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Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology

Abstract

Cortical iron has been shown to be elevated in Alzheimer’s disease (AD), but the impact of the directly measured iron on the clinical syndrome has not been assessed. We investigated the association between post-mortem iron levels with the clinical and pathological diagnosis of AD, its severity, and the rate of cognitive decline in the 12 years prior to death in subjects from the Memory and Aging Project (n = 209). Iron was elevated (β [SE] = 9.7 [2.6]; P = 3.0 × 10−4) in the inferior temporal cortex only in subjects who were diagnosed with clinical AD during life and had a diagnosis of AD confirmed post-mortem by standardized criteria. Although iron was weakly associated with the extent of proteinopathy in tissue with AD neuropathology, it was strongly associated with the rate of cognitive decline (e.g., global cognition: β [SE] = -0.040 [0.005], P = 1.6 × 10−14). Thus, cortical iron might act to propel cognitive deterioration upon the underlying proteinopathy of AD, possibly by inducing oxidative stress or ferroptotic cell death, or may be related to an inflammatory response.

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References

  1. 1.

    Price JL, Morris JC. Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol. 1999;45:358–68.

    CAS  PubMed  Google Scholar 

  2. 2.

    Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008;65:1509–17.

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology. 2006;66:1837–44.

    CAS  PubMed  Google Scholar 

  4. 4.

    Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006;67:446–52.

    CAS  PubMed  Google Scholar 

  5. 5.

    Rowe CC, Bourgeat P, Ellis KA, Brown B, Lim YY, Mulligan R, et al. Predicting Alzheimer disease with beta-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing. Ann Neurol. 2013;74:905–13.

    CAS  PubMed  Google Scholar 

  6. 6.

    Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, et al. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol. 2009;65:403–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Li G, Sokal I, Quinn JF, Leverenz JB, Brodey M, Schellenberg GD, et al. CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study. Neurology. 2007;69:631–9.

    CAS  PubMed  Google Scholar 

  8. 8.

    Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64:343–9.

    PubMed  Google Scholar 

  9. 9.

    Lim YY, Maruff P, Pietrzak RH, Ames D, Ellis KA, Harrington K, et al. Effect of amyloid on memory and non-memory decline from preclinical to clinical Alzheimer’s disease. Brain. 2014;137(Pt 1):221–31.

    PubMed  Google Scholar 

  10. 10.

    Tao Y, Wang Y, Rogers JT, Wang F. Perturbed iron distribution in Alzheimer’s disease serum, cerebrospinal fluid, and selected brain regions: a systematic review and meta-analysis. J Alzheimer’s Dis. 2014;42:679–90.

    CAS  Google Scholar 

  11. 11.

    Schneider SA, Hardy J, Bhatia KP. Syndromes of neurodegeneration with brain iron accumulation (NBIA): an update on clinical presentations, histological and genetic underpinnings, and treatment considerations. Mov Disord. 2012;27:42–53.

    CAS  PubMed  Google Scholar 

  12. 12.

    Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ayton S, Faux NG, Bush AI. Alzheimer’s Disease Neuroimaging Initiative I. Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE. Nat Commun. 2015;6:6760.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ayton S, Faux NG, Bush AI. Association of cerebrospinal fluid ferritin level with preclinical cognitive decline in APOE-epsilon4 carriers. JAMA Neurol. 2017;74:122–5.

    PubMed  Google Scholar 

  15. 15.

    Ayton S, Fazlollahi A, Bourgeat P, Raniga P, Ng A, Lim YY, et al. Cerebral quantitative susceptibility mapping predicts amyloid-beta-related cognitive decline. Brain. 2017;140:2112–9.

    PubMed  Google Scholar 

  16. 16.

    Bennett DA, Schneider JA, Buchman AS, Barnes LL, Boyle PA, Wilson RS. Overview and findings from the rush Memory and Aging Project. Curr Alzheimer Res. 2012;9:646–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34:939–44.

    CAS  Google Scholar 

  18. 18.

    Schneider JA, Arvanitakis Z, Yu L, Boyle PA, Leurgans SE, Bennett DA. Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies. Brain. 2012;135(Pt 10):3005–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Arvanitakis Z, Leurgans SE, Barnes LL, Bennett DA, Schneider JA. Microinfarct pathology, dementia, and cognitive systems. Stroke. 2011;42:722–7.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Samudralwar DL, Diprete CC, Ni BF, Ehmann WD, Markesbery WR. Elemental imbalances in the olfactory pathway in Alzheimer’s disease. J Neurol Sci. 1995;130:139–45.

    CAS  PubMed  Google Scholar 

  21. 21.

    Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci USA. 1997;94:9866–8.

    CAS  PubMed  Google Scholar 

  22. 22.

    Plascencia-Villa G, Ponce A, Collingwood JF, Arellano-Jimenez MJ, Zhu X, Rogers JT, et al. High-resolution analytical imaging and electron holography of magnetite particles in amyloid cores of Alzheimer’s disease. Sci Rep. 2016;6:24873.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    van Duijn S, Bulk M, van Duinen SG, Nabuurs RJA, van Buchem MA, van der Weerd L, et al. Cortical iron reflects severity of Alzheimer’s disease. J Alzheimer’s Dis. 2017;60:1533–45.

    Google Scholar 

  24. 24.

    Ayton S, Diouf I, Bush AI, Alzheimer’s disease Neuroimaging I. Evidence that iron accelerates Alzheimer’s pathology: a CSF biomarker study. J Neurol Neurosurg Psychiatry. 2017. https://doi.org/10.1136/jnnp-2017-316551.

  25. 25.

    Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362–81.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Meadowcroft MD, Peters DG, Dewal RP, Connor JR, Yang QX. The effect of iron in MRI and transverse relaxation of amyloid-beta plaques in Alzheimer’s disease. NMR Biomed. 2014;28:297–305.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Ayton S, James SA, Bush AI. Nanoscale imaging reveals big role for iron in Alzheimer’s disease. Cell Chem Biol. 2017;24:1192–4.

    CAS  PubMed  Google Scholar 

  28. 28.

    Telling ND, Everett J, Collingwood JF, Dobson J, van der Laan G, Gallagher JJ et al. Iron biochemistry is correlated with amyloid plaque morphology in an established mouse model of Alzheimer’s disease. Cell Chem Biol. 2017. https://doi.org/10.1016/j.chembiol.2017.1007.1014.

  29. 29.

    Everett J, Collingwood JF, Tjendana-Tjhin V, Brooks J, Lermyte F, Plascencia-Villa G et al. Nanoscale synchrotron X-ray speciation of iron and calcium compounds in amyloid plaque cores from Alzheimer’s disease subjects. Nanoscale 2018;10:11782–96.

  30. 30.

    Ayton S, Diouf I, Bush AI. Alzheimer’s disease Neuroimaging I. Evidence that iron accelerates Alzheimer’s pathology: a CSF biomarker study. J Neurol Neurosurg Psychiatry. 2018;89:456–60.

    PubMed  Google Scholar 

  31. 31.

    Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, et al. Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med. 2012;18:291–5.

    CAS  PubMed  Google Scholar 

  32. 32.

    Li X, Lei P, Tuo Q, Ayton S, Li QX, Moon S, et al. Enduring elevations of hippocampal amyloid precursor protein and iron are features of beta-amyloid toxicity and are mediated by tau. Neurother: J Am Soc Exp Neurother. 2015;12:862–73.

    CAS  Google Scholar 

  33. 33.

    van Bergen JM, Li X, Hua J, Schreiner SJ, Steininger SC, Quevenco FC, et al. Colocalization of cerebral iron with Amyloid beta in Mild Cognitive Impairment. Sci Rep. 2016;6:35514.

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Zeineh MM, Chen Y, Kitzler HH, Hammond R, Vogel H, Rutt BK. Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Neurobiol Aging. 2015;36:2483–500.

  36. 36.

    Wessling-Resnick M. Iron homeostasis and the inflammatory response. Annu Rev Nutr. 2010;30:105–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Toledo JB, Arnold SE, Raible K, Brettschneider J, Xie SX, Grossman M, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s Coordinating Centre. Brain. 2013;136(Pt 9):2697–706.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Liu T, Surapaneni K, Lou M, Cheng L, Spincemaille P, Wang Y. Cerebral microbleeds: burden assessment by using quantitative susceptibility mapping. Radiology. 2012;262:269–78.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Schneider SA, Dusek P, Hardy J, Westenberger A, Jankovic J, Bhatia KP. Genetics and pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA). Curr Neuropharmacol. 2013;11:59–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Reed T, Perluigi M, Sultana R, Pierce WM, Klein JB, Turner DM, et al. Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer’s disease. Neurobiol Dis. 2008;30:107–20.

    CAS  PubMed  Google Scholar 

  41. 41.

    Hajimohammadreza I, Brammer M. Brain membrane fluidity and lipid peroxidation in Alzheimer’s disease. Neurosci Lett. 1990;112:333–7.

    CAS  PubMed  Google Scholar 

  42. 42.

    Bradley MA, Markesbery WR, Lovell MA. Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer disease. Free Radic Biol Med. 2010;48:1570–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Williams TI, Lynn BC, Markesbery WR, Lovell MA. Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer’s disease. Neurobiol Aging. 2006;27:1094–9.

    CAS  PubMed  Google Scholar 

  44. 44.

    Montine TJ, Kaye JA, Montine KS, McFarland L, Morrow JD, Quinn JF. Cerebrospinal fluidabeta42, tau, and f2-isoprostane concentrations in patients with Alzheimer disease, other dementias, and in age-matched controls. Arch Pathol Lab Med. 2001;125:510–2.

    CAS  PubMed  Google Scholar 

  45. 45.

    Markesbery WR, Kryscio RJ, Lovell MA, Morrow JD. Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment. Ann Neurol. 2005;58:730–5.

    CAS  PubMed  Google Scholar 

  46. 46.

    Mandal PK, Saharan S, Tripathi M, Murari G. Brain glutathione levels–a novel biomarker for mild cognitive impairment and Alzheimer’s disease. Biol Psychiatry. 2015;78:702–10.

    CAS  PubMed  Google Scholar 

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Funding

This study was supported by grants from the National Institute of Health (R01AG017917, R21E2021290, and RF1AG054057). The analysis was supported by funds from the Australian Research Council, the Australian National Health & Medical Research Council (NHMRC), and the Cooperative Research Centre for Mental Health (the Cooperative Research Centre program is an Australian Government Initiative). The Florey Institute of Neuroscience and Mental Health acknowledges the support from the Victorian Government, in particular, funding from the Operational Infrastructure Support Grant. No funder of this study had any role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

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SA: scientific concept, writing the manuscript, directing the analysis. YW: performed statistical analysis. ID: performed statistical analysis, graphed the results. JB: measured iron, edited the manuscript. JAS: performed neuropathology, edited the manuscript. MCM: scientific concept, funding, writing the manuscript. AIB: scientific concept, funding, writing the manuscript.

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Correspondence to Martha Clare Morris or Ashley I. Bush.

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AIB is a shareholder in Prana Biotechnology Ltd, Cogstate Ltd, Brighton Biotech LLC, Grunbiotics Pty Ltd, Eucalyptus Pty Ltd, and Mesoblast Ltd. He is a paid consultant for, and has a profit share interest in, Collaborative Medicinal Development Pty Ltd.

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Ayton, S., Wang, Y., Diouf, I. et al. Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Mol Psychiatry 25, 2932–2941 (2020). https://doi.org/10.1038/s41380-019-0375-7

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