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Fueling Up: Glucose, Ketones & Your Brain

Fueling Up: Glucose, Ketones & Your Brain

Last week, Accera, Inc. reported that its drug AC-1204 failed in a phase 3 clinical trial for Alzheimer's disease. Unlike recent high-profile drug failures from Lilly and Merck, Accera's drug was not targeting beta-amyloid plaques. Instead, it attempted to slow the progression of Alzheimer's by affecting how neurons get and use energy.

The failure of Accera's drug is raising questions about whether targeting the energy system in neurons makes sense as an approach for treating Alzheimer's disease. Glucose (sugar) supplies most of the energy to the brain. But as we age, our brains can become less efficient at converting glucose into energy. In Alzheimer's patients, glucose utilization is even more compromised. However, when there is insufficient glucose, the brain can use a backup fuel source—ketones [1].

Accera's AC-1204 attempted to harness this backup system. AC-1204 is a formulation of caprylic acid, which is a type of medium chain triglyceride (MCT) commonly found in foods such as coconut oil. The body can convert MCTs into ketones, the brain's alternative energy source. Some evidence suggests that in early Alzheimer's patients, the brain can still use ketones, even if it is less able to use glucose [2]. Accera reported that its trial may have failed because AC-1204 failed to increase the concentration of ketones in the blood, which affects the ability of the brain to use them as energy.

The Alzheimer's Drug Discovery Foundation (ADDF), the nonprofit behind Cognitive Vitality, is funding several Alzheimer's treatments that target the brain's energy system in more direct ways. At Imperial College London, Dr. Paul Edison is conducting a clinical trial to test liraglutide, a diabetes drug that appears to increase the brain's ability to use glucose. Dr. Christian Holscher of Lancaster University is taking a similar approach, developing drugs based on those for diabetes. At Burke Medical Research Institute in New York, Dr. Gary Gibson is testing benfotiamine, a derivative of vitamin B1, in a phase 2 clinical trial in Alzheimer's patients. Vitamin B1 assists several enzymes that help the brain use glucose for energy. And Dr. Galit Weinstein at Boston University School of Medicine is investigating whether the risk of dementia can be affected by the choice of drug used to treat a patient's diabetes.

Many processes damage our neurons and contribute to Alzheimer's disease and its progression. The decline of our brain's ability to use energy efficiently is involved in Alzheimer's, so the ADDF is developing drugs to treat it. We expect patients will also need drugs to treat other factors such as inflammation, misfolded proteins, and vascular problems, and the ADDF is supporting drugs for those, too. A multi-faceted approach might be needed to cure such a complicated disease.

  1. Cunnane SC, Courchesne-Loyer A, St-Pierre V et al. (2016) Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. Annals of the New York Academy of Sciences 1367, 12-20.
  2. Castellano CA, Nugent S, Paquet N et al. (2015) Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease dementia. Journal of Alzheimer's disease: JAD 43, 1343-1353.

Nick McKeehan is Program Manager of Aging and Alzheimer's Disease Prevention at the Alzheimer’s Drug Discovery Foundation. He served as Chief Intern at Mid Atlantic Bio Angels (MABA) and was a research technician at Albert Einstein College of Medicine investigating repair capabilities of the brain. He received a bachelor of science degree in biology from Purdue University, where he was awarded a Howard Hughes Scholarship. Mr. McKeehan also writes about the biotechnology industry for 1st Pitch Life Science.

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