The pervasive and modifiable role of iron on the development of AD. The most widely accepted theories of AD causation implicate four significant changes: (1) Aβ accumulation, (2) tau hyperphosphorylation and development of neurofibrillary pathology, (3) oxidative stress and free radical damage in vulnerable neurons, and (4) expression of cell cycle proteins in post-mitotic neurons. Age-related increase in stored iron is at the apex of a pathophysiological cascade that could promote these critical changes by increasing the risk for diabetes and cardiovascular disease, two common medical conditions associated with increased risk for AD, and by expanding the pool of redox active iron (LIP) in brain cells. Insulin resistance syndrome and T2DM could increase Aβ accumulation because hyperinsulinemia modifies Aβ metabolism and glycation reactions alter Aβ aggregation [1,28]. Cardiovascular disease causing cerebral hypoperfusion and tissue hypoxia could be a cause of mitochondrial damage and dysfunction that results in increased generation of reactive oxygen species including hydrogen peroxide [45,50]. Increased redox active iron due to increased iron availability and impaired iron storage/detoxification could exacerbate Fenton reaction-mediated oxidative stress and free radical damage to essential cell components. Moreover, mitochondria are both a source of reactive oxygen species and a target of reactive oxygen-mediated oxidative stress, so a vicious circle could develop leading to increased mitochondrial damage and dysfunction. Iron-mediated oxidative stress, perhaps in association with cell signaling disturbances, could promote increased phosphorylation of microtubule-associated protein tau and expression of cell cycle proteins in post-mitotic neurons [91–94]. The figure also depicts a novel pathway by which iron could potentially regulate Aβ accumulation. Expression of furin, a subtilisin-like proprotein convertase that stimulates α-secretase activity, is decreased in AD brain, and brain from Tg2576 AD-transgenic mice [95]. Silvestri and Camaschella [96] proposed that iron-mediated decrease of furin protein and α-secretase activity in AD brain, and iron-mediated increase in APP expression [97], could favor the accumulation of Aβ. The figure does not presume to be an exhaustive review of how AD-related pathology develops, and indeed, does not depict other potentially important developments such as neuroinflammation. Our intent is to highlight potential linkage between increased body iron stores and some potentially important pathophysiological changes in AD that would possibly respond to iron reduction by calibrated phlebotomy.