Volume 30, Issue 167, January 2026

The impact of chronic oxidative stress on the development of Alzheimer's disease

Agnieszka Kowalska^1♦, Milena Kędzierska¹, Michał Biernacki¹, Justyna Gręda², Michał Wójcicki¹

¹Collegium Medicum at Jan Kochanowski University in Kielce, Poland
²St. Alexander Hospital in Kielce, Poland

^♦Corresponding author
Agnieszka Kowalska, ul. Jana Chryzostoma Paska 10/30, 25-108 Kielce, Poland

ABSTRACT

Imbalanced redox homeostasis, known as oxidative stress (OS), underpins the pathology of Alzheimer's disease (AD). Because of their high oxygen consumption and postmitotic state, neurons are exceptionally prone to injury by reactive oxygen species (ROS). This review aims to analyze the evidence for the role of oxidative stress in the development of AD, from its molecular basis to clinical implications. A review of the literature (including PubMed over the last 13 years) indicates that mitochondrial dysfunction, the principal source of ROS in the cell, is a central and early phenomenon that may even precede classic Aβ pathology. The stress generated enters a vicious cycle with the Aβ peptide; Aβ itself (especially in complexes with metals) can generate ROS, which in turn intensifies its aggregation. OS also promotes tau hyperphosphorylation, leading to the formation of NFTs. The effects of this cascade are multi-level: from lipid peroxidation and membrane damage (e.g., by HNE), through protein oxidation resulting in an energy crisis, to nucleic acid damage, with particular sensitivity of mtDNA. The result is a breakdown of calcium homeostasis and excitotoxicity, leading to neuronal death. Despite such a strong theoretical basis, translating this knowledge into effective clinical interventions has proven problematic. Clinical trials using antioxidants (vitamins E and C, CoQ10) have failed to show any effect on cerebrospinal fluid biomarkers or on slowing disease progression. The potential of polyphenols (e.g., curcumin, EGCG), although strong in vitro, is drastically limited by their negligible bioavailability.

Keywords: oxidative stress, Alzheimer’s disease, neurodegeneration, reactive oxygen species (ROS), mitochondrial dysfunction

Medical Science, 2026, 30, e1ms3756

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Published: 03 January 2026