Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial
Artikel i vetenskaplig tidskrift, 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
Författare
Burak Yulug
Alanya Alaaddin Keykubat University
Ozlem Altay
Kungliga Tekniska Högskolan (KTH)
Xiangyu Li
Kungliga Tekniska Högskolan (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
Kungliga Tekniska Högskolan (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 Üniversitesi
Ismail Bolat
Atatürk Üniversitesi
Sena Oner
Erzurum Teknik Üniversitesi
Özlem Özdemir Tozlu
Erzurum Teknik Üniversitesi
Mehmet Enes Arslan
Erzurum Teknik Üniversitesi
Ahmet Hacımuftuoglu
Atatürk Üniversitesi
Serkan Yıldırım
Atatürk Üniversitesi
Muhammad Arif
Kungliga Tekniska Högskolan (KTH)
Saeed Shoaie
Kungliga Tekniska Högskolan (KTH)
King's College London
C. Zhang
Zhengzhou University
Kungliga Tekniska Högskolan (KTH)
Jens B Nielsen
Chalmers, Life sciences, Systembiologi
Hasan Turkez
Atatürk Üniversitesi
Jan Borén
Göteborgs universitet
Mathias Uhlen
Kungliga Tekniska Högskolan (KTH)
Adil Mardinoglu
King's College London
Kungliga Tekniska Högskolan (KTH)
Translational Neurodegeneration
2047-9158 (eISSN)
Vol. 12 1 4Ämneskategorier
Neurologi
DOI
10.1186/s40035-023-00336-2
PubMed
36703196