This Is Your Brain on Ketones

A well-formulated ketogenic diet has many health benefits that span weight loss to neurological health. This blog post will dive in and explore how a ketogenic diet can affect and possibly help the brain in neurodegenerative diseases, mental health and traumatic brain injuries.

What most interests you about keto and brain health? Skip ahead to learn about the brain chemistry of ketones, keto for Alzheimer’s disease, keto for Parkinson’s disease, keto for brain injuries or how to eat keto or keto-like for brain health.

What is a ketogenic diet and how does it work?

A ketogenic diet is a high-fat, moderate-protein, low-carbohydrate way of eating. The goal of a ketogenic diet is to switch the body from burning carbohydrates as fuel to burning fat, or ketones, as fuel. When carbohydrate intake is low or in periods of fasting, glucose and insulin levels will drop and the liver will produce ketones through the process of ketogenesis.

The brain can run on ketones – almost.

When you are on a keto diet, or fasting, your brain can switch from using glucose as its main fuel source to using ketones. There are however portions of the brain that do require glucose for function. The brain will use some of the carbohydrates consumed on a ketogenic diet (~5-10% of calories is the usual range of carbohydrate consumed when eating a ketogenic diet) and the rest will be produced through gluconeogenesis in the liver. During gluconeogenesis, the liver will create glucose using amino acids from protein. Glucose can also be created through gluconeogenesis by using the backbone of fatty acids, glycerol. This process ensures that the portions of the brain that rely on glucose will have their preferred energy substrate in times of fasting or very low carbohydrate intake.

How do ketone bodies benefit the brain?

Ketone bodies (such as beta-hydroxybutyrate) can cross the blood-brain-barrier. Ketone bodies reduce reactive oxygen species (ROS), a type of by-product molecule that can react with other molecules in a cell. The build up of ROS in cells can overwhelm antioxidant activity and can cause damage to DNA, RNA, proteins and lipids. ROS have been implicated in aging, neurodegeneration and carcinogenesis (the formation of cancer).

Sidebar: What You Should Know About Oxidative Damage and Stress

One way that ketone bodies can reduce ROS is by increasing levels of glutathione in mitochondria, the powerhouses of the cell. Glutathione acts as an antioxidant defense by reacting with free radicals to form harmless inactive products. Ketone bodies also trigger expression of brain-derived-neurotrophic-factor (BDNF) that supports the growth and development of neuronal connections, and increase GABA and decrease glutamate in the brain. Ketone bodies may also work as signaling molecules in order to modify cellular processes to better fight stress and ROS.

Ketogenic diets work for neurodegenerative diseases

Alzheimer’s disease and Parkinson’s disease are two of the most common neurodegenerative diseases. While there is no cure, researchers are looking at how the ketogenic diet may help prevent or slow disease progression.

Alzheimer’s disease is the most common cause of dementia. Researchers are now suggesting that it be called “Type 3 diabetes” due to its association with metabolic insufficiencies, with insulin resistance and with “energy crisis” in the brain. Remember that the brain does require some glucose for fuel. An inability to uptake and utilize glucose efficiently in certain areas can cause energy disruption. Hallmarks of this energy disruption include an increase in reactive oxygen species (ROS), DNA damage and mitochondrial dysfunction that can lead to apoptosis or cell death in the brain.

Risk factors for Alzheimer’s disease include metabolic syndrome, obesity and type 2 diabetes. There has also been a correlation between Alzheimer’s disease and apolipoprotein E4, a cholesterol transport protein that helps control metabolism and waste clearance in the brain. Having this genetic variant can put an individual at a greater risk for Alzheimer’s disease. However, it does not mean that the individual will be affected; lifestyle and environmental factors become even more important for individuals with such a genetic predisposition.

So what does the research say about Alzheimer’s disease and ketogenic diets?

While the brain of an individual with Alzheimer’s disease may not use glucose efficiently, their brains can utilize ketone bodies just as well as can healthy brains. Ketone bodies have been used in several studies in relation to Alzheimer’s disease. These ketone bodies can be produced through consumption of a ketogenic diet, through supplementation of medium chain triglycerides (MCTs) or through supplementation* with an exogenous ketone source such as beta-hydroxybutyrate salts or esters.

*Sidebar: Supplementation with exogenous ketones likely does not reproduce all of the health benefits of a keto diet. Exogenous ketone supplements can also contain different types of ketone bodies than the body produces.

Animal studies have shown that ketone bodies can increase mitochondrial efficiency in the brain in addition to providing a new energy substrate. Ketone bodies bypass cytoplasmic glycolysis and go directly into the mitochondria where they are oxidized. The chemistry gets complicated, but basically using ketones for fuel makes mitochondria more efficient as they are able to produce more energy while using less oxygen. The use of less oxygen during production of ATP through ketones also produces fewer free radicals.

Ketone bodies have been shown to provide a positive effect on cognitive outcomes in mild-to-moderate Alzheimer’s disease and mild cognitive impairment, as well as confer protection against oxidative stress in neocortical neurons. Another animal study found that a high-fat diet rich in saturated fat and low in carbohydrates reduced levels of beta-amyloid peptide, which forms the hallmark extracellular plaque deposits seen in the brain of Alzheimer’s patients.

Human studies show similarly promising results. One small study of 23 adults found that being in a state of ketosis improved memory function in a group of older adults with mild cognitive impairment. Another study of 20 subjects found similar results. A slightly larger study looked at 152 adults diagnosed with mild-to-moderate Alzheimer’s disease. Some of these adults were given an MCT oil supplement to take. This supplement contains medium-length fatty acid chains called triglycerides (MCT). MCTs make up 50% of the total fat found in coconut and palm kernel oils and are also found in small amounts of dairy. MCTs are easily and quickly digested and are then transported directly to the liver where they are metabolized to generate energy, for example in the form of ketones. In this study, the group taking the MCT oil supplement was found to have higher ketone levels and had significant improvement in brain function when compared to the control group.

Two recent case studies have been published investigating the impacts of placing patients who have the apolipoprotein E4 (ApoE4+) genetic variant on a ketogenic diet. The first study involved a woman who had mild cognitive impairment and had been diagnosed with metabolic syndrome. She was placed on a ketogenic diet with intermittent fasting for ten weeks and received daily low-impact exercise and cognitive training. After a ten week period, her cognitive scores improved and the patient had normalized her fasting glucose, fasting insulin and blood lipids. A second case study involving a 68-year-old male who is also ApoE4+ found similar results. These preliminary results highlight the ability of the ketogenic diet to be a powerful tool for potentially preventing or delaying disease onset in certain cases.

What does the research say about Parkinson’s disease and ketogenic diets?

Parkinson’s disease is a disease that affects neurons in the area of the brain that controls movement. When these neurons become impaired or die, less dopamine – a signaling molecule that communicates between nerve cells – is produced. This causes the movement problems (tremors, muscle stiffness and balance issues) that are typical in patients with Parkinson’s disease. The brain of an individual with Parkinson’s disease also produces less norepinephrine as nerve endings die. There is no exact known cause for Parkinson’s. Researchers believe it could be a combination of many factors, genetic and environmental.

In 2018, researchers conducted a randomized-controlled trial in patients with Parkinson’s disease. They placed one group on a low-fat, high-carbohydrate diet and the other group on a ketogenic diet. The ketogenic diet group showed greater improvements in nonmotor symptoms, including urinary problems, fatigue, pain and cognitive improvement. A 2005 study looked at seven people with Parkinson’s disease on a ketogenic diet (5 of 7 adhered to the diet) for 28 days. Researchers found that there was a 43% reduction in self-reported Unified Parkinson’s Disease Rating Scale scores.

Another study, the Rotterdam study, found that consumption of foods high in essential fatty acids such as monounsaturated fats and polyunsaturated fats was associated with a lower risk of Parkinson’s disease. Foods high in monounsaturated fats include olives, olive oil, avocados, avocado oil, pumpkin seeds and almonds. Foods high in polyunsaturated fats include salmon, tuna, walnuts, flax and sesame seeds. While these people were not necessarily following a ketogenic diet exactly, it highlights the idea that a higher fat (and lower carb) diet such as a ketogenic diet might be beneficial in that it can lower inflammation and improve mitochondrial function. More research needs to be done in this area, but the initial data is promising.

A ketogenic diet for mental health?

While the research data is limited in this area, many people report relief from depression and anxiety while on a ketogenic diet. Is it because depression and anxiety are linked to inflammation in the brain and body? The ketone body beta-hydroxybutyrate has been shown to reduce inflammation in the brain and in one study, it exhibited anti-depressant activity by decreasing stress-induced inflammation in the brain. Case studies have demonstrated mood stabilizing effects of a keto diet, but there have been no clinical trials to explore this finding further.

A ketogenic diet for Traumatic Brain Injuries (TBI)?

In a traumatic brain injury, the brain has an impaired ability to utilize glucose. Coupling this impaired ability with a high blood glucose level can hinder recovery in patients with a TBI. One animal study found the ketogenic diet to be neuroprotective in the context of brain injury. It significantly improved both motor and cognitive recovery when administered for 7 days immediately after brain injury.

Ketones seem to be a great endogenous fuel source that can give the brain adequate energy during the recovery phase. But a 2018 review of the literature found that while the safety of a ketogenic diet for TBI’s has been established, more research needs to be done to further explore its potential in humans.

Gut health = brain health

The gut is also the second brain. Also known as the enteric nervous system, there is an arrangement of neurons throughout the gastrointestinal tract that “senses” what we eat! Thus what we eat affects our brains through our microbiome, the collection of microorganisms we have in our intestinal tract. The compounds these microbes produce as they break down what we eat can send signals to our brain. It would only make sense to nourish our guts with high quality foods in order to keep inflammation low.

A well-formulated ketogenic diet

One common misconception about a ketogenic diet is that it lacks variety and therefore isn’t appealing to most people. A typical ketogenic diet has a macronutrient ratio of 70-80% fat, 20-25% protein and 5-10% carbohydrates. While the diet may look different for each individual depending on the person’s needs and goals, a well-formulated ketogenic diet is full of many options that can support brain health by keeping inflammation low. There is more flexibility, palatability and nutrient density in the diet than what most people initially perceive.

Going keto or wanting to improve your brain health? Here are some tips on what foods to focus on.

For fat sources, look to healthy plant oils such as extra-virgin olive oil, avocado oil, MCT oil and coconut oil. Whole nuts and seeds are a great source of oils as well. These fats are mainly made up of monounsaturated fatty acids (MUFAs) and these fats have been linked to overall improved metabolic health. Better metabolic health can mean less inflammation in the brain. For animal fat sources, look to grass-fed beef tallow and full-fat grass-fed dairy such as butter and cream. Butter is rich in butyric acid, which can reverse inflammatory damage and lower glucose. All of these fats support overall health.

Sources of protein are wide and varied from fatty to lean cuts of meats. Good quality seafood, pork, poultry and red meats are all good choices. Salmon contains a high level of omega-3 fatty acids, which have been shown to have anti-inflammatory effects on the brain.

There are an abundance of non-starchy vegetables such as leafy greens (spinach, kale, arugula etc), cruciferous vegetables such as broccoli, brussels sprouts, bok choy, and cauliflower that are ideal keto diet foods as they are micronutrient rich while low in carbohydrates. The same applies to low-sugar fruits such as avocado, cucumbers, olives and berries.

After reading about the many benefits of a ketogenic diet for neurological health, are you thinking about starting? Although this particular area of research is still young, there is good evidence to support its proper use for brain and metabolic health. A ketogenic diet is not for everyone, so be sure to consult your doctor and a dietitian before implementing any sort of diet change.