Combined Metabolic Activators Improves Cognitive Functions in Alzheimer's Disease

YULUG, B.; ALTAY, O.; LI, X.; HANOGLU, L.; CANKAYA, S.; LAM, S.; YANG, H.; COSKUN, E.; IDIL, E.; NOGAYLAR, R.; BAYRAM, C.; BOLAT, I.; ONER, S.; TOZLU, O. O.; ARSLAN, M. E.; HACIMUFTUOGLU, A.; YILDIRIM, S.; ARIF, M.; ZHANG, C.; NIELSEN, J.; TURKEZ, H.; BOREN, J.; UHLEN, M.; MARDINOGLU, A.

Alzheimer's disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. Here, we analyzed 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 an animal model of AD, the oral administration of Combined Metabolic Activators (CMAs), consisting of NAD+ and glutathione precursors, to explore the effect for improvement of biological functions in AD. CMAs 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 CMAs improved the AD-associated histological parameters in the animals. Finally, we designed a randomized, double-blinded, placebo-controlled human phase 2 study and showed that the administration of CMAs improves cognitive functions in AD patients. 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 metabolic activators leads to enhanced cognitive functions, suggesting a role for such a therapeutic regime in treating AD and other neurodegenerative diseases.