Objective To investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF β-amyloid (Aβ) and tau.
Methods Mixed-effects models of CSF Aβ1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aβ1-42 for up to 5 years.
Results In subjects with biomarker-confirmed Alzheimer’s pathology, high CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aβ1-42 (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aβ1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aβ deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aβ from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aβ over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aβ levels to the average level of Alzheimer’s subjects from 18.8 to 10.8 years.
Conclusions Iron might facilitate Aβ deposition in Alzheimer’s and accelerate the disease process.
- alzheimer’s disease
- iron deposition
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SA and ID contributed equally.
Contributors SA: Scientific concept, wrote manuscript, data modelling. ID: Data modelling, preparation of figures and tables. AIB: Supervised analysis, edited manuscript, funded analysis.
Funding Data collection and sharing for this project was funded by ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica; Biogen Idec; Bristol-Myers Squibb Company; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; F Hoffmann-La Roche and its affiliated company Genentech; GE Healthcare; Innogenetics, NV; IXICO; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Medpace; Merck & Co; Meso Scale Diagnostics; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer; Piramal Imaging; Servier; Synarc; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organisation is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Analysis was supported by funds from the Australian Research Council, the Australian National Health & Medical Research Council (NHMRC), and the CRC for Mental Health (the Cooperative Research Centre (CRC) programme is an Australian Government Initiative). The Florey Institute of Neuroscience and Mental Health acknowledges 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; and decision to submit the manuscript for publication.
Competing interests AIB is a shareholder in Prana Biotechnology, Cogstate, Eucalyptus, Mesoblast, Brighton Biotech, Nexvet, Grunbiotics and Collaborative Medicinal Development, and a paid consultant for Collaborative Medicinal Development. SA, ID and AIB have a filed a provisional patent that contains data from this manuscript. SA and AIB have received funding relevant to this study from the NHMRC, Alzheimer’s Association, Alzheimer’s Research UK, The Michael J Fox Foundation for Parkinson’s Research, and Weston Brain Institute.
Patient consent Obtained.
Ethics approval Multiple sites.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All raw data are available on the ADNI website.
Collaborators Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp1ontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
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