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.

People with subjective cognitive decline (SCD) have a greater risk of developing dementia compared to age-matched cognitively normal individuals.

• SCD is identified as a population with elevated dementia risk.
• Impaired cerebral blood flow (CBF) and cerebral glucose hypometabolism are described as leading mechanisms underlying dementia.
• These mechanisms are identified as ideal interventional targets for the SCD population.

Oral consumption of ketone monoesters (KME) has been shown to improve cerebral blood flow and cerebral metabolism, which can in turn improve cognition.

• The authors cite 'recent research, including our own work' as evidence for KME effects on CBF and cerebral metabolism.
• Improved cognition is described as a downstream consequence of improved CBF and cerebral metabolism following KME consumption.
• This prior evidence forms the mechanistic rationale for the current trial.

The trial is designed to recruit 34 middle-to-older adults with SCD for a randomized placebo-controlled crossover double-blind trial.

• Participants will be 50% female, aged 55–75 years, with subjective cognitive decline.
• The crossover design requires each participant to complete both the KME and placebo conditions.
• A minimum 14-day washout period separates the two intervention periods.

The KME supplementation protocol involves thrice-daily dosing for 14 days, with study visits immediately before and after each 14-day supplementation period.

• Participants receive KME or placebo three times per day for 14 days.
• Study visits occur immediately before and after each 14-day intervention.
• The design is double-blind, meaning both participants and investigators are masked to treatment allocation.

The primary outcome measures include cerebral blood flow, functional brain connectivity, and cerebrovascular function assessed via brain MRI.

• Brain magnetic resonance imaging (MRI) scans are used to measure CBF, functional brain connectivity, and cerebrovascular function.
• Secondary outcomes include cognitive function assessed via a battery of validated psychometric tests.
• Additional secondary outcomes include blood-borne neurotrophic factors measured via venous blood sample collection.

The trial was registered on ClinicalTrials.gov under identifier NCT06588946, with registration dated 05 September 2024.

• The registration predates publication, consistent with prospective trial registration.
• The journal is Trials, which specializes in publishing study protocols.