The Effect of Exogenous Ketone Bodies on Cognition in Patients with Mild Cognitive Impairment, Alzheimer's Disease and in Healthy Adults: A Systematic Review and Meta-Analysis

ImportanceImpaired cognitive function is a hallmark of neuropsychiatric disease, posing a significant challenge to patients, clinicians and healthcare systems. Emerging research on ketone bodies suggests they may function as an alternative fuel for the brain, potentially enhancing cognitive function through both metabolic and signaling pathways. An alternative to inducing ketosis by lowering dietary carbohydrate intake is consumption of exogenous ketones (EK). ObjectiveIt is unknown whether the existing literature collectively supports a beneficial effect of EK on cognitive function; this systematic review and metanalysis aims to aggregate available data and address this gap. Data SourcesPubMed, Web of Science, and EMBASE databases were searched in October 2023 for key words and free words referring to ketone bodies, cognition, and health-related conditions. Study SelectionMultiple reviewers selected 29 studies for inclusion in the analysis from the initial 1678 search results, which included randomized control studies of healthy participants and patients with neuropsychiatric conditions, using exogenous ketones as an intervention alongside a placebo, that included outcomes assessing cognitive function. Data Extraction and SynthesisA PRISMA model was used for abstracting data, and the PEDRo scale was used to assess study quality. Data was extracted and verified by independent investigators. Main OutcomeCognitive function measures. Results29 studies (1,347 participants) were included, with 18 studies (875 participants) in the meta-analysis. Results indicate that EK administration has a modest but statistically significant positive effect on cognitive performance (SMD = 0.26, 95% CI: 0.11 - 0.40, p = 0.0007). Sub-group analyses showed no significant differences between study duration (acute vs. intermediate; p = 0.50), ketone form (mono-esters vs. medium-chain triglycerides; p = 0.06), population type (healthy vs. Alzheimers disease; p = 0.21), or the presence of acute cognitive stressors (p = 0. 25). ConclusionsThe findings suggest that EK could be a promising adjunctive strategy in dementia management, offering potential benefits even in patients who maintain sufficient carbohydrate intake. EK may provide psychiatrists with an innovative, non-invasive approach to supporting cognitive resilience in patients with neuropsychiatric disorders. Further clinical trials should refine the therapeutic application of EK and integrate them into comprehensive neuropsychiatric care protocols. Key pointsQuestion: Does the consumption of exogenous ketones improve cognitive function, and what are the variables that influence efficacy. Finding: Exogenous ketones have a modest but significant effect on overall cognitive performance outcomes, with no clear effect of study duration or population, ketone form or dose, or the presence of a stressor. Meaning: These findings strongly support further research to determine the ideal administration strategy for exogenous ketones to improve cognitive function.