Can ketones be used as an alternative fuel source in the Alzheimer’s brain?

Can ketones be used as an alternative fuel source in the Alzheimer’s brain?

Dementia is a progressive neurological disorder resulting in a decline in cognitive function that interferes with daily activities. The most common cause of dementia is Alzheimer’s Dementia (AD). There is currently no treatment for AD and the cause of AD is still unknown. One thing that is well established, is that there is deteriorating brain glucose utilization, both uptake and metabolism, in the Alzheimer’s brain. This is based on decades of research looking at glucose uptake in brains using PET scans. These studies have shown a 20-25% global decreased brain glucose utilization compared to normal age related controls. (See picture below) This decreased glucose utilization is localized regionally in the parietal, posterior cingulate and temporal cortex of the brain. This pattern of decreased utilization is relatively specific to AD compared to other forms of dementia and normal aging itself and is used to help diagnose people who have AD. In the past this pattern of decreased glucose utilization seen in patients with AD, generally, was believed to be a consequence of neuronal cell death.

alzheimers-PET ok

Recent evidence now reveals that this brain energy deficit is present long before the clinical diagnosis or even before the symptoms of AD start. Specifically, glucose utilization has been shown to be 9% lower in cognitively normal individuals older than 65 years of age compared to younger cognitively normal individuals. The glucose deficit is also present in adults who are less than 40 years of age who have genetic or lifestyle risk factors for AD, even before having cognitive symptoms. For example young women who have polycystic ovarian syndrome (PCOS) have been shown to have decreased brain glucose utilization deficit similar to what would be seen in people in their 70s and 80s. PCOS patients have mild insulin resistance, which is associated with an increased risk of AD. Is it plausible then that this deficit of brain glucose utilization may exacerbate or may even be the cause of, instead of the consequence of neuronal loss in AD. One theory proposed is that it is a vicious cycle in decreased glucose utilization that then causes deteriorating neuronal function, which then results in a higher demand for glucose, with the eventual emergence of cognitive decline.

So what if there is another fuel that the brain can use other than glucose?

Dr. Cahill showed in the 1960s that ketones are the main alternative fuel source/energy supply for the brain as a way to protect the brain in times of starvation. It is also known that  infant rely on ketones as the main fuel source due to the metabolic stresses that occur with the rapidly growing infant brain. (see prior blog post) So if the human species relies on ketones to confront these energy challenges why couldn’t it work for the aging or Alzheimer’s brain?

It is has been shown that the brain uptake of ketones is proportional to the plasma ketone levels, but does this change in the aging brain or AD brain? Dr Cunnane looked at just this question. He used PET studies to show that the brain uptake of ketones is the same in patients with AD as compared to age matched cognitively healthy controls. The brain ketone utilization in AD was proportional to the plasma concentration and was the same as age matched controls. I repeat, the areas of the brain that showed decreased glucose utilization in the Alzheimer’s brain had normal uptake and utilization of ketones. This, to me is very exciting! As a neurologist I have always believed that decreased glucose utilizations in patients with AD, was a sign that those brain cells were dead. This data by Dr. Cunnane, however, shows that those cells are just not able to use glucose but can use ketones, thus are NOT dead.

So then would fueling the body with ketones be a potential treatment option of AD?

Babies are born into ketosis and stay in ketosis because the breast milk contains medium chain fatty acids which are rapidly absorbed and transformed quickly into ketones.  Coconut oil is another medium chain fatty acids. When medium chain fatty acids such as coconut oil are added to the diet in patients with AD, cognitive benefits have been shown. Clinical trials using ketogenic interventions in AD have also shown improvement with cognitive function. (see prior blog post) This suggests that interventions that increase ketone levels may have beneficial therapeutics in patients with AD and deserve further study.

The take home message, to me is: there is an impairment of glucose uptake and metabolism in the brain in patients with Alzheimer disease (AD). However, the brain uptake of ketones remains the same in AD as compared to healthy controls. There for interventions that increase ketones availability, either with a ketogenic diet or ketone supplements may help improve the energy deficits seen in the AD and aging brain. Though we do not know if there will be clinical benefits without further study.  Isn’t worth a try?

 

Bibliography

Cunnane, S. (2011). Brain fuel metabolism, aging, and Alzheimer’s disease. Nutrition, 27, 3-20.
Cunnane, S. C. (2016). Can Ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer’s disease. Annuals of the New York Academy of Science, 1367, 12-20.
Cunnane, S. C. (2016). Can Ketones Help Rescue Brain Fuel Supply in Later life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease. Frontiers in Molecular Neuroscience, 9, 1-21.
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