Ketone Supplement for Mild Cognitive Impairment

(BREAK-AD Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Université de Sherbrooke

Must not be taking: Anti-cholinergic drugs

Disqualifiers: Diabetes, Neurodegenerative disease, Cancer, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

56 Participants Needed

Trial Summary

What is the purpose of this trial?

A six month randomized controlled intervention with an exogenous ketone salt (EKS) supplement in mild cognitive impairment. Participants will receive 15 g of the supplement twice daily (equivalent to 24 g/day of EKS). Outcomes: brain energy metabolism, cognition, plasma biomarkers, brain imaging (volumetric, functional, structural) and quality of life will be analyzed before and after the intervention.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you have recently changed your medication or are taking anti-cholinergic drugs (medications that block a specific neurotransmitter).

What data supports the effectiveness of the treatment Exogenous Ketone Salt (EKS) Supplement for mild cognitive impairment?

Research suggests that ketone supplements can provide an alternative energy source for the brain, which may help improve cognitive function in people with mild cognitive impairment. Studies have shown that ketogenic diets and supplements can enhance brain energy and improve some cognitive measures by supplying ketones as fuel, especially when glucose metabolism is impaired. ^{1 2 3 4 5}

Is the ketone supplement safe for humans?

Research shows that ketone supplements are generally safe for humans, with mild and temporary stomach-related side effects like discomfort or reduced appetite. These effects vary depending on the type and amount of ketone supplement taken. ^{1 6 7 8 9}

How is the Exogenous Ketone Salt (EKS) Supplement treatment different from other treatments for mild cognitive impairment?

The Exogenous Ketone Salt (EKS) Supplement is unique because it provides the brain with ketones, an alternative fuel source, which remains normally absorbed in mild cognitive impairment (MCI), potentially improving brain energy and cognition. Unlike traditional treatments, EKS focuses on enhancing brain metabolism rather than targeting specific symptoms or disease pathways. ^{1 3 6 8 10}

Eligibility Criteria

This trial is for individuals with mild cognitive impairment who can understand, read, and speak French, have good vision and hearing, feel their memory has declined, and score within a specific range on cognitive tests. Excluded are those with certain medical conditions like kidney failure or recent cancer, vitamin deficiencies, drastic weight loss recently, or taking conflicting medications.

Inclusion Criteria

You have good eyesight and hearing abilities.

Have a QAF score of less than 9/30

I can understand, read, and speak French.

Exclusion Criteria

I have had active cancer within the last 2 years.

I have a chronic disease that is not well-managed.

I have had kidney stones or high calcium levels in the past.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 15 g of the exogenous ketone salt supplement twice daily for 6 months

6 months

Regular visits for monitoring and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Open-label extension

Participants may opt into continuation of the active product for an additional 3 months

3 months

Treatment Details

Interventions

• Exogenous Ketone Salt (EKS) Supplement

Trial Overview The study is testing an exogenous ketone salt supplement given twice daily over six months against a placebo to see if it improves brain energy metabolism, cognition and quality of life in people with mild cognitive impairment. Brain imaging and plasma biomarkers will also be assessed.

Participant Groups

Group I: Active group Experimental Treatment 1 Intervention

Participants will be on the active intervention for 6 months

Group II: Open phase on active product Active Control 1 Intervention

At the end of the 6-month randomized controlled phase, participants will be unblinded and invited to continue on the active product for an additional 3 months.

Group III: Placebo Group Placebo Group 1 Intervention

Participants will be on the placebo intervention for 6 months

Exogenous Ketone Salt (EKS) Supplement is already approved in United States for the following indications:

Approved in United States as Axona for:

• Alzheimer's disease

Who Is Running the Clinical Trial?

Université de Sherbrooke

Lead Sponsor

Trials

317

Recruited

79,300+

Nestlé Health Science SA

Collaborator

Trials

1

Recruited

60+

Alzheimer's Association

Collaborator

Trials

103

Recruited

44,300+

Nestle Health Science

Industry Sponsor

Trials

12

Recruited

2,200+

Findings from Research

Recent studies indicate that ketogenic diets (KD) and ketogenic supplements (KS) may reduce neuroinflammation and improve cognitive function in Alzheimer's disease (AD), with evidence from both animal models and human trials.

In humans, KD/KS showed significant cognitive benefits and improved brain metabolism, with acceptable adherence and only minor gastrointestinal side effects, suggesting potential as a therapeutic approach for AD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketogenic diet therapy in Alzheimer's disease: an updated review. Lilamand, M., Mouton-Liger, F., Paquet, C.[2023]

The BENEFIC trial, a 6-month randomized controlled study, demonstrated that a ketogenic medium-chain triglyceride (kMCT) drink improved cognitive performance in individuals with mild cognitive impairment (MCI) compared to a placebo.

Ketogenic supplements provide an alternative energy source for brain cells, suggesting that nutritional interventions like kMCTs could be a promising approach to managing MCI, especially given the lack of approved pharmacologic treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mild cognitive impairment: when nutrition helps brain energy rescue-a report from the EuGMS 2020 Congress. Cunnane, SC., Sieber, CC., Swerdlow, RH., et al.[2022]

In a study of 52 participants with mild cognitive impairment (MCI), a daily dose of 30 g of ketogenic medium chain triglycerides (kMCT) significantly increased brain ketone metabolism by 230%, while glucose uptake remained unchanged.

The kMCT treatment led to improvements in cognitive performance, including episodic memory and processing speed, suggesting that providing ketones as an alternative fuel can enhance brain function in individuals with MCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Fortier, M., Castellano, CA., Croteau, E., et al.[2020]

In a study involving 6 participants with mild cognitive impairment (MCI), supplementation with 56 g/day of medium chain triglycerides (MCTs) for 24 weeks significantly increased serum ketone bodies and improved memory performance.

The placebo group did not show any cognitive improvements, suggesting that MCT supplementation may be a promising approach for enhancing brain function in individuals with MCI, warranting further research with larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot feasibility and safety study examining the effect of medium chain triglyceride supplementation in subjects with mild cognitive impairment: A randomized controlled trial. Rebello, CJ., Keller, JN., Liu, AG., et al.[2020]

A 12-week intervention combining a ketogenic diet, high-intensity interval training, and memory training significantly improved memory function in a 57-year-old woman with mild cognitive impairment, raising her Montreal Cognitive Assessment score from 22/30 to 30/30, indicating normal cognitive function.

The intervention also led to statistically significant improvements in physiological biomarkers related to metabolic syndrome, suggesting that ketogenic nutrition may help address both cognitive decline and metabolic health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketogenic diet, high intensity interval training (HIIT) and memory training in the treatment of mild cognitive impairment: A case study. Dahlgren, K., Gibas, KJ.[2018]

Exogenous ketone drinks, both monoester and salt forms, can cause mild gastrointestinal symptoms, with symptom severity influenced by the dose and type of drink consumed, as well as whether the individual is at rest or exercising.

High-dose ketone salt drinks resulted in more gastrointestinal symptoms compared to low-dose versions, but overall, symptoms were acute and resolved by the end of the study, indicating that while they may cause discomfort, they are generally tolerable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal Effects of Exogenous Ketone Drinks are Infrequent, Mild, and Vary According to Ketone Compound and Dose. Stubbs, BJ., Cox, PJ., Kirk, T., et al.[2021]

In a study involving 14 healthy young adults, both ketone monoester (KME) and ketone monoester/salt (KMES) formulations significantly increased circulating R-beta-hydroxybutyrate (R-βHB) levels in a dose-dependent manner, with KME10 reaching a peak concentration of 2.4 mM after 15 minutes.

Both formulations were well-tolerated, but KMES was slightly more acceptable due to a better taste, while KME was associated with a more frequent decrease in appetite, indicating that user experience may vary between different ketone products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. Bolyard, ML., Graziano, CM., Fontaine, KR., et al.[2023]

Exogenous ketone supplements, such as ketone salts or esters, have shown potential benefits for metabolic health, cognitive function, and cardiovascular health, particularly in lowering blood glucose and improving cognitive performance, which may be useful for conditions like type 2 diabetes and neurological diseases.

Current research primarily involves pre-clinical models, and while some human studies support the benefits of exogenous ketones, further clinical validation is needed, especially regarding long-term effects on cardiovascular health and lipid profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exogenous ketone supplementation: an emerging tool for physiologists with potential as a metabolic therapy. Falkenhain, K., Islam, H., Little, JP.[2023]

In a study involving 80 healthy older adults, the medium-chain triglyceride GSK2981710 increased plasma β-hydroxybutyrate (BHB) levels but did not lead to significant improvements in cognitive function or memory-related neuronal activity over 14 days.

The most common side effect was diarrhea, affecting 100% of participants in the initial part of the study, indicating that while GSK2981710 is generally well-tolerated, it may cause gastrointestinal discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study. O'Neill, BV., Dodds, CM., Miller, SR., et al.[2020]

In a study involving nine recreationally active men, ketone monoester (KME) supplementation was found to reduce cognitive fatigue during a simulated soccer match, leading to a smaller decrease in cognitive performance compared to a placebo.

KME also lowered blood glucose and lactate levels during exercise, suggesting it may help spare carbohydrates, which could be beneficial for athletes during high-intensity activities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketone Ester Supplementation Improves Some Aspects of Cognitive Function during a Simulated Soccer Match after Induced Mental Fatigue. Quinones, MD., Lemon, PWR.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Ketogenic diet therapy in Alzheimer's disease: an updated review. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Mild cognitive impairment: when nutrition helps brain energy rescue-a report from the EuGMS 2020 Congress. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. [2020]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Pilot feasibility and safety study examining the effect of medium chain triglyceride supplementation in subjects with mild cognitive impairment: A randomized controlled trial. [2020]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Ketogenic diet, high intensity interval training (HIIT) and memory training in the treatment of mild cognitive impairment: A case study. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Gastrointestinal Effects of Exogenous Ketone Drinks are Infrequent, Mild, and Vary According to Ketone Compound and Dose. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Tolerability and Acceptability of an Exogenous Ketone Monoester and Ketone Monoester/Salt Formulation in Humans. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Exogenous ketone supplementation: an emerging tool for physiologists with potential as a metabolic therapy. [2023]

9. England pubmed.ncbi.nlm.nih.gov

The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study. [2020]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Ketone Ester Supplementation Improves Some Aspects of Cognitive Function during a Simulated Soccer Match after Induced Mental Fatigue. [2023]