The wife of one of my moderately impaired Alzheimer's patients called me last October to ask if I knew about a new product called Axona® and whether I thought it was helpful in the treatment of Alzheimer's disease. I told her I had never heard of it, but I would investigate and get back to her.

Fast forward to early 2009: Axona, classified as a medical food, recently received approval from the FDA for the treatment of mild to moderate Alzheimer's disease. I am sure the majority of neurologists who read this journal have already been detailed by a representative from Accera Pharmaceuticals, the product manufacturer. The primary ingredient is a medium chain triglyceride (caprylic triglyceride) in powder form. The recommended dose is 40 grams of Axona mixed in eight ounces of water or juice, taken once a day at breakfast. This medium chain triglyceride is oxidized in the liver to form ketone bodies, the main one being betahydroxybutyrate (BHB). BHB is not used by the liver and is not stored in adipose tissue. It is free to circulate in the blood stream and provides the body and brain cells another source of energy. Most of the foods we eat on a daily basis contain 95 percent long-chain triglycerides or fatty acids, which are packaged in the liver to lipoproteins and then usually stored in the adipose tissue.

Why all the fuss about ketone bodies? You may recall from basic cerebral physiology that the normal brain accounts for two percent of our total body mass, consumes 250ml 02/minute (16 percent of the body's total oxygen), and metabolizes 110 to 140 grams per day of glucose. Most of the brain oxygen use is for oxidation of glucose for ATP synthesis, which is required for cycling neurotransmitters and functional neuronal signaling. The brain mostly relies on glucose in the circulation for the majority of its function and stores very little energy in the form of glycogen. Glycogen provides approximately five minutes of normal brain function when glucose levels drop very low. In our culture, ketones work as a source of energy for brain cells in only very unusual circumstances, such as starvation and poorly controlled diabetes. Throughout human evolution, ketosis likely served as a valuable survival mechanism to fuel the brain metabolism during times of food scarcity.

Comparing Alzheimer's disease patients with normal controls, early studies showed a 24 percent decline of cerebral metabolic rate of glucose (CMR glc) across the whole brain, and this correlated directly with low cognitive scores.1 Numerous studies since have confirmed decreased glucose uptake, especially in the posterior cingulate, and parietal temporal and prefrontal cortex on PET scans. The exact reason for this observation is not clear. It is likely due to a combination of factors, which include a reduction in the density and activity of terminal neuronal fields or glial cells and possibly a metabolic defect in neurons or glial cells themselves.

As far back as 1996, Reiman, et al.2 screened subjects between ages 50 and 65 with a family history of Alzheimer's disease and homogeneous for the E4 allele. They found 11 cases that were E4/E4 and 22 matched controls that were not E4. Cognitive tests in both groups were the same, but the E4/E4 group showed decline in glucose metabolism in the same regions found in the Alzheimer's disease subjects. The same authors studied young adults3 (mean age 31) with the same outcome. They concluded that, "carriers of a common Alzheimer's susceptibility gene, E4/E4, have decreased functional brain activity in young adulthood several decades before possible onset of dementia, and well before cell loss or plaque deposition is predicted to have occurred." Two other studies, one in 1997,4 the other in 2002,5 found no difference in the CMR glc in E4/E4, E3/E3, E4/E3 and E2/E3 with Alzheimer's disease. The only difference between the E4/E4 and other alleles was that the former had more global decline in glucose and more areas of the brain involved.

In 1920 it was discovered that the ketogenic diet, which is very low in carbohydrate and protein and high in fat was successful in treating refractory childhood epilepsy. This diet, which was badly tolerated, was a major sacrifice for patients to control their seizures. In his writings, Hippocrates noted that abstaining from all food and milk cured a man with epilepsy.

In the last seven years, several authors have wondered whether ketones could help neurodegenerative disorders of the brain. This concept was strengthened when Crafts, et al. in 20006 and Reger in 2004,7 showed that infusion of ketones (BHB) in rodents protected them from ischemia, glutamate and MPTP toxicity. Constantine, et al. in 20078 exposed cultured hippocampal cells from 18-day embryonic rats to AB42. This resulted in a 50 percent decrease in cell numbers. When exposed to BHB at the same time, doubling of cell survival was noted suggesting that BHB protects against AB 42 toxicity.

Reger did the first clinical study of ketone bodies in cognitive function in 2004.7 This was a randomized, placebo-controlled, cross-over design to measure the therapeutic effects of a single dose (40 grams) of middle chain triglyceride on memory in 20 patients ages 55 to 85 with a diagnosis with probable Alzheimer's disease (15 diagnosed with mild cognitive impairment).5 Eighty percent of the Alzheimer's patients were on Alzheimer's therapy. The level of BHB in the blood was 10 times the normal level after two hours of the ketones. Ninety minutes after the load all subjects were retested using the Alzheimer's disease assessment cognitive scale and a paragraph recall test. There was a strong and significant correlation between the paragraph recall tests with subjects with the highest BHB level. The ADAS cognition scores showed highest improvement in the E4 negative subjects compared to E4 positive subjects. The study also showed that elevated ketones and ketosis could be achieved without dietary changes.

The next major study that led to approval of Axona by the FDA was reported in 2007 by Constantine, et al.8 This was a double-blind, randomized, placebo control study of 90 days with two-week washouts at multiple US clinical centers involving 152 cases with mild to moderate Alzheimer's disease. All of these cases were allowed to remain on their Alzheimer's treatment medication, which included Aricept (50 percent), Namenda (37 percent), Exelon (13 percent) and Razadyne (four percent) were represented in both treatment and placebo groups. At day 45 the Alzheimer's disease assessment cognitive scale stabilized in the Axona group whereas a decline in cognition was observed in the placebo group. At day 90 the difference between the ADAS cognitive score of treatment group versus placebo was 1.54 points, a statistical significance. After a two-week washout (day 104) the Axona group maintained a slight improvement above baseline, but the placebo group continued to decline. When they looked at the presence of the APO E4, the APO E4 negative groups showed a greater improvement in the Alzheimer's Disease Assessment Scale at 90-days of 3.36. In the APO E4 positive patient group the difference of improvement at 90 days was much less than the E4 negative patients.

Many other studies of Alzheimer's disease treatment have shown responses that differ between the APO E4-negative and APO E4-positive types. The exact cause is not completely clear. The side effect profile in the 90-day study was mainly focused on gastrointestinal complaints. Diarrhea was the most common (occurring in 24 percent of the treatment group versus 14 percent in placebo group), flatulence (17 percent of the treatment group versus eight percent placebo), dyspepsia (nine percent of the treatment group versus four percent in placebo group).

When Axona was mixed with liquids other than water, which included Ensure® or fruit juice, the incidence of side effects was much less (diarrhea incidence reduced to three percent). No significant interaction of Axona was noted with any of the acetylcholinesterase inhibitors or NMDA antagonists.

Where does Axona fit into the current treatment of Alzheimer's disease? This was not discussed in any of the articles I reviewed. Since the mechanism of action of Axona is to supply brain cells with a different substrate of energy production, one would think that many brain cells in all stages of Alzheimer's Disease are still functioning and could benefit, especially in the APO E4-negative patients. We certainly know from clinical use that Namenda, Aricept and other acetylcholinesterase inhibitors are still effective in improving activities of daily living, behavior, and slowing cognitive decline in moderate to severe Alzheimer's patients. Unfortunately, we have no data on Axona regarding behavior and activities of daily living in the mild to moderate Alzheimer's disease group. We also have no data on cognitive function in severe stages of Alzheimer's disease.

The cost of Axona may play a role in determining its utility in treatment. I was told a month's supply of Axona costs around $80. We could wait for more studies or we could try using it for three months as an add-on to the other Alzheimer's medication to see if it affects cognition, activities of daily living, and behavior. I believe it is worth trying in mild to moderate Alzheimer's patients as an add-on to other medications for at least a six-month period. Its unique mechanism of action and the preliminary results are encouraging. You may want to monitor your patients more thoroughly with cognitive testing, activities of daily living and behavior assessments while using Axona.

I also believe that because of its unique mechanism of action, Axona should be tried in MCI patients, even though it has not been studied in this patient group. A close follow-up of memory function should be done to see if memory improves. The real question of using Axona in amnestic mild cognitive impairment is whether it delays the eventual development of Alzheimer's disease in the majority of cases. This will be harder to assess in clinical practice, and we may have to wait for long-term studies. However, if memory appears to improve or is more stable with Axona, it may be worth continuing treatment until further studies are reported.

Currently we have no pharmaceutical intervention to treat or delay progression of mild cognitive impairment. The primary treatments are reassurance and memory retraining. I see no need to determine the APO lipoprotein E type of our patients, despite the study data. This testing is associated with added expense, and many E4-positive patients still improved in the study. There is no reason to worry patients any further about the added risks of developing Alzheimer's disease if they are E4-positive.

Lastly, I believe that patients with frontal dementia should be strongly considered for treatment with Axona despite the lack of data, since glucose use has been shown to be impaired in frontal dementia disorders, as well on the PET scan. Currently, there is no specific treatment for frontal dementia. Such patients would require close follow-up of cognitive function, ADLs, and behavior until further study data become available.

Other neurological disorders are currently being studied with ketone use, including epilepsy, cerebral trauma, cerebral ischemia, Parkinson's disease, ALS, migraine, and narcolepsy. I would refer you to a recent article on this subject by Baranano.9 Two other excellent reviews of ketones in Alzheimer's disease are by Henderson10 and Costantini.11

Ronald Devere, MD is Director of the Taste & Smell Disorders Clinic and Alzheimer Disease & Memory Disorders Center in Austin, Texas.