Does Managing Oxidative Stress Hold the Key to Effectively Treating Alzheimer’s Disease

21 May 2024


Supplement to the Journal of Alzheimer’s Disease highlights oxidative stress-based research into potential therapeutic targets and protective drugs for managing Alzheimer’s disease

Amsterdam – The number of people suffering from Alzheimer’s disease (AD) is expected to reach 100 million by 2050, but there is still no effective therapy. Leading researchers from around the world assess how oxidative stress (OS) may trigger AD and consider potential therapeutic targets and neuroprotective drugs to manage the disease in a collection of articles in a special supplement to the Journal of Alzheimer’s Disease, published by IOS Press.

AD is the most common type of dementia and involves areas of the brain that control thought, memory, and language. It is the most common cause of disability in individuals over 65 years of age and is one of the top 10 leading causes of death in the United States. AD is characterized by the abnormal deposition of amyloid beta peptide and intracellular accumulation of neurofibrillary tangles of hyperphosphorylated tau protein. The diagnosis of AD has recently improved, but its exact cause has not yet been identified. The major challenges are to look beyond the two dominant hypotheses, amyloid beta deposition and tau phosphorylation.

There may be other factors responsible for triggering the disease. Are they triggered by OS, a process referring to an imbalance between antioxidants and oxidants? The OS hypothesis suggests that the brain remains multifunctional as long as “free radicals” produced during various biochemical reactions in the brain are neutralized by antioxidants.

Guest Editor of the supplement Pravat K. Mandal, PhD, Scientist and former Director-in-Charge of the National Brain Research Center, Gurgaon, India, and Honorary Professor, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia, explains: “The OS hypothesis was initiated more than quarter century ago. Recently researchers have shown renewed interest in investigating the potential benefits of OS neutralization, which had led to the design of numerous trials to examine its effects. As long as there is a balance between the pro-oxidative molecules and antioxidants to neutralize radicals, the brain remains multifunctional and healthy. While there are several of these antioxidants, a prominent one receiving significant attention is glutathione (GSH).”

Analysis based on clinical studies indicates that significant brain GSH depletion in the hippocampus initiates early onset of AD prior to amyloid beta deposition and tau phosphorylation, which is now validated by transgenic animal model study.

The 12 reviews and research articles in this supplement highlight OS-based AD research from several internationally renowned laboratories. Pioneering studies highlight:

  • Reduced risk of developing AD is associated with dietary intake of antioxidant supplements.
  • Supplementation with GSH, made from the amino acids glycine, cysteine, and glutamic acid, may be neuroprotective and reduce amyloid beta or tau phosphorylation.
  • Significant improvement of working memory in animal models with induced dementia due to Marrubium vulgare extract suggests that it may impact memory preservation.
  • Maintaining diversity in drug development for AD research is important for enhancing the flow of information from randomized clinical trials.

“Accumulating evidence from clinical studies leads us to the converging idea that enrichment of brain GSH is the way forward through candidates with superior bioavailability and efficacy,” notes Dr. Mandal.

One contribution explores the neuroprotective effect of combined treatment with epigallocatechin 3-gallate (EGCG) and melatonin (MT) on familial AD. Investigators analyzed the therapeutic potential of a combination of EGCG and MT in a three-dimensional in vitro model of rare familial AD with a mutation in the presenilin-1 gene. The combination of EGCG and MT treatment effectively reduced these pathological markers more efficiently than individual treatments.

Co-lead investigators Marlene Jimenez-Del-Rio, PhD, and Carlos Velez-Pardo, DrSci, both from the Neuroscience Research Group, Medical Research Institute, Faculty of Medicine, University of Antioquia, SIU, Medellin, Colombia, report, “Treatment with a combination of EGCG and MT can be of high therapeutic value due to the high antioxidant capacity and anti-amyloidogenic effect of both compounds compared to individual treatments and deserves further investigation.” Dr. Mandal adds: “Combined therapy of EGCG and MT holds a therapeutic promise for familial AD due to inherent antioxidant capability.”

Other important topics covered in this issue include:

  • Molecular aspects of aging and age-related disorders
  • Potential therapeutic effects of long-term administration of Tocovid, a novel vitamin E mixture
  • Protective effects of coenzyme Q10 and high-intensity interval training, both individually and in combination
  • Efficacy of docosapentaenoic acid and/or eicosapentaenoic acid supplements in patients with mild cognitive impairment
  • Protective functions of the thioredoxin system and nicotinamide adenine dinucleotide phosphate in the context of AD-induced damage
  • Potential strategies to address early events in AD involving microvascular deterioration in the hippocampus that precedes Aβ deposition
  • Antioxidative and anti-neuroinflammatory effects of Centella asiatica and its triterpene fractions on lipopolysaccharide-induced microglial cells for AD management
  • A computational system pharmacology workflow to uncover the OS triggering AD as well as the potential therapeutic targets and neuroprotective drugs

“I anticipate that the OS hypothesis will gain its rightful recognition sooner in AD research to guide drug development tbat will effectively reduce OS and preserve cognitive function,” concludes Dr. Mandal.

“The discovery of OS as upstream to amyloid beta and tau deposition places it at the crossroads of effective therapeutic intervention. Dr. Mandal’s issue explores the state of the science and inspires further development,” adds George Perry, PhD, Semmes Foundation Distinguished University Chair in Neurobiology, The University of Texas at San Antonio, and Editor-in-Chief of JAD.

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George Perry, PhD
Editor-in-Chief, Journal of Alzheimer's Disease
The University of Texas at San Antonio
+1 210-458-8660

Diana Murray
IOS Press
+1 718-640-5678

The supplement is Pro-Oxidants and Antioxidants in Alzheimer’s Disease
Volume 99, Supplement 1 of the Journal of Alzheimer’s Disease at

Guest Editor
Pravat K. Mandal, PhD, Scientist and former Director-in-Charge of National Brain Research Center, Gurgaon, India; Adjunct Professor, Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; and Honorary Professor, Florey Institute of Neuroscience and Mental Health, Melbourne, Australia

The featured article is "Neuroprotective Effect of Combined Treatment with Epigallocatechin 3-Gallate and Melatonin on Familial Alzheimer’s Disease PSEN1 E280A Cerebral Spheroids Derived from Menstrual Mesenchymal Stromal Cells,” by Viviana Soto-Mercado, Miguel Mendivil-Perez, Carlos Velez-Pardo, and Marlene Jimenez-Del-Rio ( It is openly available at

For further information contact Diana Murray, IOS Press, at +1 718-640-5678 or Journalists wishing to interview Guest Editor Pravat K. Mandal, PhD, or authors should contact

The Journal of Alzheimer's Disease (JAD) is an international multidisciplinary journal to facilitate progress in understanding the etiology, pathogenesis, epidemiology, genetics, behavior, treatment, and psychology of Alzheimer's disease. The journal publishes research reports, reviews, short communications, book reviews, and letters-to-the-editor. Groundbreaking research that has appeared in the journal includes novel therapeutic targets, mechanisms of disease, and clinical trial outcomes. JAD has a Journal Impact Factor of 4.0 according to Journal Citation Reports™ (Clarivate, 2023).

IOS Press, now part of Sage, is an international scientific, technical, medical (STM) publishing house established in 1987 in Amsterdam. We produce around 90 journals and 70 books annually in a broad range of subject categories, primarily specializing in health and life sciences (including neurosciences, medical informatics, cancer research, and rehabilitation) and computer sciences (including artificial intelligence, data science, and semantic web). In addition, we offer specialized services that support scientific advancement.

Sage is a global academic publisher of books, journals, and library resources with a growing range of technologies to enable discovery, access, and engagement. Believing that research and education are critical in shaping society, 24-year-old Sara Miller McCune founded Sage in 1965. Today, we are controlled by a group of trustees charged with maintaining our independence and mission indefinitely.