The effect of exogenous ketone monoester supplementation on cerebral blood flow and functional brain characteristics in adults with subjective cognitive decline: study protocol for a randomized crossover trial

There is an urgent need for interventions which reduce dementia risk in aging adults. People with subjective cognitive decline (SCD) have a greater risk of developing dementia compared to age-matched cognitively normal individuals. Impaired cerebral blood flow (CBF) and cerebral glucose hypometabolism are leading mechanisms underlying dementia that could be ideal interventional targets for this population. Recent research, including our own work, has shown that oral consumption of ketone monoesters (KME) can improve CBF and cerebral metabolism, which in turn can improve cognition. The purpose of this study is to investigate the hypothesis that a 14-day KME supplementation intervention in middle-to-older adults with SCD will increase CBF, brain functional connectivity, and cognitive performance in comparison to placebo. A total of 34 middle-to-older adults (50% female, aged 55-75) with SCD will be recruited for this randomized placebo-controlled crossover double-blind trial. Participants will complete study visits immediately before and after 14 days of thrice-daily supplementation with a KME or a placebo. Following a minimum 14-day washout period, participants will repeat the protocol to complete study visits immediately before and after 14 days of thrice-daily supplementation with the other intervention (KME or placebo). The outcome measures are as follows: (1) CBF, functional brain connectivity, and cerebrovascular function as measured by brain magnetic resonance imaging (MRI) scans, (2) cognitive function assessed via a battery of validated psychometric tests, and (3) blood-borne neurotrophic factors via venous blood sample collection. This novel study aims to advance our understanding of how KME could be an effective intervention to combat dementia risk factors and improve aspects of brain health in middle-to-older adults with SCD. ClinicalTrials.gov NCT06588946. Registered on 05 September 2024. [Abstract copyright: © 2026. The Author(s).]