The terms medium-chain fatty acids and medium-chain triglycerides are somewhat interchangeable. In fats and oils, such as coconut oil and medium-chain triglyceride oil, three molecules of a particular fatty acid join together with a glycerol molecule to form a triglyceride. Thus, medium-chain fatty acids join together with glycerol to form medium-chain triglycerides. Medium-chain triglyceride oil, also called MCT oil, is usually a combination of several different types of medium-chain triglycerides. The medium-chain triglycerides found in MCT oil are usually derived from coconut or palm kernel oil.
The fact that medium-chain triglycerides are metabolized to ketones in the liver is not new information. When I read this in the Accera patent application, I recalled learning this in my medical school biochemistry class in 1974.
In 1906, scientists G. Embden and F. Kalberlah reported that when caprylic acid, one of the medium-chain fatty acids, was pumped through the circulation of dog liver there was a prompt increase in the liver’s output of acetoacetate, one of the ketone bodies. In 1959, H. Schön and others fed medium-chain triglycerides (C:8 through C:12) to a group of people and found an increase in blood and urine levels of ketones; they also found that this did not occur when they were given long-chain fatty acids.
In 1966, Dr. Theodore VanItallie and his associates, Dr. Sami Hashim and Dr. S. Bergen Jr., confirmed these findings and expanded upon this research. They gave 100 milliliters (more than 3 ounces!) of either MCT oil or corn oil, along with some casein (a milk protein) and dextrose (a sugar), to twenty patients, six of whom had diabetes. Some of the people received both types of oil at least two days apart. All the people had a significant rise in their ketone levels after consuming the MCT oil, the diabetics on average slightly higher than the nondiabetics. After consuming the corn oil, there was a relatively negligible increase in ketones. The increase in ketones occurred even though the people also received glucose and protein. These researchers published several other studies in which they reported that:
• Medium-chain triglycerides are absorbed directly from the intestine without the need for digestive enzymes, which are required for the longer-chain fatty acids.
• Medium-chain triglycerides are transported directly to the liver by way of the portal vein.
• Part of medium-chain triglycerides are converted to ketone bodies in the liver.
Dr. Hashim and his associates continued to study the use of medium-chain triglycerides in the pediatric population into the 1970s and beyond. They confirmed that medium-chain triglycerides are absorbed very easily, even in the premature newborn (Tantibhedhyangkul, 1971 and 1975). They studied the addition of various percentages of MCT oil to formulas, finding for example, that calcium was more readily absorbed from the intestine if the infant formula contained higher levels of MCT oil. Thus, by the time I began my pediatric residency in 1978, it was a new practice to add MCT oil to feedings of premature newborns to help them grow faster. Special formulas were developed for premature newborns that included MCT oil and coconut oil and/or palm kernel oil, which contain about 55 to 60 percent medium-chain fatty acids. Virtually every infant formula used in the United States today contains a large amount of MCT oil and coconut and/or palm kernel oil.
The May 9, 2000, issue of Proceedings of the National Academy of Sciences included an article entitled “D-beta-hydroxybutyrate Protects Neurons in Models of Alzheimer’s and Parkinson’s Disease.” This was the landmark report on ketone research from the National Institutes of Health laboratory of Dr. Richard Veech and his associates, Yoshiro Kashiyawa, Takao Takeshima, Nozomi Mori, Kenji Nakashima, and Kieran Clarke. (This report will be discussed in more detail later in this chapter.) One important statement in the opening summary of this paper is relevant to our current discussion: “The ability of ketones to protect neurons in culture suggests that defects in mitochondrial energy generation contribute to the pathophysiology of both brain diseases [Alzheimer’s and Parkinson’s]. These findings further suggest that ketone bodies may play a therapeutic role in these most common forms of human neurodegeneration.” I don’t know if this article led to what happened next or if the timing is just a pure coincidence.
On May 1, 2000, a U.S. patent application was filed by Samuel T. Henderson, Ph.D., of Broomfield, Colorado, entitled “Use of Medium-Chain Triglycerides for the Treatment and Prevention of Alzheimer’s Disease and Other Diseases Resulting from Reduced Neuronal Metabolism” (discussed in Chapter 4). This application has been revised and continued since 2000. Dr. Henderson had the brilliant insight to consider the possibility that the relatively mild ketosis that occurs after consuming MCT oil would be sufficient to bring about improvement in people with Alzheimer’s disease, as well as other neurodegenerative diseases. This is a profound discovery that had very important ramifications eleven years later for Steve, and now for many others as well.
Dr. Henderson put two and two together and acted on it. He personally experienced the nightmare that is Alzheimer’s, losing a close family member to the disease, and he wanted to do something about it. He and his associates formed a company called Accera in 2001 where they developed a food product, initially called AC-1202, in which the active ingredient is the medium-chain triglyceride known as caprylic triglyceride, also called C:8. They determined a dose of C:8 that most people could tolerate and that would also be sufficient to increase ketone body levels significantly, aiming for a level of about 0.5 millimoles per liter (mmol/l) of beta-hydroxybutyrate.
The Accera company decided to seek Food and Drug Administration approval for their product and conducted clinical trials. One of the trials tested for tolerance of different versions of the product in normal healthy people. Other studies evaluated the effectiveness of the product in people with mild cognitive impairment and Alzheimer’s disease. Several research centers in our area of Florida were involved in these clinical trials. The product AC-1202 was given a name, initially Ketasyn, which was later changed to Axona.
The results of Accera’s first study were published in 2004 in Neurobiology of Aging (Reger, 2004). The purpose of the study was to “explore whether hyperketonemia improves cognitive functioning in individuals with memory disorders.” The researchers “tested the hypothesis that acute elevation of serum beta-hydroxy-butyrate levels through an oral dose of medium-chain triglycerides would improve memory and attention in individuals with AD or mild cognitive impairment.” They included people who were considered to have mild to moderate impairment, with an average MMSE score of 22 out of a possible 30. They also looked at the differences between people with and without the ApoE4 gene; ApoE4+ is a known risk factor for Alzheimer’s disease (discussed in Chapter 15). There appear to be some differences in how glucose is used by people based on whether they are positive or negative for this gene. Dr. Henderson and his group suggest that the ApoE4 gene may affect the way other substrates are handled in the body, including ketone bodies.
This first study included just twenty people, of whom nine were ApoE4+. Each person was studied on two different occasions, making it a crossover study in which the person serves as his or her own control. At one visit they received AC-1202, and for the other they did not. They were instructed not to eat from 8 P.M. the evening before the study. In the morning, blood was drawn and then they were given the mixture containing either MCT oil or the placebo. Ninety minutes later, blood was drawn again and they were given a series of four memory and attention tests over thirty minutes. They then had one more blood draw.
The results were quite impressive, at least for people who did not have the ApoE4 gene. The level of beta-hydroxybutyrate increased by an average of 7.7 times compared to the level before taking the MCT oil. The ApoE4- people had an average improvement of more than 6 points on the 78-point ADAS-COG memory test on the day they received the MCT oil compared to the placebo day. In another test called “paragraph recall,” a trend showed that the ApoE- people with higher beta-hydroxybutyrate levels had the most improved scores. The two other tests showed no apparent effect of the treatment. As a group, the people who were ApoE4+ actually showed slight worsening on the ADASCOG test.
In their conclusions, the researchers stated: “The rapid improvement in some areas of cognitive functioning suggests that ketones may function as an alternative fuel for cerebral neurons in MCI [mild cognitive impairment] or AD patients…. Future studies may also confirm the differential treatment effects for ApoE4+ and ApoE4- subjects in a larger sample with several MCT doses. Additionally, the cognitive effects of long-term elevation of beta-hydroxybutyrate levels may support the feasibility and efficacy of MCT administration as a novel therapeutic strategy.”
There’s an interesting sidelight about this study. In order to conduct a valid study, the people receiving the treatment and the people administering the tests must not know whether the subject is receiving the active ingredient or the placebo. So the active ingredient must be disguised in such a way that one cannot tell the difference between the two doses. In this study, the MCT oil was blended with about 5 ounces of heavy whipping cream. For the placebo, an additional amount of cream was added instead of MCT oil. There is some irony in their use of this cream to disguise the MCT oil. According to the U.S. Department of Agriculture (USDA) National Nutrient Database, the amount of heavy whipping cream added to the MCT oil provided an additional 6 grams of short- and medium-chain fatty acids, so in the placebo, the people actually received about 10 grams of these ketone-producing fatty acids. Their results might have been even more impressive had they used something other than cream to disguise the MCT oil!
One of the most significant take-home points from this study is that some people with memory impairment improve after just one sizable dose of medium-chain triglycerides. Steve improved the very first day he consumed 35 grams (seven teaspoons) of coconut oil. He said that “the lightswitch came back on” and “the fog lifted.” Steve is positive for the ApoE4 gene. So why did he respond when the folks like him in Dr. Henderson’s study did not? The primary difference between their study and what happened to Steve is the type of oil used. The Accera study used just one type of medium-chain triglyceride, caprylic triglyceride. Coconut oil contains all the medium-chain fatty acids, as well as long-chain fatty acids. Perhaps another fatty acid was responsible for his improvement. In addition, when Steve’s ketone levels were measured after he consumed MCT oil, his beta-hydroxybutyrate levels were higher than acetoacetate levels, but the reverse was true after consuming coconut oil. Perhaps the ketone body acetoacetate plays a more important role for people who are ApoE4+. Certain types of brain cells may prefer acetoacetate to beta-hydroxybutyrate, and perhaps these cells are more affected in people who are ApoE4+ like Steve. It has been suggested based on studies that acetoacetate may play a greater role than beta-hydroxybutyrate in controlling seizures using the ketogenic diet (Hartman, 2007).
There is yet another possibility. Given that medium-chain fatty acids are not stored as fat and can cross the blood/brain barrier, perhaps one or more of the other medium-chain fatty acids in coconut oil are taken into the mitochondria of various types of brain cells to produce this improvement. Further study of specific medium-chain fatty acids needs to be undertaken to learn more about exactly what happens to the portion of these fatty acids that is not converted to ketones.
In 2004, when the first Accera study was published, Steve had an MMSE of 23 and had just been diagnosed with dementia. His MRI scan was read as “normal” at that point in time; four years later, his MRI showed considerable shrinkage in his brain, classified as severe in the areas affected by Alzheimer’s disease. I have wondered so many times what our life would be like now if the results of this study had caught the attention of the media.
The results of a second, larger study by Accera were first reported at a neurology meeting in 2007 (Constantini, 2007), but they did not appear in a journal in detail until more than a year after Steve’s dramatic improvement from coconut oil (Henderson, 2009). This study was also described in the patent application for AC-1202 that I found on the Internet in May 2008, but it was not made available for the scientific community until more than a year later. There were 152 participants in this study with mild to moderate Alzheimer’s disease, of which eighty-six people received AC-1202 and sixty-six received the placebo. This time the treatment was continued for ninety days, and both the placebo and the MCT oil were in a powdered form that the subject could reconstitute in a liquid drink. This time the subjects were given 20 grams of MCT oil, a reduction from the 40 grams used in the first study. One hundred-forty people completed enough of the study to have their data included in the final results. This time, once again, the people taking AC-1202 who were ApoE4- showed improvement on the ADAS-COG test as a group over the ninety days; the ApoE4+ people as a group followed the same path as people on the placebo, declining over that period of time. Neither group showed an improvement in MMSE scores.
I have subsequently learned from one of the authors of the report that nearly half of the ApoE4+ people did, in fact, improve on the ADAS-COG. However, when they were looked at as a group, there was no statistical improvement. It would be helpful for this information to be available in their report, since some physicians may not believe it worthwhile treating someone who is ApoE4+ with Axona, when it may very well be beneficial.
Doctors know very well that many people have trouble remembering to take their medications, which can obviously have an impact on the effectiveness of the treatment. The researchers were able to keep track of how compliant the subjects were, and there was a greater than 2-point difference in improvement in the people who were compliant compared to those who were not. Also, many of the people in the study had to reduce how much AC-1202 they were taking due to adverse effects. About one fourth developed diarrhea. The people who were able to tolerate a larger dose of AC-1202 showed greater improvement in their scores. Another interesting point was that, on average, the people who had higher beta-hydroxybutyrate levels had more improvement.
At the end of the ninety days, there was a two-week “washout” period. The people were taken off AC-1202 and tested again. Compared to where they started out, the people who were ApoE4-showed some worsening in their ADAS-COG scores, but were not quite back to where they were at the start of the study. The sad news here is that they were taken off the treatment. I suppose this was deemed necessary to demonstrate that MCT oil had, in fact, brought about the improvement.
The Accera group performed another study of 159 people, this time with mild cognitive impairment, which often leads to Alzheimer’s disease (Costantini, 2009). Once again, the people receiving Axona showed improvement in response to the treatment, particularly those who were APOE4-.
In 2009, Kathleen Page, M.D., at Yale University School of Medicine and others published a study in which they administered MCT oil to people with “intensively treated” type 1 diabetes who were also prone to severe hypoglycemic (low blood sugar) attacks. Ten of the eleven people they studied were using a pump that continuously administers insulin under the skin; the eleventh person required multiple shots of insulin each day. Most of the people had between six and thirty episodes of hypoglycemia per month. The researchers deliberately caused hypoglycemic attacks in the subjects. Some of the people received MCT oil, the others placebo. Nine of the people were studied twice. On one day they received MCT oil (40 grams) and on another day the placebo, effectively serving as their own control.
The people who administered the battery of cognitive tests did not know whether the subjects received MCT oil or placebo. They also measured plasma, glucose, insulin, fatty acids, and ketone levels (beta-hydroxybutyrate). The ketone levels increased to an average of 0.35 mmol/l. When compared to the placebo, the researchers reported, “MCT prevented the decline in cognitive performance during hypoglycemia” in five of the seven tests administered. Their findings “suggest that MCT could be used as prophylactic [preventive] therapy for such patients with the goal of preserving brain function during hypoglycemic episodes….”
In summary, studies have shown that consumption of MCT oils can bring about cognitive improvement in people with memory impairment and protect cognitive function in diabetic people who experience severe hypoglycemic episodes. Presumably, these effects occur because ketones and possibly medium-chain fatty acids are available to the brain as an alternative fuel to glucose.
In January 2011, Stephen Cunnane, Ph.D., and collaborators published a review in Nutrition entitled “Brain Fuel Metabolism, Aging, and Alzheimer’s Disease,” detailing what is currently known about the connection between the deterioration of the process of glucose metabolism in the brain and the development of Alzheimer’s disease, as well as the role ketones could play in the prevention and treatment of Alzheimer’s disease (Cunnane, 2011). This review cites 217 research articles to support the concepts they present. The scientists state that to the best of their knowledge: “Hypometabolism [decreased uptake of glucose] is currently the earliest measurable abnormality in the brain that is connected to Alzheimer’s disease so its features and the reasons for it should shed light on the etiology of Alzheimer’s.” They point to PET scan studies showing small areas of lower brain glucose metabolism in people as young as thirty years old who are ApoE4+ and similar findings in the offspring of people with Alzheimer’s decades before symptoms occur.
Cunnane and his colleagues say that ketone metabolism is an important feature of brain function, as evidenced by two observations: “(1) The amounts and activities of ketone-metabolizing enzymes in the brain are not changed by glucose status and always exceed the amount necessary to supply the brain’s total energy needs; and (2) during infancy the brain appears to have an obligatory requirement for ketones.” Therefore “the brain is always prepared to burn ketones.” On the other hand, they explain why glucose is still essential for the brain and why ketones cannot completely replace glucose as a fuel. They discuss the Henderson and Page studies, demonstrating that mild elevation of ketone levels can maintain normal brain function even when blood glucose levels are low enough to cause deficits.
The researchers have learned from PET scans and other types of studies that use of ketones by the brain does not appear to be affected by aging or by Alzheimer’s disease, but is lower in diabetes mellitus. They have also discovered that the plasma concentration of ketones is directly proportional to the percent of energy supplied by ketones to the brain. Thus a ketone level of 0.4 to 0.5 mmol/l, which can be achieved by taking medium-chain fatty acids, can provide 5 to 10 percent of the brain’s energy needs. This is equivalent to the deficit in energy provided to the brain by glucose in people who are genetically at risk for Alzheimer’s.
In other words, regular consumption of coconut oil and/or MCT oil could potentially provide a nutritional prevention strategy to decrease the risk of developing Alzheimer’s, or at least delay onset of the disease. The ketone ester, which can raise ketone levels to 5 mmol/l or even higher, could provide as much as 60 percent of the energy requirement of the brain, potentially halting or even reversing the process of Alzheimer’s disease.