Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE
Authors: Ayton Scott , Faux Noel G. , Bush Ashley I. ,   Alzheimer's Disease Neuroimaging Initiative, 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 , Marcel Mesulam M. , 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 , deToledo-Morrell Leyla , Shah Raj C. , Duara Ranjan , Varon Daniel , Greig Maria T. , Roberts Peggy , Albert Marilyn , Onyike Chiadi , D’Agostino II Daniel , Kielb Stephanie , Galvin James E. , Cerbone Brittany , Michel Christina A. , Rusinek Henry , de Leon Mony J , Glodzik Lidia , De Santi Susan , Murali Doraiswamy P. , 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 MaryAnn , Simpson Donna M. , Porsteinsson Anton P. , Goldstein Bonnie S. , Martin Kim , Makino Kelly M. , Saleem Ismail M. , 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 , Robin Hsiung Ging-Yuek , 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 , Scott Turner Raymond , 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 , Elizabeth Smith Karen , Relkin Norman , Chaing Gloria , Raudin Lisa , Smith Amanda , Fargher Kristin , Ashok Raj Balebail , Neylan Thomas , Grafman Jordan , Davis Melissa , Morrison Rosemary , Hayes Jacqueline , Finley Shannon , Friedl Karl , Fleischman Debra , Arfanakis Konstantinos , James Olga , Massoglia Dino , Jay Fruehling J. , Harding Sandra , Peskind Elaine R. , Petrie Eric C. , Li Gail , Yesavage Jerome A. , Taylor Joy L. , Furst Ansgar J. 
Published: May 2015

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-ɛ4. These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.