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Cited by 66Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease: Insights into Pathophysiology and Treatment

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Alkhalifa, Amer E., Alkhalifa, Oula, Durdanovic, Iva, Ibrahim, Dalia R., Maragkou, Sofia·2025·Journal of Dementia and Alzheimer's Disease
DOI 10.3390/jdad2020017
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Abstract

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Increasing evidence highlights oxidative stress as a pivotal contributor to AD pathogenesis, closely associated with hallmark features such as amyloid-β (Aβ) plaque accumulation, tau hyperphosphorylation, and synaptic dysfunction. This review aims to elucidate the mechanisms by which oxidative stress contributes to AD and to evaluate emerging therapeutic strategies targeting oxidative damage. Methods: We conducted an extensive literature search using PubMed and Google Scholar for studies published between 1994 and 2024. This narrative review integrates findings from in vitro, in vivo, and clinical studies focusing on oxidative stress, mitochondrial dysfunction, and their roles in AD to provide a comprehensive overview of the current research landscape. Results: ROS and RNS levels are significantly elevated in aging and AD-affected brains, leading to oxidative damage to lipids, proteins, and DNA, which compromises neuronal function and structure. Mitochondrial dysfunction plays a key role by amplifying ROS production, impairing ATP synthesis, and accelerating neurodegeneration. Oxidative stress also interacts with central AD pathologies, including Aβ aggregation, tau hyperphosphorylation, and synaptic dysfunction, creating a vicious cycle of neuronal injury. Although traditional antioxidant therapies have shown limited efficacy in clinical settings, often due to poor bioavailability, limited BBB penetration, and systemic distribution, novel strategies such as mitochondrial-targeted antioxidants and combination therapies have demonstrated improved outcomes in preclinical models. Conclusions: Oxidative stress plays a multifaceted role in the progression of AD, necessitating comprehensive therapeutic approaches. Future treatments should focus on targeting multiple aspects of oxidative stress, particularly mitochondrial dysfunction, to enhance clinical outcomes and slow neurodegeneration in AD patients.

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Cited by

Sorted by citations

Authors
Alkhalifa, A. E., Alkhalifa, O., Durdanovic, I., Ibrahim, D. R., & Maragkou, S.
Affiliations
  • Auburn University (US)
  • Adana Science and Technology University (TR)
  • Saarland University (DE)
Corresponding author
Alkhalifa, Amer E.
ORCID
Venue
Journal of Dementia and Alzheimer's Disease
Publisher
MDPI AG
Published
2025-06-03
Volume
2
Issue
2
Pages
17
ISSN
3042-4518 (ISSN-L)
DOI
10.3390/jdad2020017
OpenAlex
W4411001180
Cited by
66
References
20
Citations by year
2026: 45 · 2025: 21
FWCI
41.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of dementia and Alzheimer's disease (publishedVersion, cc-by)
  • Preprints.org (acceptedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, oxidative stress, mitochondrial dysfunction, reactive oxygen species, reactive nitrogen species, amyloid plaques, tau hyperphosphorylation, synaptic dysfunction, neurodegeneration, antioxidant therapy, mitochondria-targeted antioxidants, blood-brain barrier, combination therapy

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