Alzheimer’s Disease & Ketones: The Brain’s Preferred Fuel


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May 24, 2021
Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease

Alzheimer’s Disease has at times been referred to as Type III diabetes whereby the brain is being starved of its primary fuel of glucose. Dr. Stephen Cunnane at the University Sherbrooke in Canada is one of the leading researchers in the area of examining Alzheimer’s Disease as a brain energy deficit problem, its mechanisms and how ketones may be able to circumvent this issue and provide a therapeutic treatment for this condition. Researchers have found that although the ability of Alzheimer’s brain to utilize glucose is impaired, its ability to use ketones is not.

In this study Dr. Cunnane and his fellow scientists show that a brain energy deficit can be identified many years in advance as a pre-symptomatic condition in individuals developing Alzheimer’s Disease and provide four rationales for this:
  • Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age.
  • The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD.
  • Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain’s main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD.
  • Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia.
Humans have evolved to use ketones as the primary backup fuel source for the brain in times of starvation. As a person is deprived of all food or carbohydrate containing foods, the body will switch to burning stored body fats to produce ketones in the liver to subsequently fuel the energy needs of the body, such as in the brain and heart. For the very few processes in the body that can only be fueled by glucose, the body can actually produce glucose from the burning of dietary and skeletal protein to produce glucose through a process called gluconeogenesis. It’s amazing how resourceful our bodies can be and the lengths they will go to preserve and protect the functioning of our brains.

One of the very interesting and compelling findings of this study was that ketones were found to not only be the primary alternate fuel source for the brain, but the brain in fact prefers ketones over glucose! We have known for some time that the brain primarily uses glucose for energy and then switches to ketones in times of starvation. However, until the creation of exogenous ketones and new scanning and tracing technologies, we did not know what the brain would do with a simultaneous abundant supply of glucose and ketones. The researchers in the present study were able to track the utilization of the competing fuel sources and found that the brain will preferentially take up ketones over glucose and in a linear fashion. The authors state:

“Both short-term PET and arterio-venous difference studies in humans show that brain glucose consumption decreases as ketone availability to the brain increases (Hasselbalch et al., 1995). These results suggest that ketones are actually the preferred energy substrate for the brain because they enter the brain in proportion to their plasma concentration irrespective of glucose availability; if the energy needs of the brain are being increasingly met by ketones, glucose uptake decreases accordingly. This decrease in brain glucose uptake when both ketones and glucose are available supports the notion that ketones are the brain’s preferred fuel.”

In addition to the brain preferring ketones over glucose, this study found that there is a “direct, linear relation between plasma ketone concentration (X axis), brain ketone uptake (left-hand Y axis), and percent contribution by ketones to total brain energy requirement (right-hand Y axis).” In other words, the more ketones you give the brain, the more it will use.


Important to the conversation regarding the hypometabolism of glucose found in Mild Cognitive Impairment and Alzheimer’s Disease is the fact that “the problem for the aging brain is that low glucose supply in the blood is not the same as low brain glucose utilization”. The issue that often occurs in these metabolically compromised neurological conditions is that even in the presence of low glucose in the brain patients can still have elevated levels of insulin. Elevated levels of insulin inhibits the production of ketones in the body which then creates a spiraling decline and degradation of both of the primary fuels sources for the brain. This condition led the researchers to conclude in regards to rescuing the brain’s energy deficit problem: “at present, oral ketogenic supplements are the most promising means of achieving this goal.”


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