Dysregulated metal homeostasis in Alzheimer’s disease: From pathological modulators to therapeutic targets

The "metal ion hypothesis" of Alzheimer's disease (AD) has gained widespread acceptance, but translating this understanding into effective therapies remains elusive. This likely stems from a simplistic understanding of metal homeostasis as merely a matter of "excess and deficiency." This article reviews the context-dependent roles of iron, copper, zinc, aluminum, and manganese in the pathogenesis of AD, with a particular focus on their bidirectional interactions with classic AD pathology (the ferroptosis hypothesis is relatively mature, while emerging hypotheses such as cuproptosis have not been fully elucidated). Metal homeostasis dysregulation can directly promote β-amyloid aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and regulated cell death. Conversely, these pathological processes can also alter the binding, storage, transport, and subcellular distribution of metal ions. Dysregulated metal ions function as "context-dependent" modulators of pathological processes. Their functional effects depend on metal species, concentration, binding state, subcellular compartment, and disease stage. Metal homeostasis dysregulation associated with AD may essentially reflect a redistribution between physiological and pathological pools. Ideal interventions should selectively neutralize pathological metal pools while preserving or restoring essential metal-dependent neuronal functions. By integrating the latest advances in the field of metal-targeted therapies (chelators, metabolic modulators, biomarkers, metal imaging, and gene editing), we emphasize that future treatments should shift from nonspecific metal clearance toward precise metal regulation and precision medicine.