Ferroptosis as a mechanism of neurodegeneration inAlzheimer’s disease Original paper

What was reviewed?

This paper reviewed the evidence that ferroptosis, an iron-driven form of regulated cell death marked by phospholipid lipid peroxidation, contributes to neurodegeneration in Alzheimer’s disease (AD). The authors synthesized mechanistic work on iron handling, membrane polyunsaturated fatty acid oxidation, and antioxidant defense systems, with an emphasis on glutathione peroxidase 4 (GPX4) as a key checkpoint, and then connected these pathways to clinical and neuropathology findings in AD.

Who was reviewed?

Rather than enrolling new participants, the review integrated findings from post-mortem human AD brain studies, biomarker and imaging studies that quantify brain iron burden (including MRI susceptibility approaches), and experimental models using neuronal and glial cell systems and transgenic animals that model amyloid and tau pathology. The clinical “who” therefore spans people with pathology-confirmed AD, individuals with mild cognitive impairment who progress to AD in some cited biomarker work, and matched controls used across the summarized studies.

What were the most important findings?

The review argues that multiple converging lines of data place iron dyshomeostasis and lipid peroxidation in the causal neighborhood of AD neurodegeneration, not merely as bystanders. Iron accumulation appears in vulnerable cortical and deep gray structures and associates with worse cognition and disease progression, consistent with the idea that higher iron increases susceptibility to ferroptotic stress. The authors emphasize that ferroptosis emerges when iron-catalyzed lipid peroxide generation outpaces layered defenses, especially GPX4 activity that detoxifies membrane lipid hydroperoxides. They also connect AD proteins to iron biology: APP influences neuronal iron export via ferroportin stabilization, and shifts toward amyloidogenic processing can promote intracellular iron retention; tau pathology and APOE genotype are also discussed as modifiers of iron burden and downstream damage. Importantly for clinicians building microbiome-signature context, this review does not report microbial taxa or metagenomic features, so it provides no direct major microbial associations. Its actionable bridge to microbiome thinking is mechanistic: any upstream drivers that increase brain-accessible iron, systemic inflammation, or lipid peroxidation pressure could, in principle, push patients toward ferroptotic vulnerability, making iron–redox status a plausible integrative node to track alongside gut-derived inflammatory signals.

What are the greatest implications of this study/ review?

This review reframes AD treatment opportunity around modifiable redox biology, proposing that targeting iron handling and ferroptosis defenses could complement amyloid-directed strategies that have shown limited clinical slowing. Clinically, it supports prioritizing biomarkers that reflect iron load and oxidative lipid damage when stratifying patients and monitoring therapeutic engagement, and it highlights candidate interventions already familiar in medicine, such as iron chelation, selenium-dependent support of GPX4 biology, and selected antioxidant approaches, while underscoring that definitive disease-modifying evidence still requires better-targeted trials.