The Pathological Nexus and Multipronged Approaches to Mitigate Ferroptosis and Alzheimer's Disease.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder and a leading cause of dementia. Although the amyloid cascade is a defining feature of AD pathology, the precise mechanisms underlying neurodegeneration remain unclear, and current therapeutics targeting this have shown limited efficacy. Emerging evidence implicates ferroptosis, an iron-dependent, lipid peroxidation (LPO)-driven form of regulated cell death, as a contributing factor in AD-related neuronal loss. Core biomarkers of ferroptosis, including iron dyshomeostasis, LPO, and reduced antioxidant capacity, closely align with hallmark features of AD suggesting a pathological nexus further supported by clinical evidence. While the use of LPO inhibitors and iron chelators has shown promising outcomes, there remains a significant gap in targeting key ferroptosis regulators, such as GPX4 and FSP1, which hold strong therapeutic potential in AD. This perspective explores their pathological interplay and offers strategic insights for the development of hybrid multifunctional therapeutic molecules to synergistically target these interconnected pathways.