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

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.