Boosting Brain Ketone Metabolism: A New Approach to Alzheimer's

August 03, 2017

Strategies that increase the brain's uptake of ketones as an approach to the treatment of Alzheimer's disease or mild cognitive impairment are gaining momentum, according to experts in the field.

A whole session dedicated to the topic of brain ketone metabolism and ketogenic interventions was held during the recent Alzheimer's Association International Conference (AAIC) 2017, with new clinical data showing some exciting preliminary observations.

"We know that in Alzheimer's disease, the brain loses its ability to use glucose to produce energy," Stephen Cunnane, PhD, University of Sherbrooke, Quebec, Canada, explained. "Some areas of the brain are down by 40% in terms of glucose metabolism. We believe that this energy gap increases the risk of neuronal dysfunction and cognitive decline."

Preliminary studies presented here have suggested that the brain can use ketones instead of glucose to reduce the energy gap, Dr Cunnane said. "These strategies warrant further research to see if they can delay cognitive decline in older people," he added.

The new data included a pilot trial of a ketogenic diet, which was associated with improved cognitive function in patients with Alzheimer's disease, and preliminary results from an ongoing study suggesting that giving a ketogenic supplement in the form of medium-chain triglycerides can partially restore the brain energy supply in patients who have mild cognitive impairment, with hints of associated improved cognitive function.

Another study, presented as a poster, reported that exercise increased the uptake of ketones into the brain.

"Whether this is the mechanism responsible for the well-documented beneficial effects of exercise on cognitive function we don't know, but perhaps ketogenic supplements and exercise could be combined for a greater impact on the brain energy gap," Dr Cunnane commented.

"The ketogenic diet has been used in epilepsy for almost 100 years and has been shown to reduce intractable seizures," Russell H. Swerdlow, MD, University of Kansas Alzheimer's Disease Center, Fairway, who presented the ketogenic diet study, told Medscape Medical News.

"Our results suggest it could also be useful in other forms of neurological disease like Alzheimer's, but it is not an easy diet to follow," he added. "The point of our study is that it helps to establish a principle that brain metabolism can be rescued by a fuel other than glucose."

Dr Cunnane noted that studies have shown glucose uptake into the brain frontal cortex to be 14% lower in cognitively healthy older people than in younger healthy people. Patients with early Alzheimer's have a greater deficit, with 20% to 30% less glucose uptake than cognitively normal older people.

"Anybody trying to function with 20% less brain glucose long term will suffer from brain exhaustion," he said. 

He acknowledged that there has been some debate as to whether the reduction in brain glucose metabolism seen in Alzheimer's is a cause or a consequence of the disease, "the argument being that if neurones are dead then they don't need to take up glucose."

But he pointed out that studies have shown latent presymptomatic brain glucose hypometabolism in older people, those with insulin resistance, those with a family history of Alzheimer's disease, and APOE4 carriers. "And we have shown the brain can continue to take up ketones when its ability to use glucose declines," he noted. "If the neurones are dead, they shouldn't be able to take up ketones either."

Research is therefore focusing on increasing the concentration of ketones in the blood to see if this is associated with a reduction in cognitive decline.

Ketogenic Diet

The first and most obvious way of increasing ketone concentration in the blood is through diet, but this is not straightforward because it requires very low carbohydrate intake.

Dr Swerdlow explained that ketones are produced by the body under starvation conditions when insulin levels are very low.

"When carbohydrate intake is drastically lowered without increasing protein then insulin levels go down and the body starts to mobilize its fat reserves," he explained. "Those fats are turned into ketones in the liver and released into the bloodstream, where they replace glucose. Under these conditions, neurones in the brain switch from consuming glucose carbon to consuming ketone carbon as a source of energy, but fat is only metabolized to ketones if insulin levels are very low."  

The goal of the ketogenic diet is therefore to lower insulin by consuming very little carbohydrate, with the balance of calories coming from fat, he said. "Adherence to a ketogenic diet, however, requires considerable commitment, and the ability of Alzheimer's patients to follow a ketogenic diet regimen is unknown."

Dr Swerdlow presented results of a small pilot study showing that it is possible for patients with Alzheimer's disease to follow a ketogenic diet for a short time, and this appears to be linked to improved cognitive function.  

For the study, 15 individuals with a diagnosis of mild Alzheimer's disease were placed on a ketogenic diet with additional triglyceride supplements for 3 months. The degree of ketosis achieved was measured through daily urine testing as well as through the monthly measurement of plasma betahydroxybutyrate levels. Cognitive function was assessed at baseline, at the end of the 3-month diet period, and after an additional month when patients reverted back to a normal diet. 

Results showed that 10 of the 15 patients managed to stay on the diet and achieved a sustained ketosis. These patients had milder dementia than 5 five patients who discontinued the diet. 

In the 10 patents who remained on the diet for 3 months, cognitive function improved from baseline by 4.1 points on the Alzheimer's Disease Assessment Scale-Cog (ADAS Cog) score, but the scores reverted to baseline levels after the patients returned to their normal diets. No safety issues were reported.

"As far as Alzheimer's studies go a 4 point improvement in the ADAS Cog score is fairly robust," Dr Swerdlow noted. "It is greater than that seen in the cholinesterase inhibitor studies. It suggests a meaningful improvement in cognition."

To his knowledge, he said, this is the first report of ketogenic diet study in patients with an Alzheimer's diagnosis, although there was a previous study in people with mild cognitive impairment which also suggested a beneficial effect.

"This is just a pilot study – I wouldn't go so far as to say it worked," he added. "But we can say we saw a potential therapeutic signal that warrants further studies to confirm whether there is a real effect. That is definitely exciting."

But because the diet involves such a low carbohydrate intake it is not thought feasible to recommend it for routine use in the treatment or prevention of Alzheimer's.   

"This is not a diet that people will enjoy being on," Dr Swerdlow said. "The ultimate goal is not to recommend a ketogenic diet in their daily lives – it will be too difficult. We are just trying to show proof of principle that manipulating brain energy metabolism can impact the symptoms of Alzheimer's. If we can establish that then we can try and develop other ways to simulate the effects of a ketogenic diet that would hopefully be more palatable. 

"This may be in form of supplements or a drug therapy," he added. "The end goal would be to find a pharmaceutical that will manipulate brain energy levels in a similar way."

Triglyceride Supplement

An easier way of delivering ketones to the brain may be in form of supplements without the requirement for a strict low-carbohydrate diet.

This approach is being investigated in the BENEFIC study, interim results of which were presented by Dr Cunnane.

"In this study we are not asking patients to go on a specific diet. We are just giving them a supplement — twice a day — half in morning and half in evening. That is definitely logistically easier than trying to stick to a ketogenic diet," he said.  

The study is randomly assigning 50 patients with mild cognitive impairment to 6-month treatment with a medium-chain triglyceride supplement  (30 g of ketogenic fat per day [in a lactose-free skim milk emulsion]) or placebo. Participants undergo a cognitive battery and ketone and glucose positron emission tomography tracers at baseline and at the end of the treatment phase. So far, 12 patients in each group have completed the study and results on these patients were reported.

Results showed a 4% to 8% brain energy deficit that was specific to the cerebral metabolic rate attributed to glucose in patients with mild cognitive impairment at baseline. Cerebral metabolic rate attributable to ketones increased after the intervention in the active group only and in direct proportion to the increase in plasma ketones.

In terms of cognitive function, performance in specific domains of executive function and processing speed (semantic verbal fluency score and time performance on the Trail Making Number-Letter Switching Test) showed direct correlation to plasma ketone levels. Adherence over 6 months in both groups was 78%.

"We are evaluating whether the brain can use the ketones in the supplement, and the answer is definitely yes," Dr Cunnane told Medscape Medical News. "That was a critical step. We also saw some signs of cognitive benefits, but it is too small a study to say anything definitive."

However, they are encouraged by what they have seen so far, he said. "We have shown that cognitive effects were related to the plasma ketone concentration, and if that relationship holds then we should see a significant effect on cognitive outcomes."

"From our results we estimate that we have corrected about two thirds of the brain energy gap in these patients with mild cognitive impairment with the 30-g triglyceride supplement each day," he added. "We think we need a higher dose to bring brain energy back to 100% — maybe about 45 g per day."

The BENEFIC study should be completed by the end of the year, and results should be available by next spring.

Dr Cunnane says the next step will be a multicenter trial, and he is seeking funding for such a trial.

The University of Kansas supported the ketogenic diet study. The Alzheimer's Association funded the triglyceride supplement study.      

Alzheimer's Association International Conference (AAIC) 2017. Abstracts F3-04-02 (ketogenic diet) and F3-04-04 (triglyceride supplement study). Presented July 18, 2017. Abstract IC-P-170 (exercise study). Presented July 15, 2017.

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