Effects of Exogenous Ketones on Cognitive Function in Older Adults With Prediabetes?

Can Exogenous Ketone Supplementation Compensate for Glucose Hypometabolism and Improve Cognitive Processing Speed in Veterans With Prediabetes?

Brief Summary

The goal of this clinical trial is to learn whether older adults with prediabetes, but no diagnosed cognitive impairment, show early changes in brain energy use and thinking speed compared to older adults with normal blood sugar levels. The study will also test whether a single dose of an exogenous ketone supplement can improve brain energy use and cognitive processing speed.

The main questions it aims to answer are:

Do older adults with prediabetes have lower brain glucose uptake and slower cognitive processing speed compared to those with normal glucose levels?

Does a single dose of an exogenous ketone monoester supplement improve cognitive processing speed and brain glucose uptake?

Researchers will compare older adults with prediabetes to older adults with normal glucose levels to determine whether differences exist in brain glucose metabolism and cognitive performance. In a subset of participants, researchers will also compare brain and cognitive outcomes before and after consuming a ketone monoester supplement (DeltaG, Oxford, England).

Participants will:

Complete metabolic testing to determine glucose status

Undergo brain imaging using fluorodeoxyglucose positron emission tomography combined with magnetic resonance imaging (18FDG-PET/MRI) while performing a cognitive processing speed task

Consume a single dose of a commercially available ketone monoester supplement during one study visit

Complete cognitive testing during imaging to measure processing speed and brain activity

The results of this study will help determine whether early metabolic dysfunction is linked to reduced brain energy use and whether ketones can temporarily support brain function in individuals at risk for dementia.

Study Overview

• Status: Active, not recruiting
• Conditions: Prediabetes; Healthy (Controls)
• Intervention / Treatment: Dietary supplement: Ketone Monoester (KE); Dietary supplement: Placebo

Detailed Description

Metabolic dysfunction and impaired brain energy metabolism are increasingly recognized as early contributors to cognitive decline and dementia risk. Type 2 diabetes is a well-established risk factor for cognitive impairment; however, less is known about whether cerebral metabolic alterations are already present during the prediabetes stage, prior to clinically apparent cognitive symptoms. Prediabetes is characterized by impaired glucose regulation and early insulin resistance, both of which may reduce the efficiency of glucose transport and utilization in the brain. Because glucose is the brain's primary fuel under usual dietary conditions, even subtle reductions in cerebral glucose uptake may create a relative energy deficit that affects neural efficiency and cognitive performance.

Reductions in cerebral glucose metabolism have been observed years before the onset of dementia symptoms. These changes are particularly evident in frontal and temporoparietal regions that support higher-order cognitive functions, including processing speed. Cognitive processing speed is one of the earliest cognitive domains to decline in both metabolic disease and neurodegenerative conditions and is closely linked to functional independence in older adults. Identifying early metabolic and neural alterations in individuals with prediabetes may therefore provide insight into mechanisms linking metabolic dysfunction to later dementia risk.

This study uses hybrid fluorodeoxyglucose positron emission tomography combined with magnetic resonance imaging (18F-FDG PET/MRI) to quantify regional brain glucose uptake while participants perform a cognitive processing speed task during the imaging session. Fluorodeoxyglucose (FDG) is a radiolabeled glucose analog that allows measurement of tissue glucose uptake as an index of metabolic activity. Simultaneous magnetic resonance imaging (MRI), including functional MRI (fMRI), provides complementary measures of neural activation and network engagement during task performance. This multimodal approach allows assessment of neural efficiency, defined as cognitive task performance relative to regional glucose uptake and blood oxygen level-dependent (BOLD) signal changes.

The first objective of the study is to determine whether older adults with prediabetes exhibit reduced regional brain glucose uptake and slower cognitive processing speed compared to metabolically normal older adults. Metabolic status will be characterized using standardized clinical testing to define glycemic phenotype. The primary neural outcome is regional FDG uptake during task performance, and the primary cognitive outcome is processing speed performance acquired during the scan.

The second objective is to determine whether acute elevation of circulating ketone bodies through ingestion of an exogenous ketone monoester (DeltaG, Oxford, England) modifies cognitive performance and cerebral glucose uptake. Ketone bodies, including beta-hydroxybutyrate, serve as an alternative fuel for the brain and can be utilized even when glucose metabolism is impaired. Acute ketone supplementation increases circulating ketone concentrations without requiring prolonged dietary modification. This study evaluates whether providing an alternative metabolic substrate acutely influences neural efficiency and cognitive processing speed in individuals at risk for metabolic-related cognitive decline.

Together, these aims will clarify whether early metabolic dysregulation is associated with measurable alterations in brain glucose metabolism and cognitive function, and whether short-term metabolic substrate supplementation can modulate these relationships. Findings will inform future mechanistic and interventional studies targeting metabolic pathways to preserve brain health in at-risk aging populations.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Webb Nutrition Sciences Building
    • Birmingham, Alabama, United States, 35205
      • UAB Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 60 to 75 years
• Able to provide written informed consent
• Fluent in English
• No diagnosed cognitive impairment or dementia

Classified as either:

• Prediabetes (based on American Diabetes Association criteria), or Normal glucose regulation (control group)
• Medically stable and cleared to undergo positron emission tomography and magnetic resonance imaging
• Willing to comply with study procedures, including metabolic testing, supplement ingestion, and neuroimaging

Exclusion Criteria:

• Diagnosis of mild cognitive impairment, dementia, or other neurodegenerative disorder
• Diagnosis of type 1 diabetes or type 2 diabetes
• Use of glucose-lowering medications (e.g., insulin, metformin, glucagon-like peptide-1 receptor agonists)
• History of major neurological disorder (e.g., stroke, traumatic brain injury with loss of consciousness >30 minutes, epilepsy, multiple sclerosis)
• Major psychiatric disorder not stable on treatment
• Uncontrolled hypertension or significant cardiovascular disease
• Severe renal, hepatic, or gastrointestinal disease that may affect supplement metabolism
• Contraindications to magnetic resonance imaging (e.g., non-compatible implanted devices, severe claustrophobia)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Dietary supplement: Placebo; The placebo consists of a taste-, color-, and volume-matched beverage formulated to mimic the sensory characteristics of the ketone monoester supplement but containing no active ketone ingredient. The placebo does not contain (R)-3-hydroxybutyl (R)-3-hydroxybutyrate) and does not elevate circulating beta-hydroxybutyrate concentrations. The placebo beverage will be administered orally under supervised research conditions during a study visit using procedures identical to the active supplement condition. Brain imaging with fluorodeoxyglucose F18 positron emission tomography combined with magnetic resonance imaging will be performed during the post-ingestion period while participants complete a cognitive processing speed task. This control condition allows isolation of the metabolic effects of ketone elevation from expectancy or beverage-related effects.
Experimental: Ketone	Dietary supplement: Ketone Monoester (KE); The intervention is a single acute oral dose of a commercially available ketone monoester supplement (DeltaG®, Oxford, England). The active ingredient, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, is rapidly metabolized after ingestion to raise circulating beta-hydroxybutyrate concentrations without requiring dietary carbohydrate restriction or fasting. The supplement is administered under supervised conditions during a study visit. Brain imaging with fluorodeoxyglucose F18 positron emission tomography combined with magnetic resonance imaging is performed during the post-ingestion period while participants complete a cognitive processing speed task. This protocol evaluates the immediate metabolic and neurocognitive effects of exogenous ketone administration within a single session.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Regional brain glucose uptake	Regional brain glucose uptake measured by fluorodeoxyglucose F18 positron emission tomography. The primary outcome is regional cerebral glucose uptake quantified using fluorodeoxyglucose F18 positron emission tomography integrated with magnetic resonance imaging. Glucose uptake will be assessed in prespecified frontal and temporoparietal regions implicated in early metabolic and cognitive decline. Uptake values will be expressed as standardized uptake value ratios to allow regional comparison across participants. This outcome is used to determine (1) whether older adults with prediabetes exhibit reduced task-related brain glucose uptake compared to metabolically normal older adults, and (2) whether acute ketone monoester ingestion alters regional glucose uptake during cognitive task performance.	Two visits (placebo and ketone condition in random order) will take place within 4 weeks of enrollment. Main outcome is change in cerebral glucose uptake between placebo and ketone conditions.

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2025
• Primary Completion (Estimated): May 31, 2026
• Study Completion (Estimated): May 31, 2026

Study Registration Dates

• First Submitted: April 10, 2026
• First Submitted That Met QC Criteria: April 16, 2026
• First Posted (Actual): April 22, 2026

Study Record Updates

• Last Update Posted (Actual): April 22, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Insulin Resistance; Functional Magnetic Resonance Imaging; Dementia; Magnetic Resonance Imaging; Aging; Positron-Emission Tomography; Neuroimaging; Processing Speed; Cognitive Dysfunction; Fluorodeoxyglucose F18; Prediabetic State; Ketone Bodies; Brain Energy Metabolism; Brain Glucose Metabolism; Cerebral Glucose Uptake; beta-Hydroxybutyrate
• Additional Relevant MeSH Terms: Endocrine System Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Metabolic Diseases; Neurocognitive Disorders; Glucose Metabolism Disorders; Diabetes Mellitus; Cognition Disorders; Hyperinsulinism; Nutritional and Metabolic Diseases; Cognitive Dysfunction; Insulin Resistance; Dementia; Prediabetic State
• Other Study ID Numbers: IRB-300013058; UAB NORC (Other Identifier: UAB NORC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Plan Description:

Individual participant data (IPD) will not be publicly shared due to the sensitive nature of the data collected, which includes neuroimaging scans, metabolic testing results, and cognitive performance measures. Although all data will be de-identified, neuroimaging data carry a potential risk of re-identification. Additionally, the small sample size and mechanistic design of this pilot study increase the likelihood of indirect participant identification.

Access Criteria:

De-identified data may be made available to qualified researchers upon reasonable request. Access will require institutional review board (IRB) approval or exemption, execution of a data use agreement, and confirmation that the proposed use is consistent with participant consent and applicable institutional policies. Data sharing will occur through secure, controlled-access mechanisms rather than public repositories.

Drug and device information, study documents

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