Higher levels of ferritin, an iron storage protein, are associated with reduced cognitive performance and can predict whether a patient suffering from mild cognitive impairment will go on to develop Alzheimer's disease (AD), reports a study published May 20 in Nature Communications.
Background: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.
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, C
erebrospinal 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
Related EVISA News November 20, 2006: Metal species and Alzheimer's diseaselast time modified: May 17, 2024
