They are focusing on the end product of a long, cascading process without addressing the upstream dysfunction in the mitochondria, metabolism, and oxidative stress regulation that fuels the pathological progression toward Alzheimer’s disease. But you may be curious about how a ketogenic diet can help with the neurotransmitter issues we see develop in Alzheimer’s, so let’s continue learning!

So let’s go back to reviewing the futility of medications focused on neurotransmitter problems seen in Alzheimer’s disease but also move forward in our understanding of how a ketogenic diet is a superior option to deal with them once they occur.

Keep a Handle on your Glutamate

Remember from your reading earlier in this post that NMDA receptor antagonists like Memantine (Namenda) are drugs prescribed in an attempt to regulate the activity of glutamate. It just so happens the ketogenic diet has powerful effects without the side effects.

Why wouldn’t we leverage a ketogenic diet for this purpose and avoid the side effects of dizziness, headaches, and confusion that are a part of these medications?

Ketogenic Diets Modulate GABA

It’s not all about reducing toxic levels of glutamate, though. There needs to be a balance between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). One of the main effects of a ketogenic diet on brain chemistry involves (GABA), the primary inhibitory neurotransmitter in the brain. Research has shown that ketone bodies can increase the brain’s production of GABA. This is relevant to Alzheimer’s disease because GABAergic signaling is often disturbed in Alzheimer’s patients, and improving GABAergic tone might help restore balance to the neural networks disrupted by the disease.

Also, remember that in the introduction, we discussed the use of a class of medications known as Cholinesterase inhibitors. The purpose of these drugs was to slow down the breakdown of acetylcholine, a neurotransmitter often depleted in Alzheimer’s patients.

But what about Acetylcholine?

Acetylcholine is a neurotransmitter that plays a key role in memory and learning and is notably diminished in Alzheimer’s disease. While the ketogenic diet doesn’t directly increase acetylcholine levels, it supports brain health in a way that helps preserve acetylcholine function. By reducing oxidative stress and supporting mitochondrial function, a ketogenic diet protects cholinergic neurons (neurons that use acetylcholine to transmit signals) from damage.

So knowing that oxidative stress and damaged mitochondria can impair acetylcholine release and receptors, how about we just exponentially improve mitochondrial function and reduce oxidative stress through the powerful mechanisms inherent in a ketogenic diet? I suspect we may see improved acetylcholine levels in Alzheimer’s patients without the common side effects of nausea, vomiting, and diarrhea.

Easing Neuroinflammation in Alzheimer’s Disease: The Therapeutic Impact of Ketosis

Neuroinflammation happens when your immune system is trying to protect your brain from an infection, injury, or abnormal protein accumulation. When the immune response is triggered in the brain, microglia and astrocytes actively attack the threat. And as they attack the threat, they exude and release a bunch of inflammatory cytokines. And just like in a gunfight, some bullets are going to fly around in an unprecise manner, and some collateral damage is going to occur.

If your oxidative stress levels are well managed, the brain can rebuild and repair from this process; if not, it doesn’t. And in this way, neuroinflammation helps drive neurodegenerative processes.

When neuroinflammation becomes chronic and unrelenting, it will literally change how these microglia behave (morphology) and make them quite “trigger happy” and aggressive in their behavior around dealing with assaults. When in this overactive state, microglia will begin to eat and destroy neurons that were only sick and could have been saved!

You can imagine how a poorly functioning immune system, broken blood-brain barrier (BBB) unable to protect the brain, or high levels of oxidative stress due to glucose hypometabolism (poor brain energy) or micronutrient insufficiencies can all drive a nonstop cascade of neuroinflammation. And unsurprisingly, it can contribute to the development and progression of neurodegenerative diseases, including Alzheimer’s disease.

If you are still feeling a little confused about the differences between neuroinflammation and oxidative stress and how they are related, you may find this article below helpful.