Acute effects of lactate infusion on metabolism, AD biomarkers, and cognition: The LEAN study

BACKGROUND Impaired cerebral glucose metabolism is a hallmark of Alzheimer's disease (AD). Lactate is an alternative brain fuel; however, whole‐body lactate metabolism has not been measured in AD. METHODS The Lactate for Energy and Neurocognition Trial (NCT05207397) was a single‐arm trial that enrolled 24 cognitively healthy (CH) older adults and 12 cognitively impaired (CI) participants. Subjects underwent a stable isotope lactate infusion to evaluate lactate metabolism, cognitive testing, and blood biomarker analyses. pTau217, brain‐derived tau (BD‐tau), pTau181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), total tau, and brain‐derived neurotrophic factor (BDNF) were analyzed by Simoa HD‐X (Quanterix). RESULTS Lactate metabolic clearance rate did not differ between CH and CI subjects ( p = 0.988). After infusion, global cognition was improved ( p < 0.001) and plasma pTau217 (−33.8%, p < 0.001), BD‐tau (−32.6%, p < 0.001), pTau181 (−21.4%, p < 0.001), GFAP (−39.7%, p < 0.001), and NfL (−19.5%, p < 0.001) were reduced. CONCLUSIONS Lactate turnover was not different between diagnosis groups. Lactate infusion improved cognition and reduced AD fluid biomarkers. Highlights Individuals with Alzheimer's disease (AD) can metabolize lactate as well as healthy controls. Lactate infusion might improve global cognition and processing speed. Lactate infusion results in significant decrease of AD fluid biomarkers.