Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE

Alzheimer's Disease Neuroimaging Initiative

doi:10.1038/ncomms7760

Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE

Alzheimer's Disease Neuroimaging Initiative

Research output: Contribution to journal › Article › peer-review

245 Scopus citations

Abstract

Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ε4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ε4 being the major genetic risk factor for AD.

Original language	English (US)
Article number	6760
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7760
State	Published - May 19 2015

Funding

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defence 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, N. V.; IXICO; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace; Merck & Co.; Meso Scale Diagnostics, LLC.; 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 organization 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 supported by funds from the Australian Research Council, the Australian National Health & Medical Research Council (NHMRC), the CRC for Mental Health (the Cooperative Research Centre (CRC) programme is an Australian Government Initiative), the Yulgilbar foundation, and Operational Infrastructure Support from the Victorian State Government.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms7760

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@article{f4f125eb819f485cb7a35e825c02db83,

title = "Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE",

abstract = "Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ε4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ε4 being the major genetic risk factor for AD.",

author = "{Alzheimer's Disease Neuroimaging Initiative} and Scott Ayton and Faux, {Noel G.} and Bush, {Ashley I.} and Weiner, {Michael W.} and Paul Aisen and Ronald Petersen and Jack, {Clifford R.} and William Jagust and Trojanowki, {John Q.} and Toga, {Arthur W.} and Laurel Beckett and Green, {Robert C.} and Saykin, {Andrew J.} and John Morris and Shaw, {Leslie M.} and Zaven Khachaturian and Greg Sorensen and Lew Kuller and Marc Raichle and Steven Paul and Peter Davies and Howard Fillit and Franz Hefti and Davie Holtzman and Mesulam, {M. Marcel} and William Potter and Peter Snyder and Adam Schwartz and Tom Montine and Thomas, {Ronald G.} and Michael Donohue and Sarah Walter and Devon Gessert and Tamie Sather and Gus Jiminez and Danielle Harvey and Matthew Bernstein and Nick Fox and Paul Thompson and Norbert Schuff and Bret Borowski and Jeff Gunter and Matt Senjem and Prashanthi Vemuri and David Jones and Kejal Kantarci and Chad Ward and Koeppe, {Robert A.} and Reiman, {Eric M.} and Kewei Chen",

year = "2015",

month = may,

day = "19",

doi = "10.1038/ncomms7760",

language = "English (US)",

volume = "6",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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T1 - Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE

AU - Alzheimer's Disease Neuroimaging Initiative

AU - Ayton, Scott

AU - Faux, Noel G.

AU - Bush, Ashley I.

AU - Weiner, Michael W.

AU - Aisen, Paul

AU - Petersen, Ronald

AU - Jack, Clifford R.

AU - Jagust, William

AU - Trojanowki, John Q.

AU - Toga, Arthur W.

AU - Beckett, Laurel

AU - Green, Robert C.

AU - Saykin, Andrew J.

AU - Morris, John

AU - Shaw, Leslie M.

AU - Khachaturian, Zaven

AU - Sorensen, Greg

AU - Kuller, Lew

AU - Raichle, Marc

AU - Paul, Steven

AU - Davies, Peter

AU - Fillit, Howard

AU - Hefti, Franz

AU - Holtzman, Davie

AU - Mesulam, M. Marcel

AU - Potter, William

AU - Snyder, Peter

AU - Schwartz, Adam

AU - Montine, Tom

AU - Thomas, Ronald G.

AU - Donohue, Michael

AU - Walter, Sarah

AU - Gessert, Devon

AU - Sather, Tamie

AU - Jiminez, Gus

AU - Harvey, Danielle

AU - Bernstein, Matthew

AU - Fox, Nick

AU - Thompson, Paul

AU - Schuff, Norbert

AU - Borowski, Bret

AU - Gunter, Jeff

AU - Senjem, Matt

AU - Vemuri, Prashanthi

AU - Jones, David

AU - Kantarci, Kejal

AU - Ward, Chad

AU - Koeppe, Robert A.

AU - Reiman, Eric M.

AU - Chen, Kewei

PY - 2015/5/19

Y1 - 2015/5/19

N2 - Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ε4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ε4 being the major genetic risk factor for AD.

AB - Brain iron elevation is implicated in Alzheimer's disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer's risk allele, APOE-ε4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ε4 being the major genetic risk factor for AD.

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U2 - 10.1038/ncomms7760

DO - 10.1038/ncomms7760

M3 - Article

C2 - 25988319

AN - SCOPUS:84930225631

SN - 2041-1723

VL - 6

JO - Nature communications

JF - Nature communications

M1 - 6760

ER -

Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE

Abstract

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ASJC Scopus subject areas

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