Bioenergetic data from a creatine monohydrate pilot trial in Alzheimer's disease

Abstract BACKGROUND Creatine monohydrate (CrM) may mitigate bioenergetic failure in Alzheimer's disease (AD) by supporting ATP buffering and modulating mitochondrial function. Building upon our previous findings that CrM is associated with increased brain creatine (Cr) and improved cognition in AD, we investigated our hypothesis that CrM is associated with improved bioenergetic biomarkers in AD. METHODS In this single‐arm pilot featuring participants with AD ( n = 20, 35% female), we investigated changes in bioenergetic biomarkers after 8 weeks of CrM supplementation (20 g/day). We measured brain concentration of N‐acetylaspartate (NAA) and glutathione (GSH) using 1 H magnetic resonance spectroscopy. We measured platelet and lymphocyte mitochondrial respiration using Oroboros Oxygraph‐2K respirometry, lymphocyte adenosine diphosphate (ADP) and adenosine triphosphate (ATP) using a bioluminescent assay, and lymphocyte reactive oxygen species (ROS) with flow cytometry using Amplex Red and MitoSOX. We also investigated sex‐dependent bioenergetic responses. RESULTS Brain NAA and GSH did not change. In females only, both platelet and lymphocyte mitochondrial respiration increased ( p < 0.05; trends for others) across multiple respiration states (State 2, State 3, State 3S, Leak, and Maximum oxygen consumption rate). Lymphocyte ADP ( p < 0.02) and ATP ( p < 0.001) levels rose significantly in both sexes while ATP/ADP ratio, superoxide, and hydrogen peroxide remained stable. DISCUSSION These data suggest CrM may augment systemic energy availability in both sexes and mitochondrial capacity in a sex‐specific manner in AD. Interpretation of results from this pilot study is limited by lacking a control group, small sample size, and its relatively short timeframe. However, these preliminary findings support further investigation of CrM as a potential bioenergetic intervention in AD with well‐designed RCTs, including exploration of potential sex‐specific bioenergetic responses to CrM. Trial Registration ClinicalTrials.gov, NCT05383833, registered on May 20, 2022.