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Background: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. Methods: We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. Findings: Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. Interpretation: Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs. PoLiMeR Innovative Training Network ; SNIC ; ScandiBio Therapeutics ; ScandiBio Therapeutics and Knut ; Knut och Alice Wallenbergs Stiftelse

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

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

The neuropathologic hallmarks of Parkinson’s disease (PD) are associated with mitochondrial dysfunction and metabolic abnormalities. We have reported that the Combined Metabolic Activators (CMA), consisting of L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate can be used in treating metabolic abnormalities. These metabolic activators are the precursors of nicotinamide adenine dinucleotide (NAD+) and glutathione (GSH) and used in activation of mitochondrial and global metabolism. We have performed a placebo-controlled, phase-2 study in Alzheimer’s disease (AD) patients and reported that the cognitive functions in AD patients is significantly improved 29% in the CMA group whereas it is improved only 14% in the placebo group after 84 days of CMA administration. Here, we designed a randomized, double-blinded, placebo-controlled, phase-2 study in PD patients with CMA administration. We found that the cognitive functions in PD patients is significantly improved 21% in the CMA group, whereas it is improved only 11% in the placebo group after 84 days of CMA administration. We also found that the administration of CMA did not affect motor functions in PD patients. We performed a comprehensive multi-omics analysis of plasma proteins and metabolites, and revealed the molecular mechanism associated with the treatment of the patients. In conclusion, our results show that treating PD patients with CMAs leads to enhanced cognitive function, as recently reported in AD patients.

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.