Istumbled upon it completely by accident.
The evening before the first screening, I began to think about what would happen if Steve qualified for both the ICARA and Eli Lilly studies. Which should we choose? I got on the Internet to learn as much as I could about both drugs, including the potential risks and benefits. While searching, I came across a press release for a third promising drug called AC-1202. The company making the medication, Accera, a small biotech firm, was working toward Food and Drug Administration approval. They reported that AC-1202 actually improved memory in a significant number of the people with Alzheimer’s disease.
A sugar called glucose is the primary energy source for brain cells. In people with Alzheimer’s, scientists have detected a dramatic decrease in glucose use in certain brain areas that begins ten to twenty years before any visible symptoms appear. Deprived of their primary energy source, neurons [brain nerve cells] suffer irreparable damage. The cause of decreased glucose metabolism remains uncertain.
Scientists at Accera have developed a compound called AC-1202 that provides these glucose-deprived neurons with an alternative energy source known as ketone bodies, which can be metabolized even when glucose cannot. Accera’s hypothesis is that increased availability of ketone bodies will improve memory problems and other functional losses that occur in Alzheimer’s.
At the Alzheimer’s Association Prevention Conference, Lauren Costantini, Ph.D., vice president, clinical development, at Accera, reported results of a double-blind, placebo-controlled Phase IIb clinical trial with 152 subjects with probable mild to moderate Alzheimer’s. AC-1202 was taken as a drink each morning (20 grams). Most study participants continued to take other Alzheimer’s drugs such as acetylcholinesterase inhibitors, so this study was measuring the effectiveness of AC-1202 on top of existing therapy.
Treatment lasted for three months, followed by a two-week washout, then an additional six-month follow-up where all subjects, including both placebo- and AC-1202-treated patients, were given the opportunity to receive AC-1202 in an open-label extension study. The main outcome for efficacy was improvement in the ADAS-Cog [Alzheimer’s Disease Assessment Scale–Cognition, a popular 75-point test of cognitive function used in clinical trials to detect changes in the core symptoms of Alzheimer’s].
The researchers found that, after forty-five days of treatment, participants who took AC-1202 showed statistically significant improvement compared with placebo with the highest response in subjects not carrying the E4 variant of the apolipoprotein gene (ApoE4-), which occurs in half of all Alzheimer’s patients. These effects on ApoE4- subjects were maintained for the duration of the initial study period (ninety days). In contrast, patients carrying the E4 variant of the APOE gene (ApoE4+) showed no differences between AC-1202 and placebo.
Forty-nine study participants entered the six-month open label extension; thirty-four completed the study. According to the researchers, subjects taking AC-1202 for nine months showed very little disease progression (mean change in ADAS-Cog score from baseline to day 294 = 0.8). From “A Possible Alzheimer’s Blood Test and Two Trials of Innovative Therapies” presented at the Alzheimer’s Association International Conference on Prevention of Dementia, 11, 2007.
Since we never hear the phrase “improves memory” associated with the current drugs for Alzheimer’s, I was very curious about how this treatment might work. At present, the FDA-approved drugs for Alzheimer’s disease claim at best to slow down the decline of the disease. The press release did not say what kind of drug this was or how it worked, so I performed an Internet search for AC-1202.
The first item to pop up was a 2008 patent application (U.S. Patent #20080009467) on www.freepatentsonline.com. This was a continuation of a patent application that was originally submitted by Samuel Henderson, Ph.D., executive director of research at Accera, in May 2000. I printed out the seventy-five-page document and began to read it. After several pages of legalese, there was a well-written summary of what was known about Alzheimer’s disease at that time in relation to their invention. It talked about beta-amyloid plaques and neurofibrillary tangles, but also about a problem with glucose transport into neurons. It said that researchers have discovered that neurons in certain areas of the brain in Alzheimer’s disease are unable to use glucose and that this same problem occurs in other neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, and Lou Gehrig’s disease (amyotrophic lateral sclerosis, or ALS), but in different parts of the brain.
This rang a bell because I had previously come across research about the problem of glucose transport in Alzheimer’s patients by William Klein, Ph.D., and others (Klein, 2008). Researchers described a problem with the location of insulin receptors, which would normally be found on the surface of the cell membrane but are not. The hormone insulin is needed for glucose to enter cells. Insulin attaches to the receptor on the cell membrane, initiating a chain of metabolic events that allows glucose into the cell where it is converted eventually into the energy molecule adenosine triphosphate (ATP). ATP is necessary for the cell to function and maintains its very life. Some scientists had even begun to call Alzheimer’s disease a “type 3” diabetes (de la Monte, 2005), a concept that will be discussed at length in Chapter 13.
The patent application then described the “invention,” which was based on the known fact that neurons can use a type of fuel other than glucose called ketones or ketone bodies. Ketones are transported into the cell by a different mechanism than glucose and therefore, if available in the bloodstream, can bypass the glucose/insulin transport problem and provide fuel for neurons and other brain cells, potentially keeping them alive.
Ketones are fundamental to the evolution of human beings. Without ketones, humans as a species would not have survived. Our ancient ancestors, and even people living in our world today, have endured periods of feast and famine. When food is available, we lay down stores of glucose (from ingested carbohydrates) and fat for future use as fuel and then tap into them when food is unavailable. When the stores of glucose in the body are used up, which happens after twenty-four to thirty-six hours, the body turns to burning fat and releases ketones (small carbon-containing fragments), which are then used as the primary fuel by the brain and other organs until food is once more available. This protective process is called ketosis.
Most of us these days in the United States do not have to struggle with the problem of feast and famine. As a result, there is not much ketone circulating in the bloodstream, since plenty of glucose fuel is available.
The body shifts its main fuel supply from glucose to ketones under several other conditions. Consuming a ketosis-inducing diet, an extremely high-fat, low-protein, low-carbohydrate diet that is sometimes used to treat severe childhood epilepsy, is one way. The Atkins and South Beach diets, which promote cutting carbohydrates, are less restrictive forms of the ketogenic diet and may result in mild ketosis. Diabetic ketoacidosis is a serious complication of type 1 diabetes that occurs when the levels of ketones become dangerously high, as much as five to ten times higher than one would have during starvation or on a ketogenic diet.
There is yet another way that ketones become available to brain cells. When a person eats foods with medium-chain fatty acids, they are partially metabolized in the liver to ketones and enter the bloodstream. According to one study, circulation to the brain increases by as much as 39 percent during ketosis (Hasselbalch, 1996). Ketones readily cross the blood/brain barrier and can be used by brain cells as fuel. Ketones are a more potent fuel than an equivalent amount of glucose, producing nearly twice as much ATP inside the cell. The levels of ketones from consuming medium-chain fatty acids would never come remotely close to reaching the levels of diabetic ketoacidosis.
The inventor of AC-1202 (now known by the brand name Axona), Dr. Samuel Henderson, applied for the patent to market medium-chain triglyceride (MCT) oil for people with Alzheimer’s disease. (MCT oil consists of 100 percent medium-chain fatty acids.) This was based on the company’s research showing that the mild ketosis produced by ingesting MCTs appears to improve cognitive ability in a significant number of people with Alzheimer’s disease.
When Dr. Henderson and his colleagues conducted studies of people with Alzheimer’s and mild cognitive impairment, they found that by ingesting 20 grams (about four teaspoons) of AC-1202 (which we know from the patent application is MCT oil), nearly half the subjects showed significant improvement within forty-five days as measured by the ADAS-Cog exam compared to the people taking a placebo, who declined more significantly as people with Alzheimer’s disease normally do. People who did not have the harmful ApoE4 gene, which increases the risk of developing Alzheimer’s, improved more significantly than those who had the ApoE4 gene. The researchers also found that the higher the beta-hydroxy-butyrate level (the primary ketone used by neurons), the greater the improvement. In addition, people who were taking Alzheimer’s related medications—Aricept, Namenda, Exelon, or Razadyne (formerly known as Reminyl)—appeared to particularly benefit from taking MCT oil, with the greatest improvement in people taking Razadyne. A subgroup of these subjects continued the study for an additional six months, and those who were receiving MCT oil showed very little disease progression over that time period.
I later learned that MCT oil has been available over the counter for decades and is used by bodybuilders to help increase lean body mass. Some athletes and fitness buffs use MCT oil to increase energy levels and enhance endurance during high-intensity exercise. There have also been studies showing that MCT oil increases satiety and, if substituted for other oils, can result in weight loss.
The patent application made it clear that Accera did not invent MCT oil, or even make the specific MCT oil used in its product, but rather obtained a product called Neobee from the Stepan Company. Neobee is primarily a medium-chain triglyceride known as tri-caprylic acid, or C:8. Accera mixed the oil with whipped cream to conduct its studies, which will be explained in greater detail in Chapter 18.
At some point after my discovery, I was told by a researcher at one test site that when the AC-1202 trials were completed, the participants no longer had access to the product. As the wife of a relatively young man with Alzheimer’s, I can only imagine what it must have been like to be a person with Alzheimer’s and that person’s spouse or children, to see a significant improvement, perhaps a very dramatic improvement, and then to have that taken away.
The patent application further stated that some people improved with the very first dose of MCT oil. In fact, Henderson stated that other combinations of MCT oils could be expected to produce the same effect. Then there were pages and pages of every conceivable formulation of MCT oil in powders, bars, and liquids, with numerous other additives and supplements, singly and in combination, that might improve people with Alzheimer’s, and also in various combinations with the standard medications for the disease. However, the application clearly stated repeatedly that the only ingredient tested was MCT oil.
I didn’t know while I was reading the patent application that MCT oil was readily available in many natural food stores and could easily be purchased online. But I clearly remembered using MCT oil during my training and in my practice in the late 1970s and early 1980s to supplement feedings for premature newborns. MCT oil is easily absorbed, even by infants, without digestive enzymes, and is still used today in many neonatal intensive care units (Tantibhehyangkul, 1975). The first formulas for preemies were developed thirty years ago, and since then MCT oil has been added to virtually all standard infant formulas.
And then the moment of my epiphany occurred. Just once in the patent application, Dr. Henderson mentioned (in parentheses no less) that MCT oil is derived from coconut oil or palm (kernel) oil. I remembered seeing coconut oil in natural food stores, and I could not imagine what it was doing there, since it has the reputation of being an “artery-clogging oil.” I had never taken the time to find out why it might be considered healthy.
After I finished reading the patent application, I went on an Internet frenzy, looking for everything I could find about medium-chain fatty acids, coconut oil, MCT oil, and ketones. I had to relearn biochemistry from my freshman year of medical school about what distinguishes medium-chain fatty acids from short-and long-chain fatty acids and find the fatty acid composition of coconut oil. I learned that coconut oil is nearly 60 percent medium-chain fatty acids. I calculated that about 35 grams of coconut oil (seven teaspoons, or a little more than two tablespoons) is equivalent to 20 grams of MCT oil. If I could give Steve coconut oil, we might be able to produce the same effect. Steve is an ApoE4 carrier so I had to be prepared that he might not respond at all, based on the results of the AC-1202 studies.
It was now after 1 A.M. on May 20, 2008, and Steve’s appointment was at 9 A.M. in St. Petersburg. I had to call it quits for the night. There would be no opportunity to give Steve coconut oil before the first screening.
The following morning, we got up and had breakfast as usual. On the way to the Comprehensive NeuroScience Center in St. Petersburg, I remembered the suggestion from the research assistant at the previous screening to try to prepare Steve for the Mini-Mental Status Exam test. I reviewed the various questions about orientation to time and place, such as where we were going to be, city and county, what was the current year, season, month, day of the week, and so on. I thought he would surely be able to remember the county of Pinellas that we lived in for sixteen years just before moving to our current town. We talked about other things as usual, but from time to time we went over the same questions again.
Steve went through the screening process. He met all the other criteria, but once again he scored a 14 on the MMSE, too low to be accepted into the study. Very disappointed, we sat down with the doctor. Dr. Nunez shared with us that her mother also has Alzheimer’s disease and answered our questions. She asked Steve to draw a clock, a test she said was more specific for Alzheimer’s disease. When he returned, she showed me his drawing (Figure 4.1).
FIGURE 4.1. Clock 1: The day before starting coconut oil.
His clock did not look like a clock at all. There were several random small circles and several numbers with no apparent relationship that did not even remotely resemble a clock. Dr. Nunez took me aside and said this indicated that his dementia was leaning more toward the severe than the moderate range. Surprised and yet not surprised, it was still a shock to hear this, and my thoughts drifted to the road we were heading down, the inevitable decline that no one wants to experience.
On the way home, thinking, “What have we got to lose?” we drove considerably out of the way to a natural food store in Tampa where I had seen coconut oil on the shelf. We purchased a quart and headed home.
The following day, Steve’s screening for the vaccine study was scheduled for 1 P.M. at the Johnnie Byrd Institute. To make sure Steve received at least 20 grams of medium-chain triglycerides, I put more than two tablespoons of coconut oil in his oatmeal with his blessing—and even more for good luck. I added two tablespoons to my oatmeal as well. How could I expect Steve to eat something I wouldn’t eat?
Just before noon, we began the hour-long trip to Tampa. Just like the day before, Steve agreed that we should go over some of the questions we knew they would ask and did not mind my obsession with increasing his MMSE score, if at all possible, so that he could qualify for the study. We went over and over the year, the season, the month and day of the week, as well as where we were going, the city, county, and name of the building. He repeatedly confused April for May, Wednesday for Thursday, and couldn’t even remember the word “spring,” much less where we were going. By the time we arrived, I was quite certain that he would do no better than during the previous visit.
Shortly after arriving, Steve was whisked away to another room for the test. We were told that if he scored high enough, they would continue the screening process. When I pray, it is usually to thank God for what I have rather than asking for favors. I have always believed that most of what happens to us is within our control and that if we want something special we have to use our own resources to get it. When I have a baby in dire straits, I ask God to help me do the right thing to pull the baby through. On this day, while he was gone, I prayed to God to help Steve qualify for this study. I wasn’t ready to lose him.
When Steve returned, he said he didn’t do very well, so we sat and waited, once again feeling a bit hopeless. The research assistant, Laura, entered the room and began to take Steve’s blood pressure and talked about drawing blood. I asked her if this meant Steve had qualified for the study, to which she replied, “Didn’t he tell you? He scored an 18! We are going ahead with the screening process.” This was 6 points higher than our prior visit there and 4 points higher than the previous day. Laura reviewed the MMSE with us. Steve remembered that it was spring, it was May, and it was Wednesday. He recalled that we were in Tampa, in Hillsborough County, and at the Byrd Institute. We were elated as Laura and the others proceeded with the rest of the screening process.
Was this drastic improvement the result of the coconut oil, the preparation on the way down, the prayers, or just a stroke of good luck? I had read in the AC-1202 patent application that some people improved with the very first dose. Perhaps Steve was one of the fortunate individuals who responded that quickly. According to Accera studies, since he is an ApoE4 carrier, he might not have responded at all.