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Protocol Details

Ketone ester effects on biomarkers of brain metabolism and cognitive performance in cognitively intact adults >= 55 years old. A double-blinded randomized controlled clinical trial

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Institute on Aging (NIA)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 55 Years
Max Age: N/A

Referral Letter Required


Population Exclusion(s)

Non-English Speaking;


Brain Metabolism;
Dietary Supplement;
Alzheimer's Disease

Recruitment Keyword(s)



Metabolic Syndrome;
Normal Cognition

Investigational Drug(s)


Investigational Device(s)



Dietary Supplement: Ketone Ester drink
Dietary Supplement: Placebo: isocaloric dextrose drink

Supporting Site

National Institute on Aging


In Alzheimer s disease (AD) the brain cannot use glucose as a fuel. The brain can use ketones as a fuel instead of glucose. Researchers want to test a supplement, Ketone Ester (KE). It may improve brain metabolic function and cognition in normal people and, perhaps, down the road, in patients with AD.


To study the change in brain ketone levels in people after 28 days of taking KE compared with baseline and placebo. Also, to study changes in cognitive performance.


People 55 years old or older with metabolic syndrome and no cognitive impairment


Participants will have 4 visits.

Participants will be screened at Visit 1 with:

Medical history

Physical exam

Blood and urine tests

Cognitive testing

Participants will be randomly assigned to receive either the study supplement or a placebo with same amount of calories. Neither they nor the researchers will know which they receive.

Visit 2 will include repeats of some screening tests. It will also include:

Stool sample (brought from home)

MRI/MRS: Participants will lie on a table that slides in and out of a scanner. A coil will be placed over their head. They may be asked to perform leg exercises.

First dose of study supplement or placebo

About 2 weeks after Visit 2, Visit 3 will include blood and urine tests and a questionnaire.

About 2 weeks after Visit 3, Visit 4 will include repeats of the Visit 2 tests.

Participants will drink the study supplement or placebo 3 times per day during the study. They will keep a daily log of each dose. They will bring the log to Visits 3 and 4.

Participants will by contacted by phone once per week during the study to see how they are doing.

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In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Ability to provide informed consent and willingness to sign a written informed consent document

2. Male or female, age >=55 years old

3. Cognitively intact status ascertained during screening (defined as absence of significant memory or cognitive changes in the last 2 years by subjective report, Clinical Dementia Rating (CDR) of 0, and Montreal Cognitive Assessment (MoCA) >= 26)

4. Ability to take oral medications

5. Willingness to adhere to all study procedures including having MRI/MRS.

6. Presence of Metabolic Syndrome (MetS). Specifically, they should meet three of the five following MetS diagnostic criteria to be eligible:

-Receive drug treatment for elevated triglycerides (TGs) or have serum TGs >=150mg/dL (1.7 mmol/L)

-Receive drug treatment for low HDL-cholesterol or have serum HDL-cholesterol<40 mg/dL (1.0 mmol/L) in males; <50 mg/dL (1.3 mmol/L) in females

-Receive drug treatment for high Blood Pressure (BP) or have BP>=130/85 mmHg

-Receive drug treatment for high blood glucose or have fasting plasma glucose>=mg/dL

-Central obesity, defined as a waist circumference cm (40 in) in men and>=88cm (35 in) in women.


An individual who meets any of the following criteria will be excluded from participation in this study:

1. Previously diagnosed with a condition causing clinically significant cognitive impairment, such as MCI, AD or other type of dementia (such as vascular dementia, Lewy body dementia and frontotemporal dementia).

2. History of clinically significant brain disorders, such as stroke, multiple sclerosis, Parkinson s disease or other movement disorders, brain tumors, history of meningitis or encephalitis, history of moderate or severe traumatic brain injury (defined as Glasgow Coma Scale of 12 or less), epilepsy. Certain common neurological disorders not considered relevant (e.g. migraine, essential tremor) or incidental neuroimaging findings that are common and of uncertain clinical significance (e.g. mild-moderate microvascular changes on MRI) may be allowed.

3. Chronic and significant psychiatric conditions (e.g. history of bipolar disorder, schizophrenia, PTSD, moderate to severe depression or treatment-resistant depression. Unipolar depression or anxiety disorder may be allowed if mild or if successfully treated with single anti-depressant or anti-anxiety agents.

4. Positive urine drug screen (and no prescription medication accounting for the positive test).

5. Positive HIV, HBV or HCV status during screening.

6. Contraindications for MRI (pregnancy, pacemakers or other implanted devices, ferrous metal implants or shrapnel in or around the head etc.).

7. Anemia (defined as HGB < 12 for men or < 11 g/dl for women)

8. Poor venous access.

9. Lactation or Pregnancy (positive urine pregnancy test. Pregnancy tests will not be done on post-menopausal women defined as one of the below criteria:

a. prior bilateral oophorectomy

b. Amenorrhea for 12 months or more

10. Known severe allergic reactions to the KE drinks or other ketogenic supplement or stevia products.

11. Following high fat/low carb diet (ketogenic) diet or very low calorie (<500 calories) diet or taking other ketogenic supplements (such as Medium Chain Triglycerides (MCTs), Ketone Salts) or fasting intermittently and unwilling to stop it while on the KE drink/Placebo.

12. Very high or severe hypertriglyceridemia >=886mg/dL or 10.0 mmol/L)

13. Severe Hypertension (systolic blood pressure >=180mmHg and/or diastolic blood pressure >=120mmHg)

14. Weight >=300 lbs (MRI scanner weight limit)

15. Diabetes Mellitus (type 1 or 2)

16. Taking the drug metformin.

17. Non-English speakers (given staffing constraints for cognitive testing administration and need for decreased variability in testing procedures for a small N study).

18. Participant has any concurrent medical condition, so that participation in the clinical study would not be in her/his best interest, in the PI s judgement.

19. To be eligible to consent for optional thigh MRI: Individuals with joint replacements that may be affected by the defined exercise protocol or which may prevent MRI analysis or any condition, in the opinion of the investigator, that would prevent successful completion of the exercise protocol such as, but not limited to reported osteoarthritis, rheumatoid arthritis and/or fibromyalgia.


-Children: No inclusion is planned. This study aims to investigate the effects of aging 55 years old) on brain metabolism, therefore inclusion of children is inappropriate with respect to the purpose of the research.

-Pregnant Women, Fetuses, or Neonates: No inclusion is planned. We will exclude women, fetuses or neonates with respect to the health of participants, specifically, due to the risk associated with the MRI procedure and the unknown effects of the ketone ester supplement.

-Prisoners: No inclusion is planned. This study involves several visits to the NIA Clinical Unit, which prisoners are unable to perform. Therefore, inclusion of prisoners is inappropriate with respect to the purpose of the research.

-Decisionally Impaired Adults: No inclusion is planned. Cognitive intact status will be ascertained at baseline based on Clinical Dementia Rating (CDR) of 0, and Montreal Cognitive Assessment (MoCA) > 26, since the main objective of the study is to study a population of cognitively intact individuals. Therefore, inclusion of decisionally impaired adults is inappropriate with respect to the purpose of the research. Moreover, participants are not expected to become decisionally impaired over the course of the study.

-NIH Employees: We intend to include NIH staff (to include NIH contractors and special volunteers, guest researchers and trainees) in this study. The staff will be invited to participate through standard recruitment efforts. Participation will be voluntary and neither participation nor refusal to participate will have an effect, either beneficial or adverse, on the participant s employment or position at NIH. We will follow the Guidelines for the Inclusion of Employees in NIH Research Studies and will give each employee a copy of the NIH information sheet on Staff Research Participation per NIH OHSRP SOP 14F.4: Research Involving NIH Staff as Subjects.

-Neither participation nor refusal to participate will have an effect, either beneficial or adverse, on the participant s employment or work situation.

-The NIH information sheet regarding NIH employee research participation will be distributed to all potential subjects who are NIH employees.

-The employee subject s privacy and confidentiality will be preserved in accordance with NIH Intramural policies, which define the scope and limitations of the protections.

-Subjects that are employees/staff will be consented in the usual manner. The inclusion of employees or staff is not anticipated to affect the research outcome; therefore, if the subject is a co-worker (including a supervisor, subordinate or coworker) the subject may be consented by another co-worker and/or subordinate.The study PI will not be involved in the consenting of employees or staff.

-Other vulnerable populations: No inclusion is planned.

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Fortier M, Castellano CA, Croteau E, Langlois F, Bocti C, St-Pierre V, Vandenberghe C, Bernier M, Roy M, Descoteaux M, Whittingstall K, Lepage M, Turcotte (SqrRoot) E, Fulop T, Cunnane SC. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimers Dement. 2019 May;15(5):625-634. doi: 10.1016/j.jalz.2018.12.017. Epub 2019 Apr 23. PMID: 31027873.

Soto-Mota A, Vansant H, Evans RD, Clarke K. Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults. Regul Toxicol Pharmacol. 2019 Dec;109:104506. doi: 10.1016/j.yrtph.2019.104506. Epub 2019 Oct 23. PMID: 31655093.

Cunnane SC, Courchesne-Loyer A, Vandenberghe C, St-Pierre V, Fortier M, Hennebelle M, Croteau E, Bocti C, Fulop T, Castellano CA. Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer's Disease. Front Mol Neurosci. 2016 Jul 8;9:53. doi: 10.3389/fnmol.2016.00053. PMID: 27458340; PMCID: PMC4937039.

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Principal Investigator

Referral Contact

For more information:

Dimitrios I. Kapogiannis, M.D.
National Institute on Aging (NIA)
(202) 290-0433

Sarah Park, R.N.
National Institute on Aging (NIA)
(410) 350-7315

NIA Studies Recruitment
Harbor Hospital, 5th Floor,
3001 S Hanover Street
Baltimore, MD 21225

(410) 350-3941

Clinical Trials Number:


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