Ferroptosis in Alzheimer’s Disease: Molecular Mechanisms, Chemical Modulators, and Emerging Therapeutic Strategies

Ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation, has emerged as a potential contributor to neuronal dysfunction and degeneration in Alzheimer’s disease (AD). This review critically examines the biochemical basis, AD-specific evidence, chemical modulators, and therapeutic prospects of ferroptosis, emphasizing the distinction between mechanistic compatibility and causal demonstration. Ferroptotic susceptibility is governed by the balance among polyunsaturated phospholipid substrates, redox-active iron, lipid-peroxyl radical propagation, and enzymatic or chemical termination systems, including glutathione peroxidase 4 (GPX4), FSP1, and radical-trapping antioxidants. Human and experimental AD studies show brain iron accumulation, enhanced lipid peroxidation, impaired glutathione/GPX4 defenses, and disrupted iron export, but none establishes neuronal ferroptosis as the predominant mode of cell death. Two randomized trials of brain-penetrant iron chelation lowered the bulk brain iron signal and worsened clinical outcomes, which refutes the proposition that depleting bulk brain iron is therapeutic; because neither trial measured the kinetically labile iron pool, the mechanism of that harm remains undetermined. Among emerging strategies, membrane-active radical-trapping antioxidants and substrate-directed approaches offer mechanistically rational alternatives, whereas many natural products and multitarget agents remain difficult to interpret pharmacologically. Future studies should integrate cell-type-resolved redox lipidomics, direct target engagement, and rigorous causal intervention to determine whether ferroptosis or chronic sublethal lipid peroxidation is therapeutically actionable in AD.