Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial
Journal article, 2023
Background: Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Methods: Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function 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. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. Results: We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Conclusion: Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131.
Combined metabolic activators
Systems medicine
Alzheimer’s disease
Multi-omics
Systems biology
Author
Burak Yulug
Alanya Alaaddin Keykubat University
Ozlem Altay
Royal Institute of Technology (KTH)
Xiangyu Li
Royal Institute of Technology (KTH)
Lutfu Hanoglu
Istanbul Medipol Universitesi
Seyda Cankaya
Alanya Alaaddin Keykubat University
Simon Lam
King's College London
Halil Aziz Velioglu
Istanbul Medipol Universitesi
Karolinska Institutet
Hong Yang
Royal Institute of Technology (KTH)
Ebru Coskun
Istanbul Medipol Universitesi
Ezgi Idil
Alanya Alaaddin Keykubat University
Rahim Nogaylar
Alanya Alaaddin Keykubat University
Ahmet Ozsimsek
Alanya Alaaddin Keykubat University
Cemil Bayram
Atatürk University
Ismail Bolat
Atatürk University
Sena Oner
Erzurum Technical University
Özlem Özdemir Tozlu
Erzurum Technical University
Mehmet Enes Arslan
Erzurum Technical University
Ahmet Hacımuftuoglu
Atatürk University
Serkan Yıldırım
Atatürk University
Muhammad Arif
Royal Institute of Technology (KTH)
Saeed Shoaie
Royal Institute of Technology (KTH)
King's College London
C. Zhang
Zhengzhou University
Royal Institute of Technology (KTH)
Jens B Nielsen
Chalmers, Life Sciences, Systems and Synthetic Biology
Hasan Turkez
Atatürk University
Jan Borén
University of Gothenburg
Mathias Uhlen
Royal Institute of Technology (KTH)
Adil Mardinoglu
King's College London
Royal Institute of Technology (KTH)
Translational Neurodegeneration
2047-9158 (eISSN)
Vol. 12 1 4Subject Categories
Neurology
DOI
10.1186/s40035-023-00336-2
PubMed
36703196