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Understanding the role of oxidative stress in the pathogenesis of Alzheimer's disease
Last reviewed: 02.07.2025
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The number of people suffering from Alzheimer's disease (AD) could reach 100 million by 2050, yet there is still no effective treatment for the disease. Leading researchers from around the world have assessed how oxidative stress (OS) may cause AD and reviewed potential therapeutic targets and neuroprotective drugs to combat the disease in a collection of articles in a special issue of the Journal of Alzheimer's Disease, published by IOS Press.
Characteristics of Alzheimer's disease
Alzheimer’s disease is the most common form of dementia, affecting areas of the brain responsible for thinking, memory, and language. It is the leading cause of disability in people over age 65 and is among the top 10 causes of death in the United States. AD is characterized by abnormal deposition of amyloid beta peptide and intracellular accumulation of neurofibrillary tangles of hyperphosphorylated tau protein. Although diagnosis of AD has improved significantly, the exact cause of the disease remains unknown. Key challenges include investigating factors beyond the two dominant hypotheses of amyloid beta deposition and tau phosphorylation.
Oxidative stress hypothesis
There is some speculation that other factors may be involved in the disease, and one of these is OS, a process associated with an imbalance between antioxidants and oxidants. The OS hypothesis suggests that the brain remains multifunctional as long as the "free radicals" produced by various biochemical reactions in the brain are neutralized by antioxidants.
Special issue editor Pravat K. Mandal, PhD, a scientist and former director of the National Brain Research Centre in Gurgaon, India, and an emeritus professor at the Florey Institute of Neuroscience and Mental Health in Melbourne, Australia, explains: “The OS hypothesis was put forward more than a quarter of a century ago. Recently, researchers have shown renewed interest in exploring the potential benefits of OS neutralisation, leading to the design of numerous studies to test its effects. As long as there is a balance between pro-oxidant molecules and antioxidants, the brain remains multifunctional and healthy. Although there are several such antioxidants, glutathione (GSH) has received considerable attention.”
Analysis of clinical studies shows that significant reduction in hippocampal GSH levels causes early onset of AD before amyloid beta deposition and tau protein phosphorylation, which is supported by studies in transgenic animal models.
Main results and research prospects
The special issue features 12 reviews and research articles on OS and AD research from several internationally recognized laboratories. Key findings include:
- A reduction in the risk of developing asthma is associated with dietary intake of antioxidant supplements.
- Supplementation with GSH, which consists of the amino acids glycine, cysteine, and glutamic acid, may be neuroprotective and reduce amyloid beta deposition or tau protein phosphorylation.
- Significant improvement in working memory in animal models of induced dementia with Marrubium vulgare extract suggests its effects on memory retention.
- Maintaining diversity in drug development for AD research is important to improve the flow of information from randomized clinical trials.
Combination therapy
One study is investigating the neuroprotective effect of combination treatment with epigallocatechin 3-gallate (EGCG) and melatonin (MT) in familial AD. In a three-dimensional in vitro model of a rare familial form of AD with a mutation in the presenilin-1 gene, the combination of EGCG and MT was more effective in reducing pathological markers compared to individual treatments.
Conclusion
Dr. Mandal emphasizes that the OS hypothesis in AD research deserves recognition, which may guide drug development to effectively reduce OS and preserve cognitive function. The discovery of OS as a precursor to amyloid beta and tau deposition places it at the center of effective therapeutic interventions, which is being explored in this topic.