Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults 55 Years Old or Older

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.

Background:

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.

Objective:

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.

Eligibility:

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

Design:

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.

...

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome; Normal Cognition
• Intervention / Treatment: Dietary supplement: Ketone Ester drink; Dietary supplement: Placebo: isocaloric dextrose drink

Detailed Description

Study Description:

We hypothesize that supplementation with a ketone ester drink [Ketone Ester (KE)] compared to placebo, in cognitively intact adults >= 55 years old with Metabolic Syndrome (MetS), will (i) increase peripheral and brain ketone levels [primarily beta-hydroxybutyrate (BHB) and secondarily acetoacetate (AcAc)], (ii) improve neuronal/astrocytic insulin resistance (IR) and induce a change in neuronal/astrocytic metabolism as reflected on blood Extracellular Vesicle (EV) biomarkers, (iii) improve cognitive performance, (iv) boost mitochondrial function in muscle, and (v) change gut microbiome. These effects will be examined acutely, after single-dose administration, and chronically, after 28 days on the supplement x 3 times per day. The changes in EV biomarkers and cognition will be associated with the elevation of ketones in brain. The study will involve a Screening Visit and three additional Visits to assess acute effects, compliance and chronic effects, respectively, and a follow-up visit to obtain DNA.

Objectives:

Primary: To investigate the change in brain concentration BHB, using brain Magnetic Resonance Spectroscopy, after 28 days of supplementation with the KE, compared to baseline and placebo.

Secondary: To test the hypothesis that genetic factors may affect the response to the KE supplement.

Endpoints: Primary: To detect with brain MRS, a significant change in the concentration of BHB, after 28 days of supplementation with the KE compared to baseline and placebo

Secondary: To assess whether genetic factors modulate the response to the KE supplement.

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • National Institute of Aging, Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 51 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

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 >=150 mg/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 >=100 mg/dL
   • Central obesity, defined as a waist circumference >=102 cm (40 in) in men and >=88 cm (35 in) in women.

EXCLUSION CRITERIA:

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:

   1. prior bilateral oophorectomy
   2. 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 (>=886 mg/dL or 10.0 mmol/L)
13. Severe Hypertension (systolic blood pressure >=180 mmHg and/or diastolic blood pressure >=120 mmHg)
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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ketone Ester drink/ Arm 1; 25 participants	Dietary supplement: Ketone Ester drink; The main ingredient of the Ketone Ester drink [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate)] is regulated as GRAS (Generally Recognized as Safe) substance by the FDA (https://www.accessdata.fda.gov/scripts/fdcc/index.cfm?set=GRASNotices&id=515). The Ketone Ester compound is already being sold in the market as a ketogenic supplement and is especially popular among athletes, such as cyclists (sold by the official website of the company TdeltaS(R) Global (https://www.deltagketones.com/products/g-ketone-performance). The dose and formulation (25 g of KE contained in 59 ml of a drink), daily scheme (3 times daily) and total duration (28 days) are identical to a previous safety human study. The Ketone Ester drink provided by DeltaG will be repackaged by the NIA Pharmacist into new bottles identical to the ones that will be used for the placebo to ensure the blinding of participants and researchers to the drink.
Placebo Comparator: Placebo/ Arm 2; 25 participants	Dietary supplement: Placebo: isocaloric dextrose drink; The main content of the Placebo will be an aqueous solution containing approximately 35 g of dextrose, a fruity flavor powder and stevia. We will also add Denatonium Benzoate (Bittrex) to match the bitterness of the Ketone Ester drink. The placebo will be prepared and dispensed by the NIA Pharmacist.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in β-hydroxybutyrate in the Posteromedial Cortex Measured by ¹H-MRS (PRESS)	β-hydroxybutyrate (BHB) was quantified in the posteromedial cortex (PMC) using ¹H-MRS (PRESS). Acute and acute-on-chronic responses were defined as the within-visit ratios of ~75 minutes post-drink to pre-drink (post/pre) at Weeks 0 and 4, respectively. The chronic effect was defined as the ratio of pre-drink BHB at Week 4 to pre-drink at Week 0 (Week 4 pre / Week 0 pre). BHB values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink and ~75 minutes post-drink)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum β-hydroxybutyrate		Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Serum Acetoacetate		Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Serum Non-Esterified Fatty Acids		Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Body Mass Index		Week 0, Week 4
Change in Waist Circumference		Week 0, Week 4
Change in Fasting Glucose		Week 0, Week 4
Change in Fasting Insulin		Week 0, Week 4
Change in Total Cholesterol		Week 0, Week 4
Change in Glucose in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Glucose was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a glucose-to-creatine (Glucose/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glucose/Cr at Week 4 to pre-drink Glucose/Cr at Week 0 (Week 4 pre / Week 0 pre). Glucose/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in N-acetyl-aspartate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	N-acetyl-aspartate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a N-acetyl-aspartate-to-creatine (N-acetyl-aspartate/Cr) ratio. The chronic response was defined as the ratio of pre-drink N-acetyl-aspartate/Cr at Week 4 to pre-drink N-acetyl-aspartate/Cr at Week 0 (Week 4 pre / Week 0 pre). N-acetyl-aspartate/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Lactate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Lactate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Lactate-to-creatine (Lactate/Cr) ratio. The chronic response was defined as the ratio of pre-drink Lactate/Cr at Week 4 to pre-drink Lactate/Cr at Week 0 (Week 4 pre / Week 0 pre). Lactate/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Glycine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Glycine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Glycine-to-creatine (Glycine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glycine/Cr at Week 4 to pre-drink Glycine/Cr at Week 0 (Week 4 pre / Week 0 pre). Glycine/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Glutamate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Glutamate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Glutamate-to-creatine (Glutamate/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glutamate/Cr at Week 4 to pre-drink Glutamate/Cr at Week 0 (Week 4 pre / Week 0 pre). Glutamate/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Gamma-aminobutyric Acid in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Gamma-aminobutyric acid was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Gamma-aminobutyric acid-to-creatine (Gamma-aminobutyric acid/Cr) ratio. The chronic response was defined as the ratio of pre-drink Gamma-aminobutyric acid/Cr at Week 4 to pre-drink Gamma-aminobutyric acid/Cr at Week 0 (Week 4 pre / Week 0 pre). Gamma-aminobutyric acid/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Glutamine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Glutamine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Glutamine-to-creatine (Glutamine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glutamine/Cr at Week 4 to pre-drink Glutamine/Cr at Week 0 (Week 4 pre / Week 0 pre). Glutamine/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Glutathione in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Glutathione was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Glutathione-to-creatine (Glutathione/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glutathione/Cr at Week 4 to pre-drink Glutathione/Cr at Week 0 (Week 4 pre / Week 0 pre). Glutathione/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Myo-inositol in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Myo-inositol was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Myo-inositol-to-creatine (Myo-inositol/Cr) ratio. The chronic response was defined as the ratio of pre-drink Myo-inositol/Cr at Week 4 to pre-drink Myo-inositol/Cr at Week 0 (Week 4 pre / Week 0 pre). Myo-inositol/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in N-acetyl-aspartyl-glutamate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	N-acetyl-aspartyl-glutamate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a N-acetyl-aspartyl-glutamate-to-creatine (N-acetyl-aspartyl-glutamate/Cr) ratio. The chronic response was defined as the ratio of pre-drink N-acetyl-aspartyl-glutamate/Cr at Week 4 to pre-drink N-acetyl-aspartyl-glutamate/Cr at Week 0 (Week 4 pre / Week 0 pre). N-acetyl-aspartyl-glutamate/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Aspartate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Aspartate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as an Aspartate-to-creatine (Aspartate/Cr) ratio. The chronic response was defined as the ratio of pre-drink Aspartate/Cr at Week 4 to pre-drink Aspartate/Cr at Week 0 (Week 4 pre / Week 0 pre). Aspartate/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Ascorbate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Ascorbate was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as an Ascorbate-to-creatine (Ascorbate/Cr) ratio. The chronic response was defined as the ratio of pre-drink Ascorbate/Cr at Week 4 to pre-drink Ascorbate/Cr at Week 0 (Week 4 pre / Week 0 pre). Ascorbate/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Alanine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Alanine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as an Alanine-to-creatine (Alanine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Alanine/Cr at Week 4 to pre-drink Alanine/Cr at Week 0 (Week 4 pre / Week 0 pre). Alanine/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Scyllo-inositol in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Scyllo-inositol was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Scyllo-inositol-to-creatine (Scyllo-inositol/Cr) ratio. The chronic response was defined as the ratio of pre-drink Scyllo-inositol/Cr at Week 4 to pre-drink Scyllo-inositol/Cr at Week 0 (Week 4 pre / Week 0 pre). Scyllo-inositol/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Phosphocholine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Phosphocholine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Phosphocholine-to-creatine (Phosphocholine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Phosphocholine/Cr at Week 4 to pre-drink Phosphocholine/Cr at Week 0 (Week 4 pre / Week 0 pre). Phosphocholine/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Glycerophosphocholine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Glycerophosphocholine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Glycerophosphocholine-to-creatine (Glycerophosphocholine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Glycerophosphocholine/Cr at Week 4 to pre-drink Glycerophosphocholine/Cr at Week 0 (Week 4 pre / Week 0 pre). Glycerophosphocholine/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Phosphoethanolamine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Phosphoethanolamine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Phosphoethanolamine-to-creatine (Phosphoethanolamine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Phosphoethanolamine/Cr at Week 4 to pre-drink Phosphoethanolamine/Cr at Week 0 (Week 4 pre / Week 0 pre). Phosphoethanolamine/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Taurine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	Taurine was quantified in the posteromedial cortex (PMC) using ¹H-MRS (J-PRESS) at pre-drink assessments and expressed as a Taurine-to-creatine (Taurine/Cr) ratio. The chronic response was defined as the ratio of pre-drink Taurine/Cr at Week 4 to pre-drink Taurine/Cr at Week 0 (Week 4 pre / Week 0 pre). Taurine/Cr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Post-exercise Phosphocreatine (PCr) Recovery Time Constant (τPCr) Measured by Thigh ³¹P-MRS	Post-exercise phosphocreatine (PCr) recovery time constant (τPCr) was measured by thigh ³¹P-MRS at pre-drink assessments. The chronic response was defined as the ratio of pre-drink τPCr at Week 4 to pre-drink τPCr at Week 0 (Week 4 pre / Week 0 pre). τPCr values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Phosphocreatine (PCr) Depletion Area During Exercise (PCr Drop Area) Measured by Thigh ³¹P-MRS	Phosphocreatine (PCr) depletion area during exercise (PCr drop area) was measured by thigh ³¹P-MRS at pre-drink assessments. The chronic response was defined as the ratio of pre-drink PCr drop area at Week 4 to pre-drink PCr drop area at Week 0 (Week 4 pre / Week 0 pre). PCr drop area values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Intramuscular Minimum pH During Exercise Measured by Thigh ³¹P-MRS	Intramuscular minimum pH during exercise was measured by thigh ³¹P-MRS at pre-drink assessments. The chronic response was defined as the difference between pre-drink PCr drop area at Week 4 and pre-drink PCr drop area at Week 0 (Week 4 pre - Week 0 pre). Intramuscular minimum pH values were derived from spectral fitting with predefined quality-control criteria.	Week 0 and Week 4 (pre-drink)
Change in Global Brain-age Gap (G-BrainAGE) Measured by Brain MRI (T1-weighted MP-RAGE)	G-BrainAGE was derived from pre-drink 3D T1-weighted MP-RAGE brain MRI using FreeSurfer (longitudinal pipeline) features processed through the CentileBrain platform with sex-specific pretrained models. G-BrainAGE represents the difference between the model-predicted brain age and chronological age (predicted age - chronological age), with higher values indicating an "older-appearing" brain relative to age and lower values indicating a "younger-appearing" brain. The chronic effect was assessed as the change in G-BrainAGE from Week 0 to Week 4.	Week 0 and Week 4 (pre-drink)
Change in Logical Memory Test	The Logical Memory test assesses verbal episodic memory for short stories. Participants recall two stories immediately and after a 20-30 minute delay. Outcomes include immediate and delayed recall subscores, each ranging from 0 to 50 (25 units/story × 2 stories), with higher scores indicating better performance. Verbatim subscores reflect exact recall; gist subscores reflect recall of essential elements.	Week 0, Week 4
Change in Montreal Cognitive Assessment (MoCA)	MoCA is a brief assessment of global cognitive function across multiple domains (e.g., attention, executive function, memory, language, visuospatial abilities, and orientation). Total scores range from 0 to 30, with higher scores indicating better cognitive performance.	Week 0, Week 4
Change in Eriksen Flanker	The Eriksen flanker task assesses selective attention and inhibitory control by requiring responses to a target stimulus while ignoring distracting flankers. The outcome is a composite score integrating response accuracy and response time into a single performance metric. Composite scores range from 0 to 10, with higher scores indicating better performance.	Week 0, Week 4
Change in Dimensional Set Shifting	The Dimensional Set Shifting task assesses cognitive flexibility (ability to shift between rules or stimulus dimensions). The outcome is a task-derived composite performance score; scores range from 0 to 10, with higher scores indicating better performance.	Week 0, Week 4
Change in Digit Symbol Substitution Test (DSST)	The Digit Symbol Substitution Test (DSST) assesses processing speed, attention, and visuomotor coordination by requiring participants to match symbols to digits using a provided key within a fixed time. The outcome is the total number of correct symbol-digit matches. Total scores range from 0 to 93, with higher scores indicating better performance.	Week 0, Week 4
Change in Free and Cued Selective Reminding Test (FCSRT)	The Free and Cued Selective Reminding Test (FCSRT) assesses verbal episodic memory using controlled learning and recall of a 16-word list with semantic cues. Total Free Recall (TFR) is the sum of freely recalled words across three learning trials (range 0 to 48). Total Delayed Free Recall (TDFR) is the number of freely recalled words after a delay (range 0 to 16). Higher scores indicate better memory performance.	Week 0, Week 4

Collaborators and Investigators

• Sponsor: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Dimitrios I Kapogiannis, M.D., National Institute on Aging (NIA)

Publications and helpful links

General Publications

• 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 EE, 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.
• 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.
• 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. eCollection 2016.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2021
• Primary Completion (Actual): June 2, 2025
• Study Completion (Actual): June 2, 2025

Study Registration Dates

• First Submitted: June 5, 2020
• First Submitted That Met QC Criteria: June 6, 2020
• First Posted (Actual): June 9, 2020

Study Record Updates

• Last Update Posted (Actual): April 2, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Dietary Supplement; Ketogenic; Brain Metabolism; BETA-HYDROXYBUTYRATE
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Metabolic Diseases; Neurocognitive Disorders; Glucose Metabolism Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Insulin Resistance; Hyperinsulinism; Nutritional and Metabolic Diseases; Alzheimer Disease; Metabolic Syndrome
• Other Study ID Numbers: 200087; 20-AG-0087

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: There is ongoing discussion within the NIA IRP and a plan has not been finalized yet.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No