Combined Metabolic Activators Improve Cognitive Functions in Alzheimer’s Disease Patients: A Randomised, Double-Blinded, Placebo-Controlled Phase-II Trial

Abstract

Background Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administrated Combined Metabolic Activators (CMA) to the AD rat model and observed that administration of CMA activated the mitochondrial functions and eventually improved the AD-associated histological parameters in the animals. CMA consists of NAD + and glutathione precursors and includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate. Methods Here, we designed a randomised, double-blinded, placebo-controlled phase-II trial and studied the effect of CMA administration on the global metabolism of AD patients. The primary endpoint was on the difference in cognitive and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. We also performed a comprehensive human plasma metabolome and proteome analysis. Results Based on our analysis, we showed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (p = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant enhancement (p = 0.0073) in ADAS-Cog scores between CMA and placebo groups in patients with higher ADAS-Cog scores. Improved cognitive functions were endorsed with relevant hippocampal volumes and cortical thickness alterations. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism are significantly improved after treatment. Conclusion In conclusion, our results show that treating AD patients with CMA leads to enhanced cognitive functions associated with the improved metabolome, proteome and structural neuroimaging parameters, suggesting a role for such a therapeutic regimen in treating patients, especially with severe AD. Trial registration: ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131

Deciphering Fracture Risk: A Comprehensive Analysis of Blood Metabolites via Mendelian Randomization.

“…This compound has been found as a potential indicator of endurance readiness in racehorses, with elevated levels observed in horses post-race [32] , suggesting a signi cant role in muscle endurance and energy metabolism. In Alzheimer's Disease (AD) treatment, Yulug et al [33] found a signi cant decrease in 2R,3R-dihydroxybutyrate levels in AD patients treated with Combined Metabolic Activators (CMAs), correlating signi cantly with levels of carnitine and serine. This implies a role in metabolic regulation in neurodegenerative diseases.…”