The Effects of Exogenous Ketones on Cognitive Function

University of Alabama at Birmingham45 enrolled

Overview

The purpose of this study is to evaluate the acute effects of exogenous ketone monoester (KME) supplementation on cognitive function in three groups of adults aged 19-55 years: (1) obese, sedentary individuals; (2) lean, sedentary individuals; and (3) lean individuals who engage in regular physical activity (e.g., collegiate or amateur athletes). Exogenous ketones are considered a functional food, providing potential health benefits beyond basic nutrition. Specifically, KME has been shown to elevate circulating β-hydroxybutyrate (βHB), an alternative brain fuel that may enhance cognitive performance. Prior studies have demonstrated that KME improves cognition in individuals with Alzheimer's disease and mild cognitive impairment; however, its effects in otherwise healthy, sedentary individuals-particularly those with obesity-or in physically active individuals remain unknown. Emerging evidence suggests that individuals with obesity may exhibit early cognitive deficits, especially in executive function and processing speed, which could increase their risk of accelerated cognitive decline with aging. These deficits may be partially attributed to impaired cerebral glucose metabolism. Since ketones serve as an efficient alternative energy substrate for the brain, ketone supplementation may help compensate for these metabolic deficits and enhance cognitive performance. This study aims to compare cognitive performance across the three groups and assess the effects of acute KME supplementation versus placebo on cognitive, sensorimotor, and functional outcomes. The primary outcome is cognitive performance assessed using the NIH Toolbox Cognition Battery. Secondary Outcomes include sensorimotor performance, measured using the Senaptec Sensory System, and driving performance, assessed with a driving simulator. This three-group design allows for the investigation of differential responses to ketone supplementation across a spectrum of metabolic health and physical conditioning. By using sensitive, multimodal assessment tools, this study will help determine whether exogenous ketones confer cognitive and functional benefits broadly, or whether these effects are most pronounced in metabolically impaired populations.

Interventions

Ketone Monoester (KE)DIETARY_SUPPLEMENT

Participants will undergo two test days separated by 3-7 days. On both test days, participants will arrive fasted and consume a single dose of ketone monoester or placebo (357 mg/kg of body weight) in random order. Drinks will be prepared by non-study personnel and matched in taste, texture, and appearance to maintain blinding. Thirty minutes after consuming the ketone monoester or placebo, cognitive assessments will be completed including NIH Toolbox cognitive assessments, Senaptec Sensory Station, and driving simulation.

PlaceboDIETARY_SUPPLEMENT

Participants will undergo two test days separated by 3-7 days. On one test day, participants will consume a single dose of placebo (357 mg/kg of body weight). Thirty minutes after consuming the placebo, cognitive assessments will be completed including NIH Toolbox cognitive assessments, Senaptec Sensory Station, and driving simulation.

Eligibility

Sex: ALLMin age: 19 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Age 19-55 years * BMI 30-40 (obese group) or 18-25 (lean and athlete groups) * Sedentary status (\<2 hrs/week of structured physical activity) for obese and lean groups * Active athlete status (≥5 days/week of structured activity) for athlete group Exclusion Criteria: * Diagnosed neurological conditions (e.g., Parkinson's disease, multiple sclerosis, schizophrenia, muscular dystrophy, stroke, cerebral palsy) * History of seizures * Use of medications for diabetes, mood disorders, or attention disorders * Pregnant or breastfeeding * Current or recent use (within 1 month) of exogenous ketone supplements or adherence to a ketogenic diet

Outcomes

Primary Outcomes

NIH Toolbox Cognition Battery Composite Score and Domain-Specific Subtests - Executive function

Cognitive function will be assessed using the NIH Toolbox Cognition Battery, administered on an iPad. \- Dimensional Change Card Sort Test - Measures executive function and cognitive flexibility by assessing the ability to switch between mental rules.