The brain needs lots of energy to work properly. While accounting for only about 2% of adult body weight, the brain accounts for about 20% of the body’s energy use and 16% of the body’s total oxygen supply (Harris, Jolivet & Attwell, 2012). Although the brain prefers to run on glucose blood sugar, it can also burn ketones in a pinch when glucose is unavailable. Ketones are small fuel molecules produced from fat by the liver. The body starts producing ketones only after running out of carbohydrates, which is a metabolic survival adaptation response to preserve strength and increase chances of survival, usually as a result of starvation or prolonged fasting.
Once the body starts producing ketones, it’s in a state called ketosis and begins to run almost exclusively on fat (Gasior, Rogawski & Hartman, 2006). The Ketogenic Diet (KD) mimics the effects of starvation to get the body to produce ketones. The KD eliminates sweets, starchy carbs, and grains. It also limits fruit consumption and allows for only moderate amounts of protein. It is similar to the Atkins, South Beach and other low carb, high fat diets. The difference between the KD and low fat, high fiber diets is the KD restricts proteins, which are converted into blood sugar if too many are in the bloodstream (Eenfeldt, 2017).
There are many ancillary benefits to a KD. Insulin levels drop, and since blood sugar levels are lowered, a KD is a very effective way to treat type 2 diabetes. Fat burning is dramatically increased, which is great for weight loss. The KD is also used to treat epilepsy. Epilepsy patients were first put on a KD more than 90 years ago after doctors observed that it reduced or eliminated seizures. Many high endurance athletes also favor a KD because it dramatically increase physical stamina. Although the body’s supply of carbohydrates run out after a few hours, fat stores fueling ketone production can provide a steady source of energy for days at a time (Henderson, 2006).
A KD can also help cognitive function. Ketosis sends a steady stream of ketones to the brain, avoiding the big swings found with carbohydrates and blood sugar based diet. A KD allows people suffering from AD and dementia to increase mitochondrial efficiency and give the brain an alternative fuel source (Eenfeldt, 2017). This is critical for AD and dementia patients because one of the first things that happens to people suffering from AD is a significant decline in the brain’s ability to metabolize glucose. Studies comparing AD patients to people with healthy brains found a 17% to 24% decline in the cerebral rate of glucose metabolism, which is thought to be a cause of amyloid plaque buildup and brain cell atrophy that so often characterizes AD (Henderson, 2006).
Most of the oxygen in the brain is used to oxidize glucose into carbon dioxide and water, which can cause extensive oxidative damage. The brain is protected by three cell barriers, called the blood brain barriers. Glucose can’t get through these semi-permeable barriers on it’s own, it needs to bond to specific transport proteins to cross over. The levels of these brain glucose transporters are significantly decreased in patients with AD. Several studies have found that even when some areas of the brain can no longer use glucose in the early stages of AD, there is evidence to suggest they are still able to burn ketones (Gasior, 2006).
Cunnane et al. (2016), conducted a systematic review that found that the brain is still able to burn ketones even in someone with AD or dementia who is suffering from deteriorating glucose uptake. What’s more, researchers found that AD and ARD patients showed appreciable improvements in cognitive function when their ketone levels were raised, suggesting that the troubled areas of the brain were not dead, but simply dormant and waiting for a usable supply of energy.
The researchers concluded that AD and ARD can be made worse by chronic brain fuel starvation caused by brain glucose deficit. The researchers went on to say that treating AD and dementia with ketogenic interventions is safe, ethical, and scientifically well-founded. They suggest that oral ketogenic supplements are the fastest and most effective way to provide ketones to people suffering from mild cognitive impairment and early AD (Cunnane et al., 2016).
Reger et al. (2004), organized a crossover study to see if injecting a single shot of medium chain triglycerides would jumpstart ketosis and improve cognitive function in older adults with mild cognitive impairment and AD. Medium chain triglycerides are healthy types of fat most commonly found in coconut and palm oils. They go straight to the liver, where they are converted into ketones. Because they have shorter chain length than more complex fatty acids, medium chain triglycerides are quickly broken down and absorbed by the body.
The researchers injected 20 people with mild-to-moderate AD a 40-gram dose of soluble ketone bodies called beta-hydroxybutyrates. The shot increased ketone levels by a factor of 10 after just two hours. Researchers hypothesized that elevated ketone levels would boost brain energy and temporarily improve cognitive performance without the need to wait for a long-term ketogenic diet to take effect. They tested the volunteers at baseline and 90-minutes after injection with a variety of quantitative cognitive tests (Reger et al., 2004).
All 20 subjects scored higher 90-minutes after being injected with the medium chain triglycerides. The medium chain triglyceride serum led to better performances across-the-board, particularly on a memory-intensive paragraph recall test. Not surprisingly, volunteers with higher ketone levels made the biggest gains. Reger et al. (2004), said such a dramatic increase after such a short time with no other external variables suggests the improvements in test scores were caused by increased neuronal metabolisms spurred by elevated ketone levels.
Reger’s et al. (2004), preliminary results were followed up four years later in a larger and longer-term analysis of the effects of daily oral ingestion of medium-chain triglycerides on cognitive function in mild to moderate AD patients. Henderson et al. (2009), conducted a double-blind, placebo-controlled, multi-center trial on 152 volunteers at 23 different clinical sites across the United States. Volunteers were randomly split into an intervention group and a control group. Both groups stayed on a normal diet and continued to take any prescribed AD medications. Ketosis was induced by giving study subjects a daily measure of 20 grams of an oral ketogenic compound called AC-1202 for 90 days.
Subjects blood levels were tested at baseline, and then again at 45 and 90 days. Results from the 45 and 90 days tests showed that the daily dose of medium chain triglycerides triggered significant increases in serum ketone levels. Two hours after ingesting the medium chain triglycerides, mean ketone levels rose to 0.36mM on the 45th day, and 0.39mM on the 90th day. Quantitative cognitive test scores improved for the entire intervention group. After 45 days, study subjects taking ketogenic compounds made a noteworthy 1.9-point mean gain over the control groups on standardized tests.
However, findings from both studies suggest that the cognitive benefits of induced ketosis may largely depend upon genetics. In the earlier Reger et al. (2004) study, medium chain triglycerides only improved cognitive function in participants who lacked the APOE4 gene, a known genetic risk factor for AD. In the later Henderson et al. (2006) study, cognitive improvements were much more pronounced for those lacking the APOE4 gene. Volunteers without the APOE4 gene showed an impressive 5.3 point gain from baseline ADAS-cog scores on the 90th day assessment. Both studies found that higher ketone levels correlated with improved test scores, suggesting ketosis may be helpful for AD patients, particularly if they lack the APOE4 gene (Henderson et al., 2006).
It should be noted, however, that the levels of ketosis achieved in the Reger et al. (2004), and Henderson et al. (2006), studies were substantially lower than levels used in previous, long-term infusion studies. The research suggests that the body responds quickly to medium chain triglycerides and can easily build levels of ketosis that may provide potentially life-changing benefits for AD patients.
These promising early findings on the effects of medically administered ketogenic compounds offered hope that a KD might be able to impart real, long-term brain benefits. A 2012 study by Krikorian et al., tested whether a ketogenic diet would improve memory in older adults without administering or injecting medical supplements. Researchers recruited 23 older adults with mild cognitive impairments. The study subjects were randomized. Half were put on a KD for 6 weeks, with just 5 to 10 percent of calories coming from carbohydrates. The control group ate a typical high-carbohydrate diet, with at least 50 percent of their calories coming from carbohydrates.
After six weeks, Krikorian et al. (2012), found participants following a KD showed significant improvements in verbal memory compared to the control group. The verbal memory assessments tested the participants recall of words and other abstractions. Researchers found the higher the ketone levels, the better the verbal memory. Researchers said the findings indicated that ketosis can improve memory function in older adults, even those with an increased genetic risk for AD.
However, the researchers also pointed out that the cognitive gains may have been partially due to a reduction of excess insulin in the blood which, as mentioned earlier, is known to hamper cognitive function. The researchers said that other mechanisms associated with ketosis such as reduced inflammation and oxidative stress say have also led to improved cognitive function (Krikorian et al., 2012).
Besides improvements in cognitive function, Krikorian et al. (2012), said study subjects following the KD also lost weight and had reductions in blood glucose and insulin levels. Taken as a whole, these results indicate that ketosis, in the short term at least, offers many advantages for both the brain and body.
A major drawback of all three ketogenic studies were their limited time frames. Researchers questioned whether the benefits of a low-carbohydrate diet remained after someone returned to a normal diet. If a KD has cognitive and physical benefits that last beyond the intervention period, it might be a strategy people can uses intermittently to help ease concerns over adverse effects of long-term carb restrictions.
Although some studies have analyzed the short-term effects of a ketogenic diet, very few have looked into the long-term effects. One concern about following the ketogenic diet is a gradual loss of bone mineral content. Due to time and money constraints, most controlled nutritional studies typically last anywhere from 12 weeks to a year. Clearly, this is too short a time to gauge long-term effects on the human body.
Bertoli et al. (2014), set out to examine the long-term effects of a KD on body composition and bone health. The researchers studied the bone health of three adult women with glucose transporter 1 deficiency syndrome (Glut1) who’d been following a KD from more than five years. Glut1 is a rare genetic disorder where patients lack a key protein needed to transport glucose across the blood-brain barrier. This condition leads to debilitating and potentially life threatening complications that include severe epileptic seizures, developmental delays, and cognitive decline. Doctors have prescribed a KD to counteract Glut1 for more than 80 years because it helps control epileptic seizures.
The three Bertoli et al. (2014), subjects underwent standard blood testing and an abdominal ultrasound, as well as body composition and bone mineral status measurements at baseline, and then again on an annual basis for the next five years. They were also given standardized neurologic examinations and cognitive tests along the way. All three subjects experienced a rapid and complete disappearance of paroxsmal dyskinesias, an epileptic condition characterized by sudden and often severe episodes of involuntary and uncontrollable movements, as soon as ketosis took effect.
Researchers found that long-term adherence did not produce any appreciable changes in weight or body fat. In fact, muscle strength increased in all three patients. There was also no evidence of adverse effects on bone health after five years. Cognitive function did not change appreciably for any of the study subjects (Bertoli et al., 2014).
These findings stand in direct contrast to previous studies focusing on small children suffering from Glut1 deficiencies (Bertoli et al., 2014). The Researchers found that children with intractable epilepsy following a prolonged KD resulted in a progressive loss of bone mineral content. Researchers theorized the bone loss is associated with poor bone heath, most likely as a by-product of a chronic acidic environment. The discrepancy in the findings might be explained by the fact the the the Glut1 patients were adults and had normal bone mineralization at baseline.
The main drawback of the Bertoli et al. (2014), study is it’s limited scope of just three participants. Subsequent studies need to broaden their focuses to larger populations to confirm and expand the findings.
While it’s generally accepted that a KD helps protect the brain from neurodegeneration, little is known about how ketones actually work. Van de Auwera et al. (2005), tested a KD on mouse models to investigate the specific processes. 16 mice were put on two different diets for 43 days. The control group was kept on a standard high carbohydrate/low fat diet, the intervention group was put on a high fat/low carbohydrate KD. Both groups had unlimited access to food.
The results surprised the researchers. Van de Auwera et al. (2005), thought that the high fat/low carbohydrate diet would cause an increase of plaques in the brain, but post-mortem autopsies revealed that mice following the KD experienced a 25% decrease in beta amyloid plaques and tau tangles compared to the high-carbohydrate, low-fat diet control group. The researchers said the findings indicate that anyone designing a dietary strategy to reduce harmful plaques in the brain should first consider how dietary components influence biochemistry and metabolic outcomes. Particular attention should be given to the levels of fats, carbohydrates, total calories, and presence of ketone bodies. Obvious drawbacks to this study include the short time frame and the reality that the mouse models may not accurately represent human molecular mechanisms.
Carb Cycling
One of the biggest drawbacks for active and athletic people following a KD is a lack of carbohydrate powered energy. It is possible to take a more moderated approach to KD called “carb cycling”. Carb cycling schedules a couple of carb-loading binge days every week to allow the body replenish it’s carbohydrate stores. The goal of carb cycling is not for the dieter to be in a ketogenic state all the time but to be able to easily slip in and out of ketosis (Haque, 2015).
A weeklong carb cycling strategy typically involves five or six days of a strict ketogenic diet, followed by one or two carbohydrate binge days. Carb loading days allows physicallyactive dieters to replenish depleted glycogen stores in their muscles. Glycogen helps them maintain a sufficient level of strength for their workouts (Haque, 2015).
Carb cycling is effective for athletes because once glycogen reserves are depleted, new carbs go straight to the muscles and liver, instead of the body’s fat stores. An added benefit of carb cycling is that it gives dieters a break from the relative drudgery of following a KD, which can be great for psychological well-being as well as long-term willpower.
To start carb cycling, dieters follow a strict 10 to 14 day “induction phase” where they follow a low carb diet to induce ketosis. Once they achieve ketosis, they slowly progress onto the cyclical diet where they follow the same carb cycling pattern every week. Because the glycogen goes straight to the muscles and liver on a carb cycling diet, the amount of calories consumed can be significantly greater than usual. A typical carb cycling ketosis day is limited to 50 grams or less of carbs. Binge days can include upwards of 450-600 grams of carbs (Haque, 2015).
Haque (2015), concludes that the biggest drawback of carb cycling is that it can be complex and hard to follow. Carb cycling requires the dieters to keep close track of the number of carbohydrate grams they eat. The re-feed process can also be a delicate balancing act because it can lead to significant fat gain if more carbs are consumed than are needed to replenish glycogen stores.
Risks and Drawbacks of a KD
Because switching to a KD is a significant lifestyle change, there are several short-term side-effects. As stated earlier, the brain prefers to run on glucose, so it will burn the very last stores before switching over to ketones. The worst physical reactions from a KD resemble the flu and are most evident during the first week of the diet. The first symptom is fatigue and dizziness. Headaches, nausea, and muscle cramps are other common side-effects. These symptoms are caused by low levels of minerals such as salt, magnesium, and potassium. This so-called “induction flu” eases after the body switches over to ketosis (Smith, 2015).
Other common complications include weight loss, constipation, and increased cholesterol and lipid levels. Women might also experience disruptions to the menstrual cycle. Another side- effect is the need to urinate more frequently. This is because the body is burning up glucose deposits stored in the liver and muscles. Breaking down this stored glucose down requires lots of water. The kidneys also start discharging excess sodium as insulin levels drop. These effects are usually temporary, and ease as the body adjusts to ketosis (Smith, 2015).
Smith (2015), suggests several things that can help manage the side-effects of a KD. Multivitamins, calcium and vitamin D supplements help ease the symptoms. Ingesting more salt and eating foods rich in potassium such as dairy, leafy green vegetables and avocados is also recommended.