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 4

Subject Categories

Neurology

DOI

10.1186/s40035-023-00336-2

PubMed

36703196

More information

Latest update

2/8/2023 1