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. 2009 May;72(5):504-9.
doi: 10.1016/j.mehy.2008.12.029. Epub 2009 Feb 4.

Getting the iron out: phlebotomy for Alzheimer's disease?

Barney E Dwyer  1 , Leo R Zacharski, Dominic J Balestra, Alan J Lerner, George Perry, Xiongwei Zhu, Mark A Smith
Affiliations

Getting the iron out: phlebotomy for Alzheimer's disease?

Barney E Dwyer et al. Med Hypotheses. 2009 May.

Abstract

This communication explores the temporal link between the age-associated increase in body iron stores and the age-related incidence of Alzheimer's disease (AD), the most prevalent cause of senile dementia. Body iron stores that increase with age could be pivotal to AD pathogenesis and progression. Increased stored iron is associated with common medical conditions such as diabetes and vascular disease that increase risk for development of AD. Increased stored iron could also promote oxidative stress/free radical damage in vulnerable neurons, a critical early change in AD. A ferrocentric model of AD described here forms the basis of a rational, easily testable experimental therapeutic approach for AD, which if successful, would be both widely applicable and inexpensive. Clinical studies have shown that calibrated phlebotomy is an effective way to reduce stored iron safely and predictably without causing anemia. We hypothesize that reducing stored iron by calibrated phlebotomy to avoid iron deficiency will improve cerebrovascular function, slow neurodegenerative change, and improve cognitive and behavioral functions in AD. The hypothesis is eminently testable as iron reduction therapy is useful for chronic diseases associated with iron excess such as nonalcoholic steatohepatitis (NASH), atherosclerosis, hereditary hemochromatosis and thalassemia. Testing this hypothesis could provide valuable insight into the causation of AD and suggest novel preventive and treatment strategies.

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Conflict of interest statement

Conflict of interest statement

The authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1
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 [–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.
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