Iron and ferroptosis in the pathogenesis of Alzheimer´s disease

Alzheimer's disease (AD) is an incurable dementia, with major risk factors being age and the APOE-ε4 allele. AD has a hallmark neuropathology of neuronal death, lipid peroxidation damage, extracellular Aε amyloid and intracellular tau deposition. There is also marked dysregulation of metal homeostasis, with iron elevation reported in cortex (AD) in tandem with the proteinopathies. The major proteins implicated in AD have been found to function in brain iron regulatory system that fails in aging. The amyloid protein precursor, like ceruloplasmin, facilitates the export of iron from cells by stabilizing cell surface ferroportin. Tau impacts on iron export by trafficking APP to the cell surface. CSF ferritin levels predict cognitive decline and conversion of MCI to AD and are associated with Apolipoprotein E levels. In vivo measurement of brain iron by QSM strongly adds to the prediction of cognitive decline in tandem with amyloid PET scans. These evidences, as well as a host of specific post-mortem changes, converge on ferroptosis as the pathogenic mechanism of AD. Anti-ferroptosis molecules have been effective in animal models of neurodegenerative disease, and the anti-ferroptotic chelator deferiprone is currently being tested in a phase 2 randomized controlled trial for AD.