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Iron levels linked to Alzheimer's progression


Elevation of iron levels has previously been seen in the brains of AD patients but a link between brain iron status and clinical outcomes in AD has not been established.

The new study:
Ashley Bush and colleagues examined the association of ferritin levels, detected in the cerebrospinal fluid of 302 people, with various outcomes over seven years. All of these individuals were part of the Alzheimer's Disease Neuroimaging Initiative (ADNI) prospective clinical cohort.

Structure of the murine ferritin complex (a single subunit is shown in purple)
Figure: Structure of the murine ferritin complex (a single subunit is shown in purple)

The authors found a negative association between ferritin levels and cognitive performance in cognitively normal participants, participants with mild cognitive impairment, and AD patients. The authors were able to predict the conversion of mild cognitive impairment to AD based on ferritin levels. Ferritin was strongly associated with levels of the AD biomarker apolipoprotein E and was elevated in people carrying the AD risk variant, APOE-ε4.

These studies link the APOE-ε4 variant with brain iron levels and could point to possible mechanisms by which this mutation confers a risk of developing to AD. The study also supports the implementation of therapeutic strategies that lower brain iron to treat AD, but this would need to be explored in future studies.

Source: Nature Communications

The new study:

Scott Ayton, Noel G. Faux, Ashley I. Bush, Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE, Nature Communications, 6 (2015) 6760. DOI: 10.1038/ncomms7760

Related studies (newest first):

Dominic J. Hare, James D. Doecke, Noel G. Faux, Alan Rembach, Irene Volitakis, Christopher J. Fowler, Rudolf Grimm, Philip A. Doble, Robert A. Cherny, Colin L. Masters, Ashley I. Bush, Blaine R. Roberts, Decreased Plasma Iron in Alzheimer’s Disease Is Due to Transferrin Desaturation, ACS Chem. Neurosci., 6 (2015) 398-402. doi: 10.1021/cn5003557

Erika P. Raven, Po.H. Lu, Todd A. Tishler, Panthea Heydari, George Bartzokis, Increased Iron Levels and Decreased Tissue Integrity in Hippocampus of Alzheimer's Disease Detected in vivo with Magnetic Resonance Imaging, Journal of Alzheimer's Disease, 37/1 (2013) 127-136. doi: 10.3233/JAD-130209 

Gabriela A. Salvador, Romina M. Uranga, Norma M. Giusto, Iron and Mechanisms of Neurotoxicity, Int. J. Alzheimer’s Dis., 2011, Article ID 720658.  doi:10.4061/2011/720658

Douglas B. Kell, Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples, Arch. Toxicol., 84 (2010) 825–889. doi: 10.1007/s00204-010-0577-x

Carmen Quintana, Lucía Gutiérrez, Could a dysfunction of ferritin be a determinant factor in the aetiology of some neurodegenerative diseases?, Biochim. Biophys. Acta, 1800/8 (2010) 770-782. doi:  10.1016/j.bbagen.2010.04.012

George Bartzokis, Todd A. Tishler, Po H. Lu, Pablo Villablanca, Lori L. Altshuler, Michele Carter, Danny Huang, Nancy Edwards, Jim Mintz, Brain ferritin iron may influence age- and gender-related risks of neurodegeneration,  Neurobiology of Aging 28 (2007) 414–423. doi: 10.1016/j.neurobiolaging.2006.02.005

C. Quintana, S. Bellefqih, J.Y. Laval, J.L. Guerquin-Kern, T.D. Wu, J. Avila, I. Ferrer, R. Arranz, C. Patiño, Study of the localization of iron, ferritin, and hemosiderin  in Alzheimer’s disease hippocampus by analytical microscopy at the subcellular level, J. Struct. Biol., 153 (2006) 42–54. doi: 0.1016/j.jsb.2005.11.001

Joanna Collingwood and Jon Dobson, Mapping and characterization of iron compounds in Alzheimer’s tissue, J. Alzheimer Dis., 10/2-3 (2006) 215-222.

J.S. Becker, M. Zoriy, C. Pickhardt, M. Przybylski, Johanna Sabine Becker, Investigation of Cu-, Zn- and Fe-containing human brain proteins using isotopic-enriched tracers by LA-ICP-MS and MALDI-FT-ICR-MS, Int. J. Mass Spectrom., 242/2-3 (2005) 135-144. doi: 10.1016/j.ijms.2004.10.027

Luigi Zecca,Moussa B. H. Youdim, Peter Riederer, James R. Connor, Robert R. Crichton, Iron, Brain Ageing and Neurodegenerative Disorders, Nature Rev. Neurosci., 5 (2004) 863-873. doi: 10.1038/nrn1537 

George Bartzokis,Todd A. Tishler, Il-Seon Shin, Po H. Lu, Jeffrey L. Cummmgs, Brain Ferritin Iron as a Risk Factor for Age at Onset in Neurodegenerative Diseases, Ann. New York Acad. Sci., 1012 (2004) 224–236. doi: 10.1196/annals.1306.019

M.A. Smith, P.L. Harris, L.M. Sayre, G. Perry, Iron accumulation in Alzheimer disease is a source of redox-generated free radicals, Proc. Natl Acad. Sci. USA 94 (1997) 9866–9868. doi: 10.1073/pnas.94.18.9866

M.A. Kuiper, C. Mulder, G.J. van Kamp, Ph. Scheltens, E.Ch. Wolters,  Cerebrospinal fluid ferritin levels of patients with Parkinson’s disease, Alzheimer’s disease, and multiple system atrophy, J. Neural Transm. Park. Dis. Dement. Sect. 7 (1994) 109–114. doi:  10.1007/BF02260965

J.R. Connor, S.L. Menzies, S.M. St. Martin, E.J. Mufson, A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brains, J. Neurosci. Res., 31/1 (1992) 75–83. doi: 10.1002/jnr.490310111

J.R. Connor, B.S. Snyder, J.L. Beard, R.E. Fine, and E.J. Mufson, Regional Distribution of Iron and Iron-Regulatory Proteins in the Brain in Aging and Alzheimer’s Disease, J. Neurosci. Res., 31 (1992) 327-335. doi:  10.1002/jnr.490310214

K. Jellinger, W. Paulus, I. Grundke-Iqbal, P. Riederer, M. B. H. Youdim, Brain iron and ferritin in Parkinson's and Alzheimer's diseases, J. Neural. Transm., 2/4 (1990) 327-340. doi: 10.1007/BF02252926

Related information:

Alzheimer's Disease Neuroimaging Initiative
The Florey Institute of Neuroscience and Mental Health
Home page of Professor Ashley Bush

 Related EVISA Resources

Link database: All about Alzheimer's disease
Journal database: Journals related to Alzheimer Research
Brief summary: Chemical speciation analysis for the life sciences

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November 20, 2006: Metal species and Alzheimer's disease

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