Combined Metabolic Activators Improves Cognitive Functions in Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. Here, we analysed the brain transcriptomics data of more than 600 AD patients using genome-scale metabolic models and provided supporting evidence of mitochondrial dysfunction related to the pathophysiologic mechanisms of AD progression. Subsequently, we investigated, in a rat model of AD, the oral administration of Combined Metabolic Activators (CMA), consisting of NAD+ and glutathione precursors, to explore the effect for improvement of biological functions in AD. CMA includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate, salt form of L-carnitine. The study revealed that supplementation of the CMA improved the AD-associated histological parameters in the animals. Finally, we designed a randomized, double-blinded, placebo-controlled human phase 2 clinical trial and showed that the administration of CMA improves cognitive functions in AD patients. As decreased AD Assessment Scale-cognitive subscale (ADAS-Cog) score is the indicator of the improved cognitive function in AD patients, we observed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (Log2FC= -0.37, (29% improvement), p-value=0.00001) in the CMA group. We also observed a significant decrease in the placebo group on Day 84 vs Day 0 (Log2FC= -0.19, (14% improvement), p-value=0.001) possibly due to the recommendations of exercise and Mediterranean diet to all AD patients and/or a placebo effect apparent in the early stages of AD clinical trials. A comprehensive analysis of the human plasma metabolome and proteome revealed that plasma levels of proteins and metabolites associated with redox metabolism are significantly improved after treatment. In conclusion, our results show that treating AD patients with CMA leads to enhanced cognitive functions, suggesting a role for such a therapeutic regime in treating AD and other neurodegenerative diseases. Funding: This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation. The authors would like to thank the Metabolon Inc. (Durham, USA) for generation of metabolomics data, and ChromaDex Inc. (Irvine, CA, USA) for providing NR. AM and HY acknowledge support from the PoLiMeR Innovative Training Network (Marie Sklodowska-Curie Grant Agreement No. 812616) which has received funding from the European Union’s Horizon 2020 research and innovation programme. Declaration of Interest: AM, JB and MU are the founder and shareholders of ScandiBio Therapeutics. The other authors declare no competing interests. Ethical Approval: All experiments for the treatment of the animals were approved by the Ethics Committee of Ataturk University, and were conducted following the National Institutes of Health Guide for Care and Use of Laboratory Animals.