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

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 | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search 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 Bruno Bonnechère , Elizabeth B. Stephens , Amy C. Boileau , Martin Ducker , View ORCID Profile Brianna J. Stubbs doi: https://doi.org/10.1101/2025.09.17.25335999 Bruno Bonnechère 1 University of Hasselt , Hasselt, Belgium (PhD) Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elizabeth B. Stephens 2 Buck Institute for Research on Aging , Novato, CA, USA (BS) Find this author on Google Scholar Find this author on PubMed Search for this author on this site Amy C. Boileau 3 Component Health Ltd , Dublin, Ireland (PhD) Find this author on Google Scholar Find this author on PubMed Search for this author on this site Martin Ducker 3 Component Health Ltd , Dublin, Ireland (DPhil.) Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: martin{at}juvlabs.org bstubbs{at}buckinstitute.org Brianna J. Stubbs 2 Buck Institute for Research on Aging , Novato, CA, USA (DPhil.) Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Brianna J. Stubbs For correspondence: martin{at}juvlabs.org bstubbs{at}buckinstitute.org Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Importance Impaired 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). Objective It 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 Sources PubMed, 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 Selection Multiple 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 Synthesis A 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 Outcome Cognitive function measures. Results 29 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. Alzheimer’s disease; p = 0.21), or the presence of acute cognitive stressors (p = 0. 25). Conclusions The 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 points Question: 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. Introduction Alzheimer’s Disease and related dementias (ADRD) are known to be a major public health problem for governments, particularly in those countries with ageing populations, such as the USA, UK and Japan [ 1 ]. In addition to the reduced quality of life and wellbeing for the patient, ADRD also imposes a cost on society through the significant financial burden of patient care [ 2 ]. Although pharmaceutical industries have tried to address these challenges by developing both symptomatic and disease-modifying treatments, any such treatments have to be considered in the context of possibly harmful side-effects and practicalities of long-term administration. For these reasons, there has been considerable interest in non-pharmacological strategies, such as ketogenic diets, for improving cognition in patients with mild cognitive impairment (MCI) and ADRD [ 3 ]. The canonical primary role of ketone bodies (or ketones) including β-hydroxybutyrate (BHB), acetoacetate (AcAc), and acetone, is to act as a metabolic substrate for brain function during development, and in settings of low carbohydrate availability. Indeed, classic experiments by Owen et al [ 4 ] found that ketones entering the brain via select, widely expressed mono-carboxylate transporters [ 5 ] can account for up to 60% of brain metabolic needs during prolonged starvation. Alongside their role as an alternative substrate, ketones have been hypothesized to have multiple non-energy, signaling effects in the brain, including increasing cerebral blood flow [ 6 – 9 ], modulating release of neurotransmitters [ 10 , 11 ] and neurotrophins [ 12 , 13 ], and altering proteostasis [ 9 , 14 , 15 ]. Taken together, there is a strong mechanistic rationale supporting functional benefit of strategies that increase the availability of ketones to the brain. Ketones are produced endogenously, as a result of increased peripheral lipolysis and hepatic conversion of free fatty acids to ketone bodies [ 16 ]. Ketosis is typically defined as a blood BHB concentration of > 0.5 mM [ 17 – 20 ]. Endogenous ketone production increases as a result of dietary strategies that severely restrict carbohydrate intake, such as during voluntary or involuntary fasting [ 21 ] or with consumption of a low-carbohydrate, high-fat, ketogenic diet [ 17 ]. A healthy adult can produce up to ∼150 g of ketone bodies during a prolonged fast [ 22 ], reaching a physiological ketosis of 5 – 7 mM [ 17 , 21 ]. In contrast, long-term consumption of a well formulated ketogenic diet results in a more modest ketosis of < 1 mM [ 17 ]. Whilst dietary strategies to augment ketosis have been popularized of late, there are perceived barriers to widespread implementation that include long-term poor adherence and concerns about the impact of a poorly formulated ketogenic diet on cardiovascular risk. Exogenous ketones (EK) represent an alternative to existing dietary strategies and can increase circulating ketone concentrations to 0.5 – 5 mM in a rapid and dose-dependent manner, even when consumed alongside carbohydrate that would usually prevent endogenous ketosis [ 23 – 25 ]. There are several types of EK compounds that either directly contain ketone bodies (i.e., free BHB acid, BHB or AcAc mineral salts, esters of BHB or AcAc), or contain precursors that are readily metabolized into ketone bodies (i.e., ketogenic medium chain triglycerides (MCT), medium chain fatty acid esters, ketogenic alcohol (R)-1,3-butanediol). As a category, EK have no currently known safety concerns and, although some gastrointestinal symptoms can occur which may reduce long term compliance, these appear to be reduced by a gradual increase in daily dose [ 32 , 44 – 47 ]. In the last decade, there has been a steady increase in the number of publications that have addressed the possible physical and cognitive effects of different EK compounds in healthy adults and those with neuropsychiatric disorders. As a result of the known metabolic and signaling effects on ketone bodies within the brain, there has been a growing scientific and medical interest in understanding the impact of ketone bodies on cognitive function in those with neurological conditions and healthy individuals. Given the higher chance of detecting functional improvements when there is an existing deficit, and the prominent role of deficits in brain energy metabolism in neurodegenerative disease [ 26 ], it is perhaps unsurprising that the bulk of studies investigating the cognitive effect of ketosis have focused on disease populations. In a key recent systematic review, ketogenic diet and other ketogenic interventions were suggested to positively impact cognition in patients with Alzheimer’s Disease (AD) [ 27 ]. Furthermore, ketosis may have a positive effect on cognition even in healthy adults; a recent compelling triangulation of observational studies and mendelian randomization studies found that increased circulating BHB improved general cognitive function as well as delaying the risk of cognitive decline and AD [ 28 ]. However, to our knowledge no publications to date have performed a systematic review or meta-analysis to consolidate the evidence for the cognitive effects of EK alone in humans – with or without cognitive impairment. To address this gap, we undertook this systematic review and metanalysis to evaluate the literature on the effect of EK on human cognition. Given the strong mechanistic evidence for ketones as a fuel and a signal in the brain, we aimed to determine whether EK had a beneficial effect on cognition. If a positive effect was found, we further planned to address if there was an impact of dose or EK compound, duration of intervention, as well as if any benefit was present in healthy volunteers, as well as patients with neuropsychiatric disorders. Methods This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [ 29 ] and was registered on PROSPERO (registration ID: CRD42023471727). The software program, Rayyan [ 30 ], was used during all stages of study selection and data extraction. For the present study, no ethics committee approval was necessary. Search Strategy Records were searched on three databases (PubMed electronic database of the National Library of Medicine, the Web of Science database, and Embase) to identify eligible studies published before 31 st October 2023. MeSH terms and free words referring to ketone bodies (‘ketone bodies’ OR ‘ketosis’ OR ‘ketogenic’ OR ‘ β-hydroxybutyrate’ OF ‘BHB’ OR ‘beta-hydroxybutyrate’ OR ‘acetoacetate’ OR ‘ketone’ OR ‘exogenous ketone’ OR ‘ketone ester’ OR ‘ketone salt’ OR ‘medium chain triglyceride’ OR ‘MCT’), cognition ((“cognit*” OR “memory” OR “learning” OR “attent*” OR “intellect” OR “executive funct*” OR “recognit*” OR “IQ” OR “problem solving” OR “psychomotor speed” OR “mental flexib*” OR “choice react*” OR “emotional bias” OR “planning” OR “response inhibition”)), and health-related conditions (‘dementia’ OR ‘mild cognitive impairment’ OR ‘MCI’ OR Alzheimer’s Disease’ OR ‘AD’ OR ‘Parkinson’s Disease’ OR ‘PD’ OR ‘traumatic brain injury’ OR ‘TBI’ OR ‘concussion’ OR ‘CTE’ OR ‘stroke OR ‘multiple sclerosis’ OR ‘MS’) were used as keywords. References from selected papers and from other relevant articles were screened for potential additional studies in accordance with the snowball principle. Search was limited to journal articles published in English. Two reviewers (ACB and BJS) independently screened titles and abstracts according to the inclusion/exclusion criteria. In the case of conflicts, both reviewers met to discuss their study selection decisions until they reached a mutual decision. Studies that were included based on title and abstract, advanced to full-text screening where the same process was followed (ACB and BJS review independent, resolved conflicts together). A reason for exclusion was provided during full-text screening. The final analyses were conducted using studies that advanced through both levels of screening. Eligibility criteria A PICOs approach was used as inclusion and exclusion criteria: Participants : Healthy participants and patients with neuropsychiatric conditions. Intervention : The intervention being studied was exogenous ketone products. This term encompasses any product that is administered with the aim of increasing blood ketone concentrations. These may include, but not be limited to ketone esters, ketone monoester, ketone di-ester, butanediol, ketone salt, medium chain triglycerides, tri-octanoate, coconut oil, ketone infusion. Control : Placebo Outcomes : Outcomes encompassed assessments of one or more cognitive functions conducted both prior to and following ketone body supplementation. These outcomes included a comprehensive evaluation of global cognition, as well as various subdomains of cognitive function, which include verbal memory, nonverbal memory, working memory, processing speed, attention, language proficiency, visuospatial skills, and executive functions. The evaluation of cognitive functions must have been conducted by qualified healthcare professionals such as psychologists, medical doctors, or neuropsychologists Study design : RCTs A flow diagram of the study selection with the screened articles and the selection process is presented in Figure 1 . Data extraction Data were extracted independently by a single reviewer (EBS) and confirmed by a second reviewer (BJS) to verify correct data extraction. The following information was extracted from the included studies: characteristics of the patients (age, sex ratio, general information about conditions/disease), characteristics of the intervention (molecule, dose, duration), type of control and outcomes measurements. Means and error (as standard error, standard deviation, or 95% CI) for cognitive function scores were extracted either by directly extracting from tables/text or by using the data extraction tool, WebPlotDigitizer (WebPlotDigitizer, Pacifica, CA, USA), when data were only reported in figures. Participant population, number of participants, and any co-interventions were also extracted. Quality assessment The PEDro scale, which is deemed a valid and reliable tool for assessing RCTs, was used for methodological quality assessment. RCTs’ quality was blindly judged by two different reviewers (BJS and EBS) to minimize potential bias. To ensure the rigor of this process, the final decision about each RCT quality was made by reaching a consensus. In case of discordance, a third collaborator (BB) was consulted to provide expert input. The RCTs were classified into distinct categories based on their quality: low quality (scores falling within the range of 0 to 3 out of 10; moderate quality (scores spanning 4 to 6 out of 10) and high quality (RCTs achieving scores from 7 to 10 out of 10). This methodical approach allowed for a comprehensive evaluation of the RCTs, thus facilitating an objective assessment of their respective quality levels. Statistical analysis For studies assessing the efficacy of ketone bodies and displaying complete results of the pre and post-tests, we performed a meta-analysis. The measure of treatment effect was the standardized mean difference effect size (standardized mean difference [SMD]), defined as the between-group difference in mean values divided by the pooled SD computed using the Hedge’s g method. If different tests were used to assess the cognitive in the same study, the different results were pooled to have one unique SMD as recommended by Cochrane’s group. A positive SMD implies an increased cognitive function in comparison with the control group. We calculated the variance estimate tau² as a measure of between-trial heterogeneity. We prespecified a tau² of 0.0 to represent no heterogeneity, 0.0–0.2 to represent low heterogeneity, 0.2–0.4 to represent moderate heterogeneity, and above 0.4 to represent high heterogeneity between trials. To deal with high or moderate heterogeneity we used random-effect models and presented forest plots for the different comparators. We checked for publication bias using funnel plot [ 15 ] and Egger’s test for the intercept was applied to check the asymmetry [ 16 ] and performed sensitivity analysis to detect potential outliers. Meta-regression was performed to assess a possible effect of the dose, the duration (long term = > 13 days; immediate = single administration and same-day measurement) of the intervention and the type of supplementation on the results. The statistics were conducted in RStudio (version 2023.06.2) with R version 4.4.2. and the significance level set at p < 0.05. Results Search results Twenty-nine studies have been finally included in the systematic review. The PRISMA flowchart of the study selection is presented in Figure 1 . Characteristics of the participants Table 1 provides a comprehensive overview of the 29 included studies, detailing their respective characteristics. In total 1347 participants were included in this review, amongst them 1288 (95%) completed the full protocol. The complete characteristics of the participants and interventions are presented in Table 1 . View this table: View inline View popup Table 1: Characteristics of studies included in the systematic review and meta-analysis. Concerning the quality of the individual studies we found an overall PEDRO score of 8 (1.6) out of 10 indicating high quality studies, with only seven studies being judged as moderate quality. Individual results are presented in Table 1 and summarized in Figure 2 . Systematic review Characteristics of the intervention The studies reviewed encompass a wide range of geographic locations, with the largest number of participants coming from the United States, which contributed 664 participants across 9 studies. Japan followed with 189 participants across 5 studies, while Canada included 190 participants in 5 studies. Other countries with fewer participants included the United Kingdom (126 participants across 2 studies), Ireland (19 participants across 2 studies), Spain (44 participants in 1 study), Germany (19 participants in 1 study), Belgium (18 participants in 1 study), and China (53 participants in 1 study). The types of supplementations presented high heterogeneity, with lipid-based precursors being the most common. MCTs were used in 1,038 participants across 18 studies, with dosages that ranged from 6 g/day to 56 g/day, with common formulations including caprylic acid (C8:0) and capric acid (C10:0). Coconut oil was used in a single study with 44 participants, administered at a dosage of 36 g/day, in the context of AD. AC-1202 and AC-1204 (proprietary, purified caprylic triglycerides), were used in studies involving 565 participants across 2 studies in the USA. Non-lipid-based ketone supplements included BHB salts, which were used in 44 participants across 2 studies, primarily in athletic performance contexts, and ketone monoester (KME), involving 172 participants across 6 studies. The dosages for the KME interventions varied, typically ranging from 573 mg/kg to 162.5 g total, and were predominantly used in studies focusing on athletic performance and cognitive function under stress. The duration of the interventions also varied widely. The intervention duration ranged from single-dose studies to longer studies lasting up to 6 months, with the most common durations being between 1.5 to 3 months. The most common outcomes evaluated across these studies focused on cognitive function and physical performance. Cognitive function was assessed using various tools, with the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) being the most frequently used. Neuropsychological tests such as the Trail Making Test and Stroop Test were also commonly employed. These assessments were applied across diverse populations, including healthy adults, individuals with MCI, and patients with AD. Physical performance outcomes were primarily measured in athletes and healthy adults, focusing on endurance performance (e.g., time trials), muscle strength (e.g., grip strength, knee extension time), and reaction times. Additionally, biomarkers like plasma BHB levels were often measured to confirm ketosis, alongside glucose and lactate concentrations, particularly in studies involving KME. Clinical efficacy Our interest focused on the clinical effects of ketone supplementation on cognitive performance. The relevant outcomes and main results of the included studies are presented in Table 2 . View this table: View inline View popup Table 2: Description of participants’ outcomes and main tests of the included studies Many of the studies focused on long-term use of MCTs and structurally related EK compounds in older adults Several studies demonstrated improvements in cognitive performance in older adults with frailty, MCI or AD after long-term MCT supplementation [ 31 – 33 ], or coconut oil enriched Mediterranean diet [ 34 ]. EK were associated with increased MMSE scores and improvements in episodic memory, language, and executive function. Of note, two studies found that the cognitive benefits of long-term EK might be greater in individuals without the APOE4 allele [ 35 , 36 ]. Only one long-term study utilized a non-MCT product, finding that 14 days of KME supplementation improved performance of the Digit Symbol Substitution Task in obese adults [ 8 ]. Of the studies investigating the immediate effects of EK supplements, a large proportion of these were in a younger, healthy population and utilized KME. The results were mixed, with some studies finding attenuation of exercise-induced decline in cognitive function [ 37 ] and visual reaction time [ 38 ] in the KME group, however, other studies used similar young, healthy populations in the context of exercise, or exercise plus hypoventilation found no protective effect of KME against cognitive decline [ 39 , 40 ]. Two studies reported that a single MCT dose improved immediate cognitive task performance in AD [ 41 ] and in the context of hypoglycemia [ 42 ], although the effects were dose-dependent and varied by cognitive domain. Meta-analysis Out of the 29 studies included in the systematic review, 18 were included in the meta-analysis, representing 875 participants, to quantify the effect of EK supplementation on cognitive function. The remaining 11 studies failed to report complete results (i.e., pre-post intervention), or presented the results as median. First, we assessed the overall effect of EK on cognitive function, pooling results from 18 studies. The overall pooled effect was positive and statistically significant (SMD = 0.26, [95% CI 0.11 – 0.40], p = 0.0007) (using fixed effect model due to high heterogeneity (I² = 93%, p < 0.001) Figure 3 ). Risk of bias was assessed using funnel plot and Egger’s regression and did not show asymmetry (Egger’s intercept = 2.75 (0.87), p = 0.06, Supplementary Figure 1 ). The sensitivity analysis did not highlight the presence of outliers or studies with implausible results (extremely large effect) ( Supplementary Figure 2) . Next, we analyzed the differences between studies assessing the long-term (> 13 days) and immediate effects of EK. While no statistically significant difference between the duration groups (p = 0.50) was found, the overall effect was only statistically significantly different for studies assessing the long-term effect (SMD = 0.20 [0.11 – 0.28], p < 0.001, Supplementary Figure 3 ). For studies assessing the immediate effect, the results were at the border of the significance level (SMD = 0.31 [-0.01 – 0.64], p = 0.061). When comparing the type of supplementation, the two most common supplement types, KME and MCT, were studied. As KME have a greater ketogenic effect than MCT [ 23 , 43 ], we hypothesized that there might be a greater effect on cognition in KE studies. We did not find statistically significant differences between KME and MCT (p = 0.06, Supplementary Figure 4 ). However, the overall positive effect on cognition was only statistically significant for the MCT supplementation (SMD = 0.15 [0.05 – 0.25], p = 0.002) not for the KME (SMD = 0.31 [-0.07 – 0.68], p = 0.11). As only one study described the combination of MCT and BHB salt, it was not included in this analysis. We then compared the cognitive effects of EK in studies of subjects with, and without the most included pathologies, MCI and AD. We expected that EK might provide greater benefit to subjects with a pathology that compromised their cognitive function. Surprisingly, we did not find a statistically significant difference (p = 0.21, Supplementary Figure 5 ) between the effect on healthy subjects (SMD = 0.32 [0.10 – 0.55], p = 0.004) and between subject with MCI or AD (SMD = 0.15 [0.01 – 0.30], p = 0.038). We were interested to explore if the presence of a stressor such as exercise or hypoglycemia would modulate any effect of EK on cognition. However, no statistically significant differences (p = 0.25) were found between studies using no stressor (SMD = 0.17 [0.07 – 0.27], p < 0.001) and studies that included an exercise-based stress (SMD = 0.33 [-0.04 – 0.71], p = 0.081), although the latter was not significant in the standalone analysis. Next, we performed meta-regression analysis to assess the relationship between cognitive outcomes and variables of interest. Firstly, we used meta-regression to determine if the duration of the EK intervention was related to cognitive outcomes. We did not find a significant relationship between the total duration of supplementation and cognitive outcomes for the overall dataset (β =-0.0007 (SE = 0.0013), p = 0.56, Figure 4A ). However, when analyzed by subgroups, the data showed a tendency toward a positive effect of longer interventions for MCT supplementation, although this effect was not statistically significant (β = 0.001 (0.0006), p = 0.089), see Table 3 for complete results. View this table: View inline View popup Download powerpoint Table 3: Meta-regression between the effect of ketone bodies supplementation on cognitive function for the total dose, the dose by day and the total duration of the supplementation Secondly, we examined how the dose of EK consumed influenced the observed cognitive outcomes for the overall dataset. While a greater total EK dose over the study period did not significantly correlate with additional cognitive improvements (β = 0.0001 (0.0001), p = 0.75, Figure 4D ), increasing daily dose of EK was strongly related to greater improvement in cognitive function across all studies (β = 0.0023 (0.0004), p < 0.001, Figure 4C-D ). We then repeated the meta-regression to determine if the relationship between daily dose against and outcomes persisted in further subgroup analyses. The relationship between greater daily dose and cognitive improvements remained significant for studies using KME (β = 0.0026 (0.003), p < 0.001) and for both healthy participants (β = 0.0022 (0.0004), p < 0.001) and those with AD (β = 0.0231 (0.0032), p < 0.001). These findings imply that higher daily doses of EK consistently result in greater cognitive improvements across different populations and supplement types. Discussion The aim of this systematic review and meta-analysis was to determine the effect of EK supplementation on cognitive function. The findings indicate that EK consumption can beneficially impact cognitive outcomes, with evidence highlighting the possible importance of both intervention duration and EK compound used and supporting efficacy in healthy and non-healthy adults. Overall, these findings highlight the promise of exogenous ketones as a novel strategy to target cognitive function, although further research is needed to support and inform clinical translation. The positive effect of EK on cognition demonstrated by our overall, pooled analysis is in alignment with the primary teleological function of ketones as a back-up substrate for the brain during starvation [ 4 ]. However, considering the context of cerebral substrate provision during fasting (i.e., low carbohydrate availability) compared to in the studies included here (i.e., EK alongside sufficient carbohydrate) it is, in fact, perhaps surprising that cognitive function following EK exceeded function under conditions of normal, ample substrate availability. This observation hints at the importance of mechanisms beyond simple substrate oxidation to the functional effect of EK. A recent large observational study found a cognitive benefit of BHB concentrations over as low as ∼0.3 mM, at which oxidation would likely be low-to-minimal [ 28 ]. Recent clinical studies have proposed that EK may act to increase cerebral blood flow [ 7 , 8 ], or increase brain network stability [ 44 ]. Preclinical data also demonstrates changes neurotransmitter release in the state of ketosis [ 10 , 11 ]. Taken together, the additional cognitive benefit of EK in the context of sufficient carbohydrate substrate, suggests that ketones are not only a fuel for the brain, but that they have physiological signaling effects distinct from glucose [ 45 ] which translate to improved cognitive function. The observation that only the ‘long-term’ (> 13 days) EK supplementation studies resulted in a significant effect on cognition in standalone analysis, but not ‘acute’ studies, suggests that consistent use of EK may be required for the emergence of a cognitive effect. However, our overall meta-regression did not highlight duration as a critical factor, with only a non-significant trend in the MCT subgroup analysis. Notably, there were very few long-term studies with KME. The possibility that EK efficacy builds over time is suggestive of a non-energy, signaling mechanistic contribution to their effect on cognition, as outlined above. If BHB’s role as an oxidative substrate were a primary driver of its effect on cognition, it would likely reach maximal effect while blood BHB was elevated as a substrate for cerebral metabolism. Ultimately, the latency of onset and persistence of cognitive effects following EK consumption is unknown; studies that help to define the latency and persistence will be foundational for any future translation of EK for cognitive function. The results of our analysis leave many open questions about EK supplement type and dose selection. Whilst only studies using MCTs found a significant effect on cognition when analyzed as a standalone subgroup, the high heterogeneity in the KME studies made it difficult to detect an effect. The finding that daily dose was related to cognitive improvement in our meta regression is suggestive that higher, more sustained increases in blood ketones could be required for cognitive benefits. The only study to directly interrogate this was Fortier et al, who found that greater circulating ketone concentrations were associated with a greater cognitive improvement during a study of long-term MCT supplementation [ 32 ]. In other physiological systems greater ketone concentrations have been linked to larger functional changes, notably the cardiovascular system where cardiac output improves to a greater extent as ketone concentration increases [ 46 ]. As KME have a larger impact on circulating ketones concentrations that both MCT and ketone salts [ 23 , 24 ], using these EK supplements in long term studies is a promising direction for future research. Despite their potent effect on blood ketone concentration, KME are known for a having a difficult to mask, bitter taste which could pose a barrier to long-term use. In contrast, both MCTs and medium chain fatty acid esters have a neutral taste, making them more translatable for long-term use. There are several notable limitations to the generalizability of these results. The first, and the most important, is the high heterogeneity between studies. We noted significant variability in participant population, interventions, and outcome measures. This high level of heterogeneity (I² = 93%) across the studies, especially regarding the type of ketone supplementation and intervention duration, makes it difficult to generalize the findings. A second important limitation is that many of the studies were short-term interventions. There is a lack of long-term studies and long-term follow up, particularly with KME, which limits the understanding of the sustainability of the cognitive benefits. These limitations suggest that while the findings of the review are promising, more standardized, long-term studies with larger sample sizes are necessary to fully understand the efficacy of EK on cognition. Despite these limitations, our results are promising and offer interesting perspective for future research and clinical translation. Given the beneficial cognitive effects of EK in both healthy and cognitively impaired individuals, no known safety concerns and acceptable tolerance profiles, EK are a candidate for further research and clinical translation. It is likely that the greatest effect would be seen if EK were used in synergy with other interventions, such as diet and exercise; this should be addressed in future research. No studies have addressed if EK can play a role in prevention, this too is an avenue of potential application. Other key questions highlighted by this analysis and foundational to the field of EK application at large include the choice of EK supplement type (MCT vs KME), dose selection and possible drivers of individual differences between individuals including metabolic responsiveness, cognitive and physical health. In conclusion, this systematic review and meta-analysis found that exogenous ketone supplementation has a positive effect on cognitive performance. Future work should explore the relative contribution of ketones as fuel substrates vs signaling metabolite to the observed effects and determine if there is a threshold for dosing or blood ketone concentrations that delivers the greatest improvement with the lowest practical dosing. Data Availability All data produced in the present work are contained in the manuscript Footnotes Funding: BJS was supported by the NIA under award number K01AG078125. Disclosure : BJS. has an equity interest in HVMN Inc., and stock options in BHB Therapeutics Ltd who both market products related to ketone bodies. BJS. is an inventor on patents related to the use of ketone bodies assigned to The Buck Institute for Research on Aging. MD and ACB were employed by Component Health Ltd, who commercialize ketone ester product, at the time the work was carried out. All other authors have no disclosures. Acknowledgements: The authors thank Dr Barbara Sahakian for her thoughtful comments on this manuscript Abbreviations AcAc Acetoacetate AD Alzheimer’s Disease ADAS-Cog Alzheimer’s Disease Assessment Scale-Cognitive Subscale ADRD Alzheimer’s Disease and Related Dementias BHB D-β-hydroxybutyrate EK Exogenous ketones kMCT Ketogenic MCT KME Ketone monoester MCI Mild cognitive impairment MCT Medium chain triglyceride mM millimolar MMSE Mini mental state examination PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses SD Standard deviation of the mean References 1. ↵ Collins , P.Y. , et al. , Grand challenges in global mental health . Nature , 2011 . 475 ( 7354 ): p. 27 – 30 . OpenUrl CrossRef PubMed Web of Science 2. ↵ Beddington , J. , et al. , The mental wealth of nations . Nature , 2008 . 455 ( 7216 ): p. 1057 – 60 . OpenUrl CrossRef PubMed Web of Science 3. ↵ Robbins , J.P. and E. Solito , Does Neuroinflammation Underlie the Cognitive Changes Observed With Dietary Interventions? Front Neurosci , 2022 . 16 : p. 854050 . OpenUrl PubMed 4. ↵ Owen , O.E. , et al. , Brain Metabolism during Fasting . Journal of Clinical Investigation , 1967 . 46 ( 10 ): p. 1589 -&. OpenUrl CrossRef PubMed Web of Science 5. ↵ Halestrap , A.P. and D. Meredith , The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond . Pflugers Archiv - European Journal of Physiology , 2004 . 447 ( 5 ): p. 619 – 28 . OpenUrl CrossRef PubMed Web of Science 6. ↵ Hasselbalch , S.G. , et al. , Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia . Am J Physiol , 1996 . 270 ( 5 Pt 1 ): p. E746-51. 7. ↵ Svart , M. , et al. , Regional cerebral effects of ketone body infusion with 3-hydroxybutyrate in humans: Reduced glucose uptake, unchanged oxygen consumption and increased blood flow by positron emission tomography. A randomized, controlled trial . PLoS One , 2018 . 13 ( 2 ): p. e0190556 . OpenUrl CrossRef PubMed 8. ↵ Walsh , J.J. , et al. , Short-term ketone monoester supplementation improves cerebral blood flow and cognition in obesity: A randomized cross-over trial . J Physiol , 2021 . 599 ( 21 ): p. 4763 – 4778 . OpenUrl CrossRef PubMed 9. ↵ Neth BJ , et al. , Modified ketogenic diet is associated with improved cerebrospinal fluid biomarker profile, cerebral perfusion, and cerebral ketone body uptake in older adults at risk for Alzheimer’s disease: a pilot study . Neurobiol Aging , 2020 . 86 : p. 54 – 63 . OpenUrl CrossRef PubMed 10. ↵ Juge , N. , et al. , Metabolic Control of Vesicular Glutamate Transport and Release . Neuron , 2010 . 68 ( 1 ): p. 99 – 112 . OpenUrl CrossRef PubMed Web of Science 11. ↵ Erecinska , M. , et al. , Regulation of GABA level in rat brain synaptosomes: Fluxes through enzymes of the GABA shunt and effects of glutamate, calcium, and ketone bodies . Journal of Neurochemistry , 1996 . 67 ( 6 ): p. 2325 – 2334 . OpenUrl CrossRef PubMed Web of Science 12. ↵ Sleiman , S.F. , et al. , Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body beta-hydroxybutyrate . Elife , 2016 . 5 . 13. ↵ Walsh , J.J. , É. Myette-Côté , and J.P. Little , The Effect of Exogenous Ketone Monoester Ingestion on Plasma BDNF During an Oral Glucose Tolerance Test . Frontiers in Physiology , 2020. 11 ( 1094 ). 14. ↵ Kashiwaya , Y. , et al. , A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease . Neurobiol Aging , 2013 . 34 ( 6 ): p. 1530 – 9 . OpenUrl CrossRef PubMed Web of Science 15. ↵ Madhavan , S.S. , et al. , beta-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain . bioRxiv , 2023 . 16. ↵ Robinson , A.M. and D.H. Williamson , Physiological Roles of Ketone-Bodies as Substrates and Signals in Mammalian-Tissues . Physiological Reviews , 1980 . 60 ( 1 ): p. 143 – 187 . OpenUrl CrossRef PubMed Web of Science 17. ↵ Hallberg , S.J. , et al. , Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study . Diabetes Ther , 2018 . 9 ( 2 ): p. 583 – 612 . OpenUrl CrossRef PubMed 18. Laffel , L ., Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes . Diabetes Metab Res Rev , 1999 . 15 ( 6 ): p. 412 – 26 . OpenUrl CrossRef PubMed Web of Science 19. Norgren , J. , et al. , Capillary blood tests may overestimate ketosis: triangulation between three different measures of beta-hydroxybutyrate . Am J Physiol Endocrinol Metab , 2020 . 318 ( 2 ): p. E184 – e188 . OpenUrl PubMed 20. ↵ Mitchell , G.A. , et al. , Medical aspects of ketone body metabolism . Clin Invest Med , 1995 . 18 ( 3 ): p. 193 – 216 . OpenUrl PubMed Web of Science 21. ↵ Cahill , G.F. , Jr . ., Starvation in man . New England Journal of Medicine , 1970 . 282 ( 12 ): p. 668 – 75 . OpenUrl CrossRef PubMed 22. ↵ Reichard Jr , G. , et al. , Ketone-body production and oxidation in fasting obese humans . Journal of Clinical Investigation , 1974 . 53 ( 2 ): p. 508 . OpenUrl CrossRef PubMed Web of Science 23. ↵ Stubbs , B.J. , et al. , On the Metabolism of Exogenous Ketones in Humans . Front Physiol , 2017 . 8 : p. 848 . OpenUrl CrossRef PubMed 24. ↵ St-Pierre , V. , et al. , Plasma Ketone and Medium Chain Fatty Acid Response in Humans Consuming Different Medium Chain Triglycerides During a Metabolic Study Day . Front Nutr , 2019 . 6 ( 46 ): p. 46 . OpenUrl PubMed 25. ↵ Lowder , J. , et al. , An open-label, acute clinical trial in adults to assess ketone levels, gastrointestinal tolerability, and sleepiness following consumption of (R)-1,3-butanediol (Avela) . Front Physiol , 2023 . 14 : p. 1195702 . OpenUrl PubMed 26. ↵ Cunnane , S.C. , et al. , Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing . Nat Rev Drug Discov , 2020 . 27. ↵ Grammatikopoulou , M.G. , et al. , To Keto or Not to Keto? A Systematic Review of Randomized Controlled Trials Assessing the Effects of Ketogenic Therapy on Alzheimer Disease . Adv Nutr , 2020 . 11 ( 6 ): p. 1583 – 1602 . OpenUrl PubMed 28. ↵ Sae-Jie , W. , et al. , Triangulating evidence from observational and Mendelian randomization studies of ketone bodies for cognitive performance . BMC Med , 2023 . 21 ( 1 ): p. 340 . OpenUrl PubMed 29. ↵ Moher , D. , et al. , Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement . BMJ , 2009 . 339 : p. b2535 . OpenUrl FREE Full Text 30. ↵ Ouzzani , M. , et al. , Rayyan-a web and mobile app for systematic reviews . Syst Rev , 2016 . 5 ( 1 ): p. 210 . OpenUrl CrossRef PubMed 31. ↵ Abe , S. , O. Ezaki , and M. Suzuki , Medium-Chain Triglycerides (8:0 and 10:0) Increase Mini-Mental State Examination (MMSE) Score in Frail Elderly Adults in a Randomized Controlled Trial . J Nutr , 2020 . 150 ( 9 ): p. 2383 – 2390 . OpenUrl PubMed 32. ↵ Fortier , M. , et al. , A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment . Alzheimer’s & Dementia , 2019 . 15 ( 5 ): p. 625 – 634 . OpenUrl 33. ↵ Fortier , M. , et al. , A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT . Alzheimers Dement , 2021 . 17 ( 3 ): p. 543 – 552 . OpenUrl PubMed 34. ↵ De la Rubia Orti , J.E. , et al. , [How does coconut oil affect cognitive performance in alzheimer patients? ]. Nutr Hosp , 2017 . 34 ( 2 ): p. 352 – 356 . OpenUrl PubMed 35. ↵ Henderson , S.T. , et al. , Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial . Nutr Metab (Lond ), 2009 . 6 : p. 31 . OpenUrl CrossRef PubMed 36. ↵ Xu , Q. , et al. , Medium-chain triglycerides improved cognition and lipid metabolomics in mild to moderate Alzheimer’s disease patients with APOE4(-/-): A double-blind, randomized, placebo-controlled crossover trial . Clin Nutr , 2020 . 39 ( 7 ): p. 2092 – 2105 . OpenUrl PubMed 37. ↵ Evans , M. and B. Egan , Intermittent Running and Cognitive Performance after Ketone Ester Ingestion . Med Sci Sports Exerc , 2018 . 50 ( 11 ): p. 2330 – 2338 . OpenUrl CrossRef 38. ↵ Poffe , C. , et al. , Exogenous ketosis increases circulating dopamine concentration and maintains mental alertness in ultra-endurance exercise . J Appl Physiol ( 1985 ), 2023. 134 ( 6 ): p. 1456 – 1469 . OpenUrl 39. ↵ Evans , M. , et al. , No Benefit of Ingestion of a Ketone Monoester Supplement on 10-km Running Performance . Med Sci Sports Exerc , 2019 . 51 ( 12 ): p. 2506 – 2515 . OpenUrl 40. ↵ Prins , P.J. , et al. , Ketone Bodies Impact on Hypoxic CO(2) Retention Protocol During Exercise . Front Physiol , 2021 . 12 : p. 780755 . OpenUrl PubMed 41. ↵ Ota , M. , et al. , Effects of a medium-chain triglyceride-based ketogenic formula on cognitive function in patients with mild-to-moderate Alzheimer’s disease . Neuroscience Letters , 2019 . 690 : p. 232 – 236 . OpenUrl CrossRef PubMed 42. ↵ Page , K.A. , et al. , Medium-chain fatty acids improve cognitive function in intensively treated type 1 diabetic patients and support in vitro synaptic transmission during acute hypoglycemia . Diabetes , 2009 . 58 ( 5 ): p. 1237 – 44 . OpenUrl Abstract / FREE Full Text 43. ↵ Vandenberghe , C. , et al. , Tricaprylin Alone Increases Plasma Ketone Response More Than Coconut Oil or Other Medium-Chain Triglycerides: An Acute Crossover Study in Healthy Adults . Curr Dev Nutr , 2017 . 1 ( 4 ): p. e000257 . OpenUrl Abstract / FREE Full Text 44. ↵ Mujica-Parodi , L.R. , et al. , Diet modulates brain network stability, a biomarker for brain aging, in young adults . Proceedings of the National Academy of Sciences , 2020 . 117 ( 11 ): p. 6170 . OpenUrl Abstract / FREE Full Text 45. ↵ Newman , J.C. and E. Verdin , Ketone bodies as signaling metabolites . Trends in Endocrinology & Metabolism , 2017 . 25 ( 1 ): p. 42 – 52 . OpenUrl 46. ↵ Nielsen , R. , et al. , Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients . Circulation , 2019 . 139 ( 18 ): p. 2129 – 2141 . OpenUrl CrossRef PubMed 47. ↵ Ashton , J.S. , et al. , The effects of medium chain triglyceride (MCT) supplementation using a C(8):C(10) ratio of 30:70 on cognitive performance in healthy young adults . Physiol Behav , 2021 . 229 : p. 113252 . OpenUrl CrossRef PubMed 48. Heidt , C. , et al. , Beta-Hydroxybutyrate (BHB), Glucose, Insulin, Octanoate (C8), and Decanoate (C10) Responses to a Medium-Chain Triglyceride (MCT) Oil with and without Glucose: A Single-Center Study in Healthy Adults . Nutrients , 2023 . 15 ( 5 ). 49. Henderson , S.T. , et al. , A Placebo-Controlled, Parallel-Group, Randomized Clinical Trial of AC-1204 in Mild-to-Moderate Alzheimer’s Disease . J Alzheimers Dis , 2020 . 75 ( 2 ): p. 547 – 557 . OpenUrl PubMed 50. Lee , J.E. , et al. , A Modified MCT-Based Ketogenic Diet Increases Plasma beta-Hydroxybutyrate but Has Less Effect on Fatigue and Quality of Life in People with Multiple Sclerosis Compared to a Modified Paleolithic Diet: A Waitlist-Controlled, Randomized Pilot Study . J Am Coll Nutr , 2021 . 40 ( 1 ): p. 13 – 25 . OpenUrl CrossRef PubMed 51. Mutoh , T. , et al. , Impact of medium-chain triglycerides on gait performance and brain metabolic network in healthy older adults: a double-blind, randomized controlled study . Geroscience , 2022 . 44 ( 3 ): p. 1325 – 1338 . OpenUrl PubMed 52. Ohnuma , T. , et al. , Benefits of use, and tolerance of, medium-chain triglyceride medical food in the management of Japanese patients with Alzheimer’s disease: a prospective, open-label pilot study . Clin Interv Aging , 2016 . 11 : p. 29 – 36 . OpenUrl PubMed 53. O’Neill , B.V. , et al. , The effects of GSK2981710, a medium-chain triglyceride, on cognitive function in healthy older participants: A randomised, placebo-controlled study . Hum Psychopharmacol , 2019 . 34 ( 3 ): p. e2694 . OpenUrl PubMed 54. Ota , M. , et al. , Effect of a ketogenic meal on cognitive function in elderly adults: potential for cognitive enhancement . Psychopharmacology (Berl ), 2016 . 233 ( 21-22 ): p. 3797 – 3802 . OpenUrl 55. Prins , P.J. , et al. , Effects of an Exogenous Ketone Supplement on Five-Kilometer Running Performance . Journal of human kinetics , 2020 . 72 : p. 115 – 127 . OpenUrl PubMed 56. Quinones , M.D. and P.W.R. Lemon , Ketone Ester Supplementation Improves Some Aspects of Cognitive Function during a Simulated Soccer Match after Induced Mental Fatigue . Nutrients , 2022 . 14 ( 20 ). 57. Rebello , C.J. , et al. , Pilot feasibility and safety study examining the effect of medium chain triglyceride supplementation in subjects with mild cognitive impairment: A randomized controlled trial . BBA Clin , 2015 . 3 : p. 123 – 5 . OpenUrl PubMed 58. Reger , M.A. , et al. , Effects of beta-hydroxybutyrate on cognition in memory-impaired adults . Neurobiology of Aging , 2003 . 25 ( 3 ): p. 311 – 314 . OpenUrl 59. Roy , M. , et al. , A ketogenic intervention improves dorsal attention network functional and structural connectivity in mild cognitive impairment . Neurobiol Aging , 2022 . 115 : p. 77 – 87 . OpenUrl PubMed 60. Veneman , T. , et al. , Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans . Diabetes , 1994 . 43 ( 11 ): p. 1311 – 7 . OpenUrl Abstract / FREE Full Text 61. Waldman , H.S. , et al. , Exogenous ketone salts do not improve cognitive responses after a high-intensity exercise protocol in healthy college-aged males . Applied Physiology, Nutrition, and Metabolism , 2018 . 43 ( 7 ): p. 711 – 717 . OpenUrl 62. Waldman , H.S. , et al. , Exogenous Ketone Salts Do Not Improve Cognitive Performance During a Dual-Stress Challenge . Int J Sport Nutr Exerc Metab , 2020 . 30 ( 2 ): p. 120 – 127 . OpenUrl PubMed 63. Yomogida , Y. , et al. , An fMRI Investigation into the Effects of Ketogenic Medium-Chain Triglycerides on Cognitive Function in Elderly Adults: A Pilot Study . Nutrients , 2021 . 13 ( 7 ). View the discussion thread. Back to top Previous Next Posted September 18, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following 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 Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share 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 Bruno Bonnechère , Elizabeth B. Stephens , Amy C. Boileau , Martin Ducker , Brianna J. Stubbs medRxiv 2025.09.17.25335999; doi: https://doi.org/10.1101/2025.09.17.25335999 Share This Article: Copy Citation Tools 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 Bruno Bonnechère , Elizabeth B. Stephens , Amy C. Boileau , Martin Ducker , Brianna J. Stubbs medRxiv 2025.09.17.25335999; doi: https://doi.org/10.1101/2025.09.17.25335999 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Nutrition Subject Areas All Articles Addiction Medicine (568) Allergy and Immunology (863) Anesthesia (299) Cardiovascular Medicine (4425) Dentistry and Oral Medicine (443) Dermatology (382) Emergency Medicine (607) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1507) Epidemiology (15222) Forensic Medicine (30) Gastroenterology (1123) Genetic and Genomic Medicine (6589) Geriatric Medicine (667) Health Economics (997) Health Informatics (4525) Health Policy (1368) Health Systems and Quality Improvement (1612) Hematology (540) HIV/AIDS (1264) Infectious Diseases (except HIV/AIDS) (15910) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (145) Nephrology (667) Neurology (6588) Nursing (346) Nutrition (998) Obstetrics and Gynecology (1143) Occupational and Environmental Health (956) Oncology (3331) Ophthalmology (971) Orthopedics (369) Otolaryngology (420) Pain Medicine (435) Palliative Medicine (129) Pathology (663) Pediatrics (1690) Pharmacology and Therapeutics (691) Primary Care Research (710) Psychiatry and Clinical Psychology (5440) Public and Global Health (9221) Radiology and Imaging (2195) Rehabilitation Medicine and Physical Therapy (1369) Respiratory Medicine (1196) Rheumatology (593) Sexual and Reproductive Health (710) Sports Medicine (529) Surgery (711) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'9ffe8f1cd8730db4',t:'MTc3OTQ4MTYxOQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();