The Dose and Duration-dependent Association between Melatonin Treatment and Overall Cognition in Alzheimer’s Dementia: A Network Meta- Analysis of Randomized Placebo-Controlled Trials

Abstract

Background: While Alzheimer’s dementia (AD) has a prevalence as high as 3-32% and is associated with cognitive dysfunction and the risk of institutionalization, no efficacious and acceptable treatments can modify the course of cognitive decline in AD. Potential benefits of exogenous melatonin on cognition have been divergent across trials. Objective: The current network meta-analysis (NMA) was conducted under frequentist model to evaluate the potential benefits of exogenous melatonin supplementation on overall cognitive function in participants with AD in comparison with other FDA-approved medications (donepezil, galantamine, rivastigmine, memantine, and Namzaric). Methods: The primary outcome was the changes of the cognitive function [measured by mini-mental state examination (MMSE)] after treatment in patients with Alzheimer’s dementia. The secondary outcomes were change in the quality of life, behavioral disturbance, and acceptability (i.e. drop-out due to any reason and rate of any adverse event reported). Results: The current NMA of 50 randomized placebo-controlled trials (RCTs) revealed that the medium-term low-dose melatonin was associated with the highest post-treatment MMSE (mean difference = 1.48 in MMSE score, 95% confidence intervals [95% CIs] = 0.51 to 2.46) and quality of life (standardized mean difference = -0.64, 95% CIs = -1.13 to -0.15) among all of the investigated medications in the participants with AD. Finally, all of the investigated exogenous melatonin supplements were associated with similar acceptability as was the placebo. Conclusions: The current NMA provides evidence for the potential benefits of exogenous melatonin supplementation, especially medium-term low-dose melatonin, in participants with AD.

Why do anti-amyloid beta antibodies not work? Time to reconceptualize dementia pathophysiology by incorporating astrocyte melatonergic pathway desynchronization from amyloid-beta production

“…Given that melatonin treatment in human dementia and animal models shows benefits, 7 it is surprising that its local production in the central nervous system has not been clinically investigated. Notably, exogenous melatonin induces the mitochondrial melatonergic pathway, partly via Bmal1, SIRT1, and SIRT3 induction, 8 thereby disinhibiting the pyruvate dehydrogenase complex and the conversion of pyruvate to acetyl-CoA, which is required as an AANAT co-substrate to initiate the melatonergic pathway ( Figure 1 ).…”

Mapping new pharmacological interventions for cognitive function in Alzheimer’s disease: a systematic review of randomized clinical trials

“…Given that pharmacology and nutrition have some points in common, we will also discuss some data we have found regarding the relationship between nutrition and AD. Various nutrients and nutraceuticals have been linked to improvements in cognition and other psychological aspects related to AD ( Guzman-Martinez et al, 2021 ; Abduljawad et al, 2022 ; Mahnashi et al, 2022 ; Xu Lou et al, 2023 ) Some examples include Gingko Biloba ( Liao et al, 2020 ), Melissa Officinalis ( Noguchi-Shinohara et al, 2020 ; Noguchi-Shinohara et al, 2022 ), Ginseng ( Ahmad et al, 2023 ), anti-inflammatory fatty acids ( Albrahim, 2020 ), medium-chain fatty acids ( Juby et al, 2022 ), ketone bodies ( Avgerinos et al, 2020a ), saffron ( Avgerinos et al, 2020b ; Talebi et al, 2021 ), fenugreek seed ( Foroumandi et al, 2023 ), genistein ( Viña et al, 2022 ), sodium oligomannate ( Xiao et al, 2021 ), anthocyanin ( Suresh et al, 2022 ), microbiota and probiotics ( Den et al, 2020 ; Maitre et al, 2021 ; Liu et al, 2022 ; Naomi et al, 2022 ), benfotiamine ( Gibson et al, 2020 ), omega-3 fatty acids ( Canhada et al, 2018 ; Jernerén et al, 2019 ), resveratrol ( Gu et al, 2021 ; Buglio et al, 2022 ; Fang et al, 2022 ; Tosatti et al, 2022 ), melatonin ( Tseng et al, 2022 ), citicoline ( Bonvicini et al, 2023 ), folic acid, vitamin B12 ( Chen et al, 2021 ), vitamins and minerals ( Mccleery et al, 2018 ; Karthika et al, 2022 ), selenium ( Pereira et al, 2022 ), vitamin D ( Jia et al, 2019 ), and mangosteen ( Muangpaisan et al, 2022 ). However, some studies do not support the efficacy of certain nutrients ( Zhu et al, 2018 ; Thancharoen et al, 2019 ; Araya-Quintanilla et al, 2020 ; Burckhardt et al, 2020 ; Du et al, 2020 ; Prabhakar et al, 2020 ; Shim et al, 2021 ; Tofiq et al, 2021 ; Takada et al, 2022 ).…”

The Vital Role of Melatonin and Its Metabolites in the Neuroprotection and Retardation of Brain Aging

“…Numerous experimental studies and clinical trials confirm the therapeutic neuroprotective potential of melatonin and its derivatives. They exert powerful neuroprotection through myriad of different mechanisms, allowing for the prevention of neurodegeneration and/or cognitive improvement, along with sleep maintenance [153][154][155][156][157][158]. Studies have demonstrated that melatonin inhibits the nuclear translocation of NF-κBp65 and the activation of glycogen synthase kinase (GSK)-3β, through melatonin receptor activation in Aβ1-42-treated SH-SY5Y neuroblastoma cells [159].…”