No disease-modifying drug currently exists for neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s diseases (PD). While iron has been implicated in neurodegeneration for many years, the extent to which iron elevation contributes to pathogenesis, and the origin of its elevation, had remained unknown. We were the first to demonstrate that the AD-implicated amyloid precursor protein (APP) binds to the iron exporting protein, ferroportin, tethering it to the membrane for efficient iron efflux. We also showed that the AD-implicated tau protein maintains neuronal iron homeostasis by facilitating APP trafficking to the cell surface, and the ferroxidase ceruloplasmin, recruited from astrocytes, is involved in neuronal iron release. We also quantified the contribution of iron on progression of AD, and revealed that the iron burden of the brain has a similar magnitude impact on longitudinal (7 years) outcomes of AD (cognition, brain atrophy) compared to more established factors in the disease (e.g. CSF tau and Aβ).Therefore pre-clinical and clinical studies demonstrate the potential of iron to contribute to disease progression and iron presents as an unexplored prognostic, and tractable therapeutic target.