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 | |
| State | Published - May 19 2015 |
ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
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Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. / Ayton, Scott; Faux, Noel G.; Bush, Ashley I.; Weiner, Michael W.; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowki, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Shaw, Leslie M.; Khachaturian, Zaven; Sorensen, Greg; Kuller, Lew; Raichle, Marc; Paul, Steven; Davies, Peter; Fillit, Howard; Hefti, Franz; Holtzman, Davie; Mesulam, M. Marcel; Potter, William; Snyder, Peter; Schwartz, Adam; Montine, Tom; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Jiminez, Gus; Harvey, Danielle; Bernstein, Matthew; Fox, Nick; Thompson, Paul; Schuff, Norbert; Borowski, Bret; Gunter, Jeff; Senjem, Matt; Vemuri, Prashanthi; Jones, David; Kantarci, Kejal; Ward, Chad; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Mathis, Chet; Landau, Susan; Cairns, Nigel J.; Householder, Erin; Taylor-Reinwald, Lisa; Lee, Virginia; Korecka, Magdalena; Figurski, Michal; Crawford, Karen; Neu, Scott; Foroud, Tatiana M.; Potkin, Steven; Shen, Li; Faber, Kelley; Kim, Sungeun; Nho, Kwangsik; Thal, Leon; Buckholtz, Neil; Albert, Marylyn; Frank, Richard; Hsiao, John; Kaye, Jeffrey; Quinn, Joseph; Lind, Betty; Carter, Raina; Dolen, Sara; Schneider, Lon S.; Pawluczyk, Sonia; Beccera, Mauricio; Teodoro, Liberty; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Fleisher, Adam; Heidebrink, Judith L.; Lord, Joanne L.; Mason, Sara S.; Albers, Colleen S.; Knopman, David; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Rountree, Susan; Dang, Mimi; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Ances, Beau; Carroll, Maria; Leon, Sue; Mintun, Mark A.; Schneider, Stacy; Oliver, Angela; Marson, Daniel; Griffith, Randall; Clark, David; Geldmacher, David; Brockington, John; Roberson, Erik; Grossman, Hillel; Mitsis, Effie; De Toledo-Morrell, Leyla; Shah, Raj C.; Duara, Ranjan; Varon, Daniel; Greig, Maria T.; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; D'Agostino, Daniel; Kielb, Stephanie; Galvin, James E.; Cerbone, Brittany; Michel, Christina A.; Rusinek, Henry; De Leon, Mony J.; Glodzik, Lidia; De Santi, Susan; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Wong, Terence Z.; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Smith, Charles D.; Jicha, Greg; Hardy, Peter; Sinha, Partha; Oates, Elizabeth; Conrad, Gary; Lopez, Oscar L.; Oakley, Mary Ann; Simpson, Donna M.; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Mulnard, Ruth A.; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Diaz-Arrastia, Ramon; King, Richard; Weiner, Myron; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Swerdlow, Russell H.; Apostolova, Liana; Tingus, Kathleen; Woo, Ellen; Silverman, Daniel H S; Lu, Po H.; Bartzokis, George; Graff-Radford, Neill R.; Parfitt, Francine; Kendall, Tracy; Johnson, Heather; Farlow, Martin R.; Hake, Ann Marie; Matthews, Brandy R.; Herring, Scott; Hunt, Cynthia; Van Dyck, Christopher H.; Carson, Richard E.; MacAvoy, Martha G.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Hsiung, Ging Yuek Robin; Feldman, Howard; Mudge, Benita; Assaly, Michele; Kertesz, Andrew; Rogers, John; Bernick, Charles; Munic, Donna; Kerwin, Diana; Mesulam, Marek Marsel; Lipowski, Kristine; Wu, Chuang Kuo; Johnson, Nancy; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad; Frey, Meghan; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan N.; Belden, Christine M.; Jacobson, Sandra A.; Sirrel, Sherye A.; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Allard, Joanne; Lerner, Alan; Ogrocki, Paula; Hudson, Leon; Fletcher, Evan; Carmichael, Owen; Olichney, John; DeCarli, Charles; Kittur, Smita; Borrie, Michael; Lee, T. Y.; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W.; Kataki, Maria; Adeli, Anahita; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Santulli, Robert B.; Kitzmiller, Tamar J.; Schwartz, Eben S.; Sink, Kaycee M.; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Mintzer, Jacobo; Spicer, Kenneth; Bachman, David; Finger, Elizabether; Pasternak, Stephen; Rachinsky, Irina; Drost, Dick; Pomara, Nunzio; Hernando, Raymundo; Sarrael, Antero; Schultz, Susan K.; Boles Ponto, Laura L.; Shim, Hyungsub; Smith, Karen Elizabeth; Relkin, Norman; Chaing, Gloria; Raudin, Lisa; Smith, Amanda; Fargher, Kristin; Raj, Balebail Ashok; Neylan, Thomas; Grafman, Jordan; Davis, Melissa; Morrison, Rosemary; Hayes, Jacqueline; Finley, Shannon; Friedl, Karl; Fleischman, Debra; Arfanakis, Konstantinos; James, Olga; Massoglia, Dino; Fruehling, J. Jay; Harding, Sandra; Peskind, Elaine R.; Petrie, Eric C.; Li, Gail; Yesavage, Jerome A.; Taylor, Joy L.; Furst, Ansgar J.
In: Nature Communications, Vol. 6, 6760, 19.05.2015.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE
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 - Foster, Norm
AU - Reiman, Eric M.
AU - Chen, Kewei
AU - Mathis, Chet
AU - Landau, Susan
AU - Cairns, Nigel J.
AU - Householder, Erin
AU - Taylor-Reinwald, Lisa
AU - Lee, Virginia
AU - Korecka, Magdalena
AU - Figurski, Michal
AU - Crawford, Karen
AU - Neu, Scott
AU - Foroud, Tatiana M.
AU - Potkin, Steven
AU - Shen, Li
AU - Faber, Kelley
AU - Kim, Sungeun
AU - Nho, Kwangsik
AU - Thal, Leon
AU - Buckholtz, Neil
AU - Albert, Marylyn
AU - Frank, Richard
AU - Hsiao, John
AU - Kaye, Jeffrey
AU - Quinn, Joseph
AU - Lind, Betty
AU - Carter, Raina
AU - Dolen, Sara
AU - Schneider, Lon S.
AU - Pawluczyk, Sonia
AU - Beccera, Mauricio
AU - Teodoro, Liberty
AU - Spann, Bryan M.
AU - Brewer, James
AU - Vanderswag, Helen
AU - Fleisher, Adam
AU - Heidebrink, Judith L.
AU - Lord, Joanne L.
AU - Mason, Sara S.
AU - Albers, Colleen S.
AU - Knopman, David
AU - Johnson, Kris
AU - Doody, Rachelle S.
AU - Villanueva-Meyer, Javier
AU - Chowdhury, Munir
AU - Rountree, Susan
AU - Dang, Mimi
AU - Stern, Yaakov
AU - Honig, Lawrence S.
AU - Bell, Karen L.
AU - Ances, Beau
AU - Carroll, Maria
AU - Leon, Sue
AU - Mintun, Mark A.
AU - Schneider, Stacy
AU - Oliver, Angela
AU - Marson, Daniel
AU - Griffith, Randall
AU - Clark, David
AU - Geldmacher, David
AU - Brockington, John
AU - Roberson, Erik
AU - Grossman, Hillel
AU - Mitsis, Effie
AU - De Toledo-Morrell, Leyla
AU - Shah, Raj C.
AU - Duara, Ranjan
AU - Varon, Daniel
AU - Greig, Maria T.
AU - Roberts, Peggy
AU - Albert, Marilyn
AU - Onyike, Chiadi
AU - D'Agostino, Daniel
AU - Kielb, Stephanie
AU - Galvin, James E.
AU - Cerbone, Brittany
AU - Michel, Christina A.
AU - Rusinek, Henry
AU - De Leon, Mony J.
AU - Glodzik, Lidia
AU - De Santi, Susan
AU - Doraiswamy, P. Murali
AU - Petrella, Jeffrey R.
AU - Wong, Terence Z.
AU - Arnold, Steven E.
AU - Karlawish, Jason H.
AU - Wolk, David
AU - Smith, Charles D.
AU - Jicha, Greg
AU - Hardy, Peter
AU - Sinha, Partha
AU - Oates, Elizabeth
AU - Conrad, Gary
AU - Lopez, Oscar L.
AU - Oakley, Mary Ann
AU - Simpson, Donna M.
AU - Porsteinsson, Anton P.
AU - Goldstein, Bonnie S.
AU - Martin, Kim
AU - Makino, Kelly M.
AU - Ismail, M. Saleem
AU - Brand, Connie
AU - Mulnard, Ruth A.
AU - Thai, Gaby
AU - Mc-Adams-Ortiz, Catherine
AU - Womack, Kyle
AU - Mathews, Dana
AU - Quiceno, Mary
AU - Diaz-Arrastia, Ramon
AU - King, Richard
AU - Weiner, Myron
AU - Martin-Cook, Kristen
AU - DeVous, Michael
AU - Levey, Allan I.
AU - Lah, James J.
AU - Cellar, Janet S.
AU - Burns, Jeffrey M.
AU - Anderson, Heather S.
AU - Swerdlow, Russell H.
AU - Apostolova, Liana
AU - Tingus, Kathleen
AU - Woo, Ellen
AU - Silverman, Daniel H S
AU - Lu, Po H.
AU - Bartzokis, George
AU - Graff-Radford, Neill R.
AU - Parfitt, Francine
AU - Kendall, Tracy
AU - Johnson, Heather
AU - Farlow, Martin R.
AU - Hake, Ann Marie
AU - Matthews, Brandy R.
AU - Herring, Scott
AU - Hunt, Cynthia
AU - Van Dyck, Christopher H.
AU - Carson, Richard E.
AU - MacAvoy, Martha G.
AU - Chertkow, Howard
AU - Bergman, Howard
AU - Hosein, Chris
AU - Black, Sandra
AU - Stefanovic, Bojana
AU - Caldwell, Curtis
AU - Hsiung, Ging Yuek Robin
AU - Feldman, Howard
AU - Mudge, Benita
AU - Assaly, Michele
AU - Kertesz, Andrew
AU - Rogers, John
AU - Bernick, Charles
AU - Munic, Donna
AU - Kerwin, Diana
AU - Mesulam, Marek Marsel
AU - Lipowski, Kristine
AU - Wu, Chuang Kuo
AU - Johnson, Nancy
AU - Sadowsky, Carl
AU - Martinez, Walter
AU - Villena, Teresa
AU - Turner, Raymond Scott
AU - Johnson, Kathleen
AU - Reynolds, Brigid
AU - Sperling, Reisa A.
AU - Johnson, Keith A.
AU - Marshall, Gad
AU - Frey, Meghan
AU - Lane, Barton
AU - Rosen, Allyson
AU - Tinklenberg, Jared
AU - Sabbagh, Marwan N.
AU - Belden, Christine M.
AU - Jacobson, Sandra A.
AU - Sirrel, Sherye A.
AU - Kowall, Neil
AU - Killiany, Ronald
AU - Budson, Andrew E.
AU - Norbash, Alexander
AU - Johnson, Patricia Lynn
AU - Allard, Joanne
AU - Lerner, Alan
AU - Ogrocki, Paula
AU - Hudson, Leon
AU - Fletcher, Evan
AU - Carmichael, Owen
AU - Olichney, John
AU - DeCarli, Charles
AU - Kittur, Smita
AU - Borrie, Michael
AU - Lee, T. Y.
AU - Bartha, Rob
AU - Johnson, Sterling
AU - Asthana, Sanjay
AU - Carlsson, Cynthia M.
AU - Potkin, Steven G.
AU - Preda, Adrian
AU - Nguyen, Dana
AU - Tariot, Pierre
AU - Reeder, Stephanie
AU - Bates, Vernice
AU - Capote, Horacio
AU - Rainka, Michelle
AU - Scharre, Douglas W.
AU - Kataki, Maria
AU - Adeli, Anahita
AU - Zimmerman, Earl A.
AU - Celmins, Dzintra
AU - Brown, Alice D.
AU - Pearlson, Godfrey D.
AU - Blank, Karen
AU - Anderson, Karen
AU - Santulli, Robert B.
AU - Kitzmiller, Tamar J.
AU - Schwartz, Eben S.
AU - Sink, Kaycee M.
AU - Williamson, Jeff D.
AU - Garg, Pradeep
AU - Watkins, Franklin
AU - Ott, Brian R.
AU - Querfurth, Henry
AU - Tremont, Geoffrey
AU - Salloway, Stephen
AU - Malloy, Paul
AU - Correia, Stephen
AU - Rosen, Howard J.
AU - Miller, Bruce L.
AU - Mintzer, Jacobo
AU - Spicer, Kenneth
AU - Bachman, David
AU - Finger, Elizabether
AU - Pasternak, Stephen
AU - Rachinsky, Irina
AU - Drost, Dick
AU - Pomara, Nunzio
AU - Hernando, Raymundo
AU - Sarrael, Antero
AU - Schultz, Susan K.
AU - Boles Ponto, Laura L.
AU - Shim, Hyungsub
AU - Smith, Karen Elizabeth
AU - Relkin, Norman
AU - Chaing, Gloria
AU - Raudin, Lisa
AU - Smith, Amanda
AU - Fargher, Kristin
AU - Raj, Balebail Ashok
AU - Neylan, Thomas
AU - Grafman, Jordan
AU - Davis, Melissa
AU - Morrison, Rosemary
AU - Hayes, Jacqueline
AU - Finley, Shannon
AU - Friedl, Karl
AU - Fleischman, Debra
AU - Arfanakis, Konstantinos
AU - James, Olga
AU - Massoglia, Dino
AU - Fruehling, J. Jay
AU - Harding, Sandra
AU - Peskind, Elaine R.
AU - Petrie, Eric C.
AU - Li, Gail
AU - Yesavage, Jerome A.
AU - Taylor, Joy L.
AU - Furst, Ansgar J.
N1 - Funding Information: 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. Publisher Copyright: © 2015 Macmillan Publishers Limited. All rights reserved.
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.
UR - http://www.scopus.com/inward/record.url?scp=84930225631&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930225631&partnerID=8YFLogxK
U2 - 10.1038/ncomms7760
DO - 10.1038/ncomms7760
M3 - Article
C2 - 25988319
AN - SCOPUS:84930225631
VL - 6
JO - Nat Commun
JF - Nat Commun
SN - 2041-1723
M1 - 6760
ER -