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Original research
CSF ferritin in the clinicopathological progression of Alzheimer’s disease and associations with APOE and inflammation biomarkers
  1. Scott Ayton1,2,
  2. Shorena Janelidze3,
  3. Pawel Kalinowski1,2,
  4. Sebastian Palmqvist3,4,
  5. Abdel Ali Belaidi1,2,
  6. Erik Stomrud3,5,
  7. Anne Roberts6,
  8. Blaine Roberts6,
  9. Oskar Hansson7,
  10. Ashley Ian Bush1,2
  1. 1Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
  2. 2The University of Melbourne, Melbourne, Victoria, Australia
  3. 3Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden
  4. 4Department of Neurology, Skåne University Hospital, Lund, Sweden
  5. 5Skåne University Hospital, Memory Clinic, Malmö, Sweden
  6. 6Emory University, Atlanta, Georgia, USA
  7. 7Clinical Memory Research Unit, Lund University, Malmö, Sweden
  1. Correspondence to Professor Ashley Ian Bush, Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia; ashley.bush{at}florey.edu.au

Abstract

Background A putative role for iron in driving Alzheimer’s disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aβ42/t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.

Methods Ferritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF samples from BioFINDER (n=1239; 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aβ42/t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort.

Results In both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%–40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-.

Conclusions CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.

  • alzheimer's disease
  • iron deposition

Data availability statement

Data are available on reasonable request. Anonymised data will be shared by request from a qualified academic investigator for the sole purpose of replicating procedures and results presented in the article and as long as data transfer is in agreement with EU legislation on the general data protection regulation and decisions by the Ethical Review Board of Sweden and Region Skåne, which should be regulated in a material transfer agreement.

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Data availability statement

Data are available on reasonable request. Anonymised data will be shared by request from a qualified academic investigator for the sole purpose of replicating procedures and results presented in the article and as long as data transfer is in agreement with EU legislation on the general data protection regulation and decisions by the Ethical Review Board of Sweden and Region Skåne, which should be regulated in a material transfer agreement.

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Footnotes

  • Collaborators Alzheimer’s Disease Neuroimaging Initiative; Swedish BioFINDER study.

  • Contributors Primary data collection: SJ, SP, ES and OH. Sample analysis: SA, SJ, SP, ES, OH, AAB, AR and BR. Statistical analysis: SA, PK and AIB. Manuscript drafting: SA, SJ, PK, SP, AAB, ES, AR, BR, OH and AIB.

  • Funding BioFINDER is funded by the Swedish Research Council, the Knut and Alice Wallenberg foundation, the Marianne and Marcus Wallenberg foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, The Parkinson foundation of Sweden, The Parkinson Research Foundation, the Skåne University Hospital Foundation, and the Swedish federal government under the ALF agreement. 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, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N. V.; 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. This study was supported by a grant from the BAND consortium: Alzheimer’s Association, Westin Brain Institute, Michael J Fox Foundation, Alzheimer’s Research UK. Fellowship support from the National Health & Medical Research Council of Australia. Additional support from the Alzheimer’s Drug Discovery Foundation, the Cooperative Research Centre for Mental Health, and the Victorian Government’s Operational Infrastructure Support Programme.

  • Competing interests AIB is a shareholder in Alterity Cogstate and Mesoblast. He is a paid consultant for, and has a profit share interest in, Collaborative Medicinal Development. AIB and SA hold a patent related to CSF ferritin as a diagnostic for dementia (US patent app: 15/562,801). OH has acquired research support (for the institution) from Roche, Pfizer, GE Healthcare, Biogen, Eli Lilly and AVID Radiopharmaceuticals. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche. BR is an inventor on patent application AU2014/00849 for diagnosis of neurological disorders and receives research support from Agilent Technologies, eMSion and Neurovision.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.