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Cortical iron reflects severity of Alzheimer's disease
Open accessAbstract
Abnormal iron distribution in the isocortex is increasingly recognized as an in vivo marker for Alzheimer's disease (AD). However, the contribution of iron accumulation to the AD pathology is still poorly understood. In this study, we investigated: 1) frontal cortical iron distribution in AD and normal aging and 2) the relation between iron distribution and degree of AD pathology. We used formalin fixed paraffin embedded frontal cortex from 10 AD patients, 10 elder, 10 middle aged, and 10 young controls and visualized iron with a modified Perl's histochemical procedure. AD and elderly subjects were not different with respect to age and sex distribution. Iron distribution in the frontal cortex was not affected by normal aging but was clearly different between AD and controls. AD showed accumulation of iron in plaques, activated microglia, and, in the most severe cases, in the mid-cortical layers along myelinated fibers. The degree of altered iron accumulations was correlated to the amount of amyloid-β plaques and tau pathology in the same block, as well as to Braak stage (p < 0.001). AD and normal aging show different iron and myelin distribution in frontal cortex. These changes appear to occur after the development of the AD pathological hallmarks. These findings may help the interpretation of high resolution in vivo MRI and suggest the potential of using changes in iron-based MRI contrast to indirectly determine the degree of AD pathology in the frontal cortex.
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From Diffusion MRI reveals amyloid plaque–associated cellular signatures through spatial transcriptomic integration (2026) · cites this paper as [31]
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The Role of Trace Metals in Alzheimer’s Disease
Benedictis, C. A. D., Vilella, A., & Grabrucker, A. M. (2019) · Codon Publications eBooks · doi:10.15586/alzheimersdisease.2019.ch6 · Cited by 31
“However, these changes appear to occur after the development of the AD pathological hallmarks (53).”
BackgroundRETRACTED: Characterising the spatial and temporal brain metal profile in a mouse model of tauopathy
Rao, S. S., Lago, L., de Vega, R. G., Bray, L., Hare, D. J., Clases, D., Doble, P., & Adlard, P. A. (2019) · Metallomics · doi:10.1039/c9mt00267g · Cited by 27
RetractedIron Responsive Element-Mediated Responses to Iron Dyshomeostasis in Alzheimer’s Disease
Hin, N., Newman, M., Pederson, S., & Lardelli, M. T. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210200 · Cited by 28
Ferroptosis: a potential therapeutic target for Alzheimer’s disease
Yang, L., & Nao, J. (2022) · Reviews in the Neurosciences · doi:10.1515/revneuro-2022-0121 · Cited by 28
Yu, B., Shan, Y., & Ding, J. (2021) · Annals of Palliative Medicine · doi:10.21037/apm-21-825 · Cited by 26
“Detailed histological and pathological analyses of human tissues have shown that a decrease in T2 relaxation time in AD-affected brain tissue is related to an increase in iron (37), and that the accumulation of iron in activated microglia and the myelin sheath of the middle cortex is related to the Braak stage (38).”
BackgroundAyton, S., Janelidze, S., Kalinowski, P., Palmqvist, S., Belaidi, A. A., Stomrud, E., Roberts, A., Roberts, B. R., Hansson, O., & Bush, A. I. (2022) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2022-330052 · Cited by 27
“A+T+ CU and MCI subjects.”
Rao, S. S., Lago, L., Volitakis, I., Shukla, J. J., McColl, G., Finkelstein, D. I., & Adlard, P. A. (2021) · Neurotherapeutics · doi:10.1007/s13311-020-00972-w · Cited by 24
RetractedChiang, G. C.-Y., Cho, J., Dyke, J. P., Zhang, H., Zhang, Q., Tokov, M., Nguyen, T. D., Kovanlıkaya, İ., Amoashiy, M., de Leon, M. J., et al. (2022) · Journal of Neuroimaging · doi:10.1111/jon.12990 · Cited by 23
van der Weerd, L., Lefering, A. J. E., WEBB, A. G., Egli, R., & Bossoni, L. (2020) · Scientific Reports · doi:10.1038/s41598-020-73324-5 · Cited by 23
Apolipoprotein E is required for brain iron homeostasis in mice
Ma, J., Guo, Q., Shen, M., Li, W., Zhong, Q.-X., & Qian, Z. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102779 · Cited by 22
Upregulation of Local Hepcidin Contributes to Iron Accumulation in Alzheimer’s Disease Brains
Chaudhary, S., Ashok, A., McDonald, D., Wise, A. S., Kritikos, A. E., Rana, N. A., Harding, C. V., & Singh, N. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210221 · Cited by 23
Ma, M., Jing, G., Tian, Y., Yin, R., & Zhang, M. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04417-9 · Cited by 22
Scherlek, A. A., Kozberg, M. G., Nicoll, J. A. R., Perosa, V., Freeze, W. M., van der Weerd, L., Bacskai, B. J., Greenberg, S. M., Frosch, M. P., Boche, D., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac021 · Cited by 20
Kim, H. W., Lee, S., Yang, J. H., Moon, Y., Lee, J., & Moon, W. (2023) · Korean Journal of Radiology · doi:10.3348/kjr.2023.0490 · Cited by 20
“Our results are consistent with those of previous studies showing that cortical iron is elevated in AD in postmortem studies [10,14], QSM studies [29], T2* imaging at 7T [30], and R2* relaxation imaging [12].”
InfluentialLi, C., Cui, K., Zhu, X., Wang, S., Yang, Q., & Fang, G. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1453582 · Cited by 22
Tiepolt, S., Rullmann, M., Jochimsen, T. H., Gertz, H., Schroeter, M. L., Patt, M., Sabri, O., & Barthel, H. (2020) · European Journal of Radiology · doi:10.1016/j.ejrad.2020.109243 · Cited by 20
Ferroptosis in Alzheimer’s Disease: The Regulatory Role of Glial Cells
Xu, J., Shen, R., Qian, M., Zhou, Z., Xie, B., Jiang, Y. Q., Yu, Y., & Dong, W. (2025) · Journal of Integrative Neuroscience · doi:10.31083/jin25845 · Cited by 20
“Iron accumulation is also consistently found in activated microglia in the frontal cortex of AD patients and is normally located near the A β plaques [133].”
Nagani, A., Shah, M., Patel, S., Patel, H., Parikh, V., Patel, A. D., Patel, S. P., Patel, K. V., Parmar, H., Bhimani, B., et al. (2024) · Molecular Diversity · doi:10.1007/s11030-024-10927-4 · Cited by 21
“Elevated levels of iron are found in brain-damaged areas of AD patients, correlating significantly with Aβ plaques and Tau pathology [18, 19].”
Finnegan, M. E., Visanji, N. P., Romero‐Canelón, I., House, E. R., Rajan, S., Mosselmans, J. F. W., Hazrati, L., Dobson, J., & Collingwood, J. F. (2019) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2019.03.002 · Cited by 19
Metabolic Derangement of Essential Transition Metals and Potential Antioxidant Therapies
Fontes, A., Jauch, A. T., Sailer, J., Engler, J., Azul, A. M., & Zischka, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147880 · Cited by 20
Microglia Biomarkers in Alzheimer’s Disease
Zhang, P., Hu, H., Tan, L., & Yu, J. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02348-3 · Cited by 19
Marchi, N. A., Pizzarotti, B., Solelhac, G., Berger, M., Haba‐Rubio, J., Preisig, M., Vollenweider, P., Marques-Vidal, P. M., Lutti, A., Kherif, F., et al. (2022) · Journal of Sleep Research · doi:10.1111/jsr.13698 · Cited by 17
“…and related features (i.e., nocturnal hypoxaemia and/or sleep fragmentation) may promote inflammatory processes and the recruitment of ironaccumulating microglia, which has been shown to contribute to increased brain iron load in neurodegeneration (Kenkhuis et al., 2021; van Duijn et al., 2017).”
BackgroundInfluentialLeVine, S. M. (2024) · Cells · doi:10.3390/cells13080689 · Cited by 20
“Indeed, iron accumulation was observed within neurons, i.e., in association with tangles, in CNS tissue samples from both patients with Alzheimer’s disease and from patients with mild cognitive impairment [38,43,44].”
BackgroundJiao, Q., Du, X., Wei, J., Li, Y. H., & Jiang, H. F. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00020 · Cited by 18
Research progress on ferroptosis in the pathogenesis and treatment of neurodegenerative diseases
Wang, L., Fang, X., Ling, B., Wang, F., Xia, Y., Zhang, W., Zhong, T., & Wang, X. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1359453 · Cited by 18
Park, M., Moon, Y., Han, S., & Moon, W. (2019) · Neuroradiology · doi:10.1007/s00234-019-02159-3 · Cited by 17
O′Neill, E., Mela, V., Gaban, A. S., Béchet, S., McGrath, A., Walsh, A., McIntosh, A. L., & Lynch, M. A. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.939830 · Cited by 17
Metadata
- Authors
- van Duijn, S., Bulk, M., van Duinen, S. G., Nabuurs, R. J. A., van Buchem, M. A., van der Weerd, L., & Natté, R.
- Affiliations
- Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands
- Leiden University Medical Center (NL)
- Department of Radiology, Leiden University Medical Centre, Leiden, The Netherlands
- Corresponding author
- Natté, Remco
- Venue
- Journal of Alzheimer s Disease
- Publisher
- SAGE Publications
- Published
- 2017-11-07
- Volume
- 60
- Issue
- 4
- Pages
- 1533-1545
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- PMC
- PMC5676973
- OpenAlex
- W2765714249
- Cited by
- 172
- References
- 66
- Citations by year
- 2026: 18 · 2025: 14 · 2024: 24 · 2023: 17 · 2022: 28 · 2021: 22 · 2020: 15 · 2019: 20 · 2018: 13 · 2017: 1
- FWCI
- 9.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Alzheimer s Disease (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- FP7 People: Marie-Curie Actions (612360, FP7-PEOPLE-2013-IAPP, FP7-PEOPLE-2013)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- Alzheimer's disease
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Female, Frontal Lobe, Humans, Immunohistochemistry, Iron, Male, Middle Aged, Myelin Sheath, Severity of Illness Index, tau Proteins, Young Adult, Plaque, Amyloid
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