CompletedNCT04421014Updated Apr 2, 2026Results posted

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

An interventional study of Ketone Ester drink and Placebo: isocaloric dextrose drink in Metabolic Syndrome and Normal Cognition, sponsored by National Institute on Aging (NIA). Completed at 1 site in United States. Open to participants aged 55 Years and older. Per ClinicalTrials.gov, last updated 2026-04-02.

Sponsored by National Institute on Aging (NIA) · Not applicable, Interventional, and Basic science

Phase: Not applicable
Study type: Interventional
Enrollment: 99
Allocation: Randomized
Ages: 55 Years and older
Sex: All

Study summary

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.

...

Read the 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.

Conditions studied

Metabolic Syndrome
Normal Cognition

Browse trials for

Keywords

Ketogenic
Brain Metabolism
BETA-HYDROXYBUTYRATE
Dietary Supplement
Alzheimer's Disease

In context

Metabolic Syndrome

1,963 studies on the registry are indexed under Metabolic Syndrome; 329 are open to participants now.

This study's enrollment of 99 is above the median of 60 across 1,459 interventional studies indexed under Metabolic Syndrome.

Browse Metabolic Syndrome studies →

Lead sponsor

National Institute on Aging (NIA) is the lead sponsor of 157 studies on the registry; 13 are open to participants now.

Of its 7 completed or terminated interventional studies of FDA-regulated products, 2 (29%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 55 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

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

Ability to provide informed consent and willingness to sign a written informed consent document
Male or female, age >=55 years old
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)
Ability to take oral medications
Willingness to adhere to all study procedures including having MRI/MRS.
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

EXCLUSION CRITERIA:

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

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).
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.
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.
Positive urine drug screen (and no prescription medication accounting for the positive test).
Positive HIV, HBV or HCV status during screening.
Contraindications for MRI (pregnancy, pacemakers or other implanted devices, ferrous metal implants or shrapnel in or around the head etc.).
Anemia (defined as HGB \< 12 for men or \< 11 g/dl for women)
Poor venous access.
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
Known severe allergic reactions to the KE drinks or other ketogenic supplement or stevia products.
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.
Very high or severe hypertriglyceridemia (>=886 mg/dL or 10.0 mmol/L)
Severe Hypertension (systolic blood pressure >=180 mmHg and/or diastolic blood pressure >=120 mmHg)
Weight >= 300 lbs (MRI scanner weight limit)
Diabetes Mellitus (type 1 or 2)
Taking the drug metformin.
Non-English speakers (given staffing constraints for cognitive testing administration and need for decreased variability in testing procedures for a small N study).
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.
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 design

Phase: Not applicable
Primary purpose: Basic science
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Triple (Participant, Investigator, Outcomes assessor)
Enrollment: 99 participants (actual)

Study arms

Active comparator
Ketone Ester drink/ Arm 1
25 participants
Dietary Supplement: Ketone Ester drink
Placebo comparator
Placebo/ Arm 2
25 participants
Dietary Supplement: Placebo: isocaloric dextrose drink

Interventions

Dietary supplementKetone 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.
Dietary supplementPlacebo: 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 researchers measure

Primary outcomes

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.
Time frame: Week 0 and Week 4 (pre-drink and ~75 minutes post-drink)

Secondary outcomes

Change in Serum β-hydroxybutyrate
Time frame: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Serum Acetoacetate
Time frame: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Serum Non-Esterified Fatty Acids
Time frame: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Change in Body Mass Index
Time frame: Week 0, Week 4
Change in Waist Circumference
Time frame: Week 0, Week 4
Change in Fasting Glucose
Time frame: Week 0, Week 4
Change in Fasting Insulin
Time frame: Week 0, Week 4
Change in Total Cholesterol
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Week 0, Week 4

Results

Posted Apr 2, 2026

Participant flow

Recruitment took place between September 29, 2020 and August 16, 2023.

Participant flow — Overall Study
Milestone	Ketone Ester Drink	Placebo
Started	26	28
Completed	25	25
Not completed	1	3
Withdrew: Physician decision	1	2
Withdrew: Lost to follow-up	0	1

Outcome measures

PrimaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink and ~75 minutes post-drink)
Reported as:: Geometric least squares mean · Ratio

Change in β-hydroxybutyrate in the Posteromedial Cortex Measured by ¹H-MRS (PRESS)
Ratio	Ketone Ester Drink	Placebo
Acute ratio (Week 0 Post/Pre)	1.847 ± 0.130	0.922 ± 0.076
Acute-on-chronic ratio (Week 4 Post/Pre)	1.265 ± 0.081	1.172 ± 0.095
Chronic ratio (Week 4 Pre/Week 0 Pre)	1.064 ± 0.089	0.900 ± 0.072

SecondaryChange in Serum β-hydroxybutyrate

Time frame:: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Serum β-hydroxybutyrate
Ratio	Ketone Ester Drink	Placebo
Acute ratio (Week 0 Post/Pre)	6.136 ± 0.540	0.970 ± 0.085
Acute-on-chronic ratio (Week 4 Post/Pre)	5.737 ± 0.500	0.174 ± 0.015
Chronic ratio (Week 4 Pre/Week 0 Pre)	1.072 ± 0.092	1.015 ± 0.087

SecondaryChange in Serum Acetoacetate

Time frame:: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Serum Acetoacetate
Ratio	Ketone Ester Drink	Placebo
Acute ratio (Week 0 Post/Pre)	9.862 ± 1.090	1.655 ± 0.183
Acute-on-chronic ratio (Week 4 Post/Pre)	8.217 ± 0.862	1.453 ± 0.152
Chronic ratio (Week 4 Pre/Week 0 Pre)	1.180 ± 0.110	1.095 ± 0.102

SecondaryChange in Serum Non-Esterified Fatty Acids

Time frame:: Week 0 and Week 4 (pre-drink and ~60 minutes post-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Serum Non-Esterified Fatty Acids
Ratio	Ketone Ester Drink	Placebo
Acute ratio (Week 0 Post/Pre)	0.785 ± 0.084	0.884 ± 0.094
Acute-on-chronic ratio (Week 4 Post/Pre)	0.611 ± 0.059	0.720 ± 0.070
Chronic ratio (Week 4 Pre/Week 0 Pre)	1.030 ± 0.105	1.051 ± 0.108

SecondaryChange in Body Mass Index

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · kg/m²

Change in Body Mass Index
kg/m²	Ketone Ester Drink	Placebo
Change in Body Mass Index	0.447 ± 0.264	0.386 ± 0.264

SecondaryChange in Waist Circumference

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · cm

Change in Waist Circumference
cm	Ketone Ester Drink	Placebo
Change in Waist Circumference	0.368 ± 0.863	-1.745 ± 0.908

SecondaryChange in Fasting Glucose

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · mg/dL

Change in Fasting Glucose
mg/dL	Ketone Ester Drink	Placebo
Change in Fasting Glucose	2.68 ± 1.77	1.28 ± 1.77

SecondaryChange in Fasting Insulin

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · μIU/mL

Change in Fasting Insulin
μIU/mL	Ketone Ester Drink	Placebo
Change in Fasting Insulin	1.436 ± 1.63	-0.676 ± 1.63

SecondaryChange in Total Cholesterol

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · mg/dL

Change in Total Cholesterol
mg/dL	Ketone Ester Drink	Placebo
Change in Total Cholesterol	0.28 ± 2.94	4.88 ± 2.94

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Glucose in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Glucose in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	1.10 ± 0.052	1.06 ± 0.051

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in N-acetyl-aspartate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in N-acetyl-aspartate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.978 ± 0.023	0.965 ± 0.023

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Lactate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Lactate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	1.07 ± 0.061	1.01 ± 0.058

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Glycine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Glycine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.957 ± 0.056	1.047 ± 0.064

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Glutamate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Glutamate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.955 ± 0.019	0.992 ± 0.020

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Gamma-aminobutyric Acid in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Gamma-aminobutyric Acid in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	1.025 ± 0.056	0.957 ± 0.056

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Glutamine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Glutamine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.926 ± 0.062	0.942 ± 0.060

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Glutathione in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Glutathione in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.969 ± 0.035	0.980 ± 0.036

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Myo-inositol in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Myo-inositol in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.994 ± 0.020	0.951 ± 0.019

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in N-acetyl-aspartyl-glutamate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in N-acetyl-aspartyl-glutamate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	1.20 ± 0.148	1.28 ± 0.165

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Aspartate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Aspartate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.910 ± 0.041	0.914 ± 0.041

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Ascorbate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Ascorbate in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.974 ± 0.045	1.015 ± 0.046

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Alanine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Alanine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.939 ± 0.044	1.023 ± 0.047

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Scyllo-inositol in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Scyllo-inositol in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	1.06 ± 0.055	1.02 ± 0.061

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Phosphocholine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Phosphocholine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	1.041 ± 0.068	0.852 ± 0.056

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Glycerophosphocholine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Glycerophosphocholine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.999 ± 0.921	5.464 ± 5.340

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Phosphoethanolamine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Phosphoethanolamine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	0.971 ± 0.049	1.007 ± 0.051

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Taurine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)
Ratio	Ketone Ester Drink	Placebo
Change in Taurine in the Posteromedial Cortex Measured by ¹H-MRS (J-PRESS)	1.057 ± 0.188	0.785 ± 0.156

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Post-exercise Phosphocreatine (PCr) Recovery Time Constant (τPCr) Measured by Thigh ³¹P-MRS
Ratio	Ketone Ester Drink	Placebo
Change in Post-exercise Phosphocreatine (PCr) Recovery Time Constant (τPCr) Measured by Thigh ³¹P-MRS	1.06 ± 0.072	1.17 ± 0.090

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Geometric least squares mean · Ratio

Change in Phosphocreatine (PCr) Depletion Area During Exercise (PCr Drop Area) Measured by Thigh ³¹P-MRS
Ratio	Ketone Ester Drink	Placebo
Change in Phosphocreatine (PCr) Depletion Area During Exercise (PCr Drop Area) Measured by Thigh ³¹P-MRS	1.178 ± 0.057	0.993 ± 0.055

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Least squares mean · pH units

Change in Intramuscular Minimum pH During Exercise Measured by Thigh ³¹P-MRS
pH units	Ketone Ester Drink	Placebo
Change in Intramuscular Minimum pH During Exercise Measured by Thigh ³¹P-MRS	-0.042 ± 0.014	0.037 ± 0.017

SecondaryChange 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.

Time frame:: Week 0 and Week 4 (pre-drink)
Reported as:: Least squares mean · years

Change in Global Brain-age Gap (G-BrainAGE) Measured by Brain MRI (T1-weighted MP-RAGE)
years	Ketone Ester Drink	Placebo
Change in Global Brain-age Gap (G-BrainAGE) Measured by Brain MRI (T1-weighted MP-RAGE)	0.713 ± 0.402	0.311 ± 0.391

SecondaryChange 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.

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · points

Change in Logical Memory Test
points	Ketone Ester Drink	Placebo
Immediate Verbatim Recall	3.72 ± 0.866	2.00 ± 0.866
Immediate Gist Recall	3.84 ± 0.904	2.24 ± 0.904
Delayed Verbatim Recall	2.84 ± 1.05	1.88 ± 1.05
Delayed Gist Recall	4.68 ± 1.17	3.44 ± 1.17

SecondaryChange 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.

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · points

Change in Montreal Cognitive Assessment (MoCA)
points	Ketone Ester Drink	Placebo
Change in Montreal Cognitive Assessment (MoCA)	0.007 ± 0.393	0.040 ± 0.386

SecondaryChange 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.

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · scores on a scale

Change in Eriksen Flanker
scores on a scale	Ketone Ester Drink	Placebo
Change in Eriksen Flanker	0.052 ± 0.082	0.010 ± 0.087

SecondaryChange 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.

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · scores on a scale

Change in Dimensional Set Shifting
scores on a scale	Ketone Ester Drink	Placebo
Change in Dimensional Set Shifting	0.156 ± 0.196	0.170 ± 0.202

SecondaryChange 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.

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · correct responses

Change in Digit Symbol Substitution Test (DSST)
correct responses	Ketone Ester Drink	Placebo
Change in Digit Symbol Substitution Test (DSST)	2.64 ± 1.27	1.92 ± 1.27

SecondaryChange 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.

Time frame:: Week 0, Week 4
Reported as:: Least squares mean · words recalled

Change in Free and Cued Selective Reminding Test (FCSRT)
words recalled	Ketone Ester Drink	Placebo
Total Free Recall	4.12 ± 0.843	3.84 ± 0.843
Total Delayed Free Recall	0.92 ± 0.348	0.92 ± 0.348

Adverse events

Collected over 4 weeks. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Ketone Ester Drink	0/25 (0%)	0/25 (0%)	1/25 (4%)
Placebo	0/26 (0%)	0/26 (0%)	3/26 (11.5%)

Most frequent other events

Most frequent other events
Event	Ketone Ester Drink	Placebo
ALT and AST elevation (~3× ULN)Investigations	1/25	0/26
DiarrheaGastrointestinal disorders	0/25	1/26
Abdominal bloatingGastrointestinal disorders	0/25	1/26
Dizziness posturalGeneral disorders	0/25	1/26

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Ketone Ester Drink	Placebo	Total
Mean	65.9 ± 4.9	65.8 ± 7.1	65.9 ± 6.0

Sex: Female, Male
Sex: Female, Male(Participants)	Ketone Ester Drink	Placebo	Total
Female	12	12	24
Male	13	13	26

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Ketone Ester Drink	Placebo	Total
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	7	5	12
White	18	20	38
More than one race	0	0	0
Unknown or Not Reported	0	0	0

Body Mass Index, Continuous
Body Mass Index, Continuous(kg/m^2)	Ketone Ester Drink	Placebo	Total
Mean	33.4 ± 4.7	31.9 ± 3.9	32.6 ± 4.3

Waist Circumference, Continuous
Waist Circumference, Continuous(cm)	Ketone Ester Drink	Placebo	Total
Mean	115.9 ± 11.1	112.3 ± 8.2	114.1 ± 9.8

Montreal Cognitive Assessment (MoCA) score, Continuous
Montreal Cognitive Assessment (MoCA) score, Continuous(units on a scale)	Ketone Ester Drink	Placebo	Total
Mean	28.2 ± 1.4	27.6 ± 1.2	27.9 ± 1.3

Study locations

1 site

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

References and documents

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. PubMed 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. PubMed 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. eCollection 2016. PubMed 27458340 ↗

Study documents

Study protocol · Oct 29, 2024
Statistical analysis plan · Oct 29, 2024
Informed consent form · Oct 31, 2024
Informed consent form · Feb 3, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Undecided — There is ongoing discussion within the NIA IRP and a plan has not been finalized yet.

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Apr 2, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT04421014
Lead sponsor: National Institute on Aging (NIA)
Responsible party: Sponsor
First posted: Jun 9, 2020
Start date: Jun 24, 2021
Primary completion: Jun 2, 2025
Completion: Jun 2, 2025
Results posted: Apr 2, 2026
Last update: Apr 2, 2026

Study contacts

Dimitrios I Kapogiannis, M.D.

principal investigator · National Institute on Aging (NIA)

Oversight

FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Mar 2026. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Metabolic Syndrome→

Other studies from this sponsor

National Institute on Aging (NIA)

Start the discussion