Study concept and design: Jansen, Ossenkoppele, Verhey, Visser.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Jansen, Visser.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Jansen, Knol, Visser.
Administrative, technical, or material support: All authors.
Study supervision: Visser.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Scheltens reported having received grants from GE Healthcare, Piramal, and Merck, paid to his institution. Dr Verhey reported having received compensation as a speaker and consultant for Nutricia Advanced Medical Food. Dr Visser reported having received grants from EU/EFPIA Innovative Medicines Initiative Joint Undertaking, EU Joint Programme–Neurodegenerative Disease Research (JPND), ZonMw, and Bristol-Myers Squibb; having served as member of the advisory board of Roche Diagnostics; and having received nonfinancial support from GE Healthcare. Dr Aarsland reported having received research support or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, and GE Health. Dr Alexander reported being an employee of Roche Products. Dr Barthel reported having received speaker and consultant honoraria as well as travel expenses from Piramal Imaging (Berlin) and personal fees from Siemens Healthcare. Dr Bibeau reported being a share-holding employee of GlaxoSmithKline. Dr Blennow reported having received personal fees (advisory board) from Roche Diagnostics, IBL International, Novartis, and Eli Lilly. Dr Brooks reported having served as consultant for GE Healthcare. Dr Camus reported having received grants from the French Ministry of Health. Dr Chen reported having received grants from the National Institutes of Health (NIH). Dr Drzezga reported having received speaker honoraria and consulting fees from GE Healthcare, AVID/Lilly, and Piramal. Dr Fagan reported having received grants from NIH, Fred Simmons and Olga Mohan, and Charles and Joanne Knight Alzheimer’s Research Initiative of the Washington University Knight Alzheimer’s Disease Research Center; having received personal fees from IBL International, Roche, and AbbVie; and having a patent, 6,465,195 B2, “Predictive diagnostic for Alzheimer’s disease,” issued and a patent, PCT/US09/050255, “A risk factor and new therapeutic target for Alzheimer’s disease,” pending. Dr Fladby reported having a patent “Methods and compositions for monitoring phagocytic activity,” PCT/US2011/062233, pending. Dr Fleisher reported having been a full-time employee of the Banner Alzheimer’s Institute; being a full-time employee of Eli Lilly; maintaining a voluntary faculty appointment at the University of California, San Diego; having been a member of data and safety monitoring boards for Merck, Pfizer, and the National Institute of Aging (NIA); having received grant funding from NIA and Avid Radiopharmaceutical; and having been a consultant for Eli Lilly, Grifols, Avid Radiopharmaceuticals, and Siemens Imaging. Dr van der Flier reported having received grants from Boehringer Ingelheim, Piramal Imaging, and Roche. Dr Förster reported having received personal fees (consultancy) from Piramal, Bayer, and GE. Dr Foskett reported being a full-time employee of Roche Prod and holding Roche shares and share options. Dr Frisoni reported having received grants and/or personal fees from Lilly, Bristol-Myers Squibb, Bayer, Lundbeck, Elan, AstraZeneca, Pfizer, Taurx, Wyeth, GE, Baxter, Avid, Roche, Piramal, and the Alzheimer’s Association. Dr Gill reported having received grants from the Indian Council of Medical Research, New Delhi, India. Dr Gordon reported being a salaried employee of Boehringer Ingelheim Pharmaceuticals. Dr Grimmer reported having received personal fees from Eli Lilly. Dr Hampel reported having received grants, personal fees, and/or nonfinancial support from Boehringer-Ingelheim, Bristol-Myers Squibb, Elan, Novartis, Eisai, Pfizer, sanofi-aventis, Roche Pharmaceuticals and Diagnostics, GE Healthcare, Avid, Eli Lilly, GlaxoSmithKline Biologicals, Jung-Diagnostics, and Cytox and having a patent, “Method for predicting whether subjects with mild cognitive impairment (MCI) will develop Alzheimer’s disease,” pending; a patent, “3-Hydroxykynurenin im Serum als diagnotischer Marker für die Demenz vom Alzheimer-Typ,” pending; a patent, “Neurodegenerative markers for psychiatric conditions,” pending; a patent, “Ratio Aß42/40 im Plasma in der Früh- und Differentialdiagnose der Alzheimer Krankheit,” pending; a patent “Liquordiagnostisches in vitro Verfahren zur Diagnose von Demenz Erkrankungen und neuroinflammatorischen Erkrankungen,” pending; and a patent, “In vitro Verfahren zur Diagnose von neurodegenerativen Erkrankungen,” pending. Dr Hellwig reported having received grants from GE Healthcare and Medical Faculty, University of Freiburg. Dr Ishihara reported being an employee and shareholder of GlaxoSmithKline. Dr Jagust reported having received personal fees from Banner Alzheimer Institute/Genentech, Synarc/Bioclinica, and Novartis. Dr Kandimalla reported having received grants from the Indian Council of Medical Research, India. Dr Kapaki reported having received grants from the European Union (European Regional Development Fund [ERDF]) and Greek national funds through the Operational Program “Competitiveness and Entrepreneurship” of the National Strategic Reference Framework (NSRF) Research Funding Program: Joint Programming Neurodegenerative Disease, “Biomarkers for Alzheimer’s disease and Parkinson’s disease.” Dr Klunk reported being a co-inventor of the amyloid imaging tracer PiB and, as such, having a financial interest in the license agreement. (PiB intellectual property is owned by the University of Pittsburgh, and GE Healthcare holds a license agreement with the University of Pittsburgh based on the PiB technology described in this article. Dr Klunk receives “inventors share” payments from the University of Pittsburgh based on income from that license.) Dr Koglin reported having received personal fees from employment at Piramal Imaging, who is marketing Neuraceq (florbetaben F18) as an amyloid-beta PET imaging agent. Dr Kornhuber reported having received grants from German Federal Ministry of Education and Research (BMBF): Kompetenznetz Demenzen (01GI0420) and German Federal Ministry of Education and Research (BMBF): The Frontotemporo-Lobar Degeneration Consortium (FTDL-C), 01GI1007A and having a patent, PCT/EP2004/003963, “Diagnosis of Alzheimer’s disease,” issued; a patent, EP 1811304 A1, “Large Aß-peptide binding particles (LAPS) in diagnosis and therapy of Alzheimer’s dementia,” issued; a patent, WO2007/082750 A1, “Immunoglobulin-bound Ab-peptides and immunoglobulins-binding Ab-peptides in diagnosis and therapy of Alzheimer’s dementia,” issued; a patent, EP 2437067A2, “Methods of differentially diagnosing dementias,” issued; and a patent, “New formulations for diagnosis of Alzheimer’s disease,” pending. Dr Van Laere reported having received grants from Merck, Janssen Pharmaceuticals, and GE Healthcare. Dr Landau reported having received grants from NIH and personal fees from Biogen Idec, Genentech, and Synarc. Dr Lleo reported having received grants from Instituto de Salud Carlos III (Fondo de Investigación Sanitario, PI10/01878; PI13/01532; PI11/2425; PI11/3035 and the CIBERNED program). Dr Madsen reported having received grants from the Lundbeck Foundation, Danish Medical Research Council, and Rigshospitalet. Dr Meyer reported having received money from GE Healthcare for an ongoing research study (IIT). Dr Mintun reported being an employee of Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly. Dr Morris reported having received grants from NIH (P50AG005681, P01AG003991, P01AG026276, U19AG032438). Dr Mroczko reported having received grants and personal fees from the Leading National Research Centre (KNOW), Medical University of Bialystok, Poland. Dr Novak reported being an employee of Janssen Research and Development and holding stock in the same. Dr Paraskevas reported having received grants from European Union (European Regional Development Fund [ERDF]) and Greek national funds through the Operational Program “Competitiveness and Entrepreneurship” of the National Strategic Reference Framework (NSRF) Research Funding Program: Joint Programming Neurodegenerative Disease, “Biomarkers for Alzheimer’s disease and Parkinson’s disease.” Dr Peters reported having received grants and/or personal fees from Lilly, Roche, Genentech, Lundbeck, Affiris, Piramal, Novartis, and Trx-Pharmaceuticals. Dr Popp reported having received grants from the Swiss National Science Foundation. Dr Rabinovici reported having received grants from Avid Radiopharmaceuticals and personal fees from GE Healthcare and Piramal. Dr Rinne reported having received grants from Sigrid juselius Foundation and Turku University Hospital clinical grants. Dr Rot reported having received grants from JPND BIOMARKAPD. Dr Rowe reported having received grants from Avid Radiopharmaceuticals, Piramal Imaging, AstraZeneca, GE Healthcare, Avid/Lilly, Navidea, CSIRO, NHMRC, Alzheimer’s Association, and an anonymous foundation and having had a patent licensed for PET image processing. Dr Sabri reported having received grants and/or personal fees from Piramal Imaging, Bayer Healthcare, and Siemens Healthcare. Dr Sarazin reported having received personal fees from Novartis (lecture) and Allianz (lecture). Dr Soininen reported having received grants from the Academy of Finland, European Union 7ThFP 601055 VPH-DARE, Kuopio University Hospital VTR, and University of Eastern Finland. Dr Teunissen reported being a member of the international advisory board at Innogenetics and Roche; having received free kit-reagents for experiments from IBL, Innogenetics, Mesoscale Discovery, Invitrogen, Euroimmun, and FluidX; and having research contracts at Probiodrug, IBL, and Abbott. Dr Vandenberghe reported having received clinical trial agreements with GEHC, Merck, Forum, and Roche; grants from Research Foundation–Flanders (FWO) and KU Leuven; and nonfinancial support from GEHC. Dr Verbeek reported having served on an advisory board for Roche. Dr Waldemar reported being a board member of the Lundbeck Foundation. Dr Anders Wallin reported having received speakers’ bureau fees from Esai and Triolab and serving on the advisory board for Nutrica and Esai. Dr Wolk reported having received personal fees from GE Healthcare and Piramal Pharma and grants from Avid Radiopharmaceuticals. The authors received compensation (ie, salary) as employees of their respective organizations. No other disclosures were reported.
Funding/Support: The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement No. 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. BIOMARKAPD is an EU Joint Programme–Neurodegenerative Disease Research (JPND) project. The project is supported through national funding organizations under the aegis of JPND (http://www.jpnd.eu). In the Netherlands, this is ZonMw. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission as part of the 6th framework programme (contract No. 37670). This research was performed within the framework of the Center for Translational Molecular Medicine (CTTM) (http://www.ctmm.nl), project LeARN (grant 02N-101). The AIBL study was funded in part by the study partners (Australian Commonwealth Scientific Industrial and Research Organization [CSIRO], Edith Cowan University [ECU], Mental Health Research Institute [MHRI], Alzheimer’s Australia [AA], National Ageing Research Institute [NARI], Austin Health, CogState, Hollywood Private Hospital, Sir Charles Gardner Hospital). The study also received support from the National Health and Medical Research Council (NHMRC) and the Dementia Collaborative Research Centres program (DCRC2), as well as ongoing funding from the Science and Industry Endowment Fund (SIEF). 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 the US Department of Defense ADNI (W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging and 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; F. Hoffmann-La Roche and its affiliated company Genentech; GE Healthcare; Innogenetics; IXICO; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Medpace; Merck; Meso Scale Diagnostics; NeuroRx Research; Novartis Pharmaceuticals; Pfizer; Piramal Imaging; Servier; Synarc; and Takeda Pharmaceutical. 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 (http://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. The Dementia Competence Network (DCN) has been supported by a grant from the German Federal Ministry of Education and Research (BMBF): Kompetenznetz Demenzen (01GI0420). Additional funding related to the randomized clinical trials came from Janssen-Cilag and Merz Pharmaceuticals. The latter funds were exclusively used for personnel, pharmaceuticals, blistering and shipment of medication, and monitoring and as capitation fees for recruiting centers. Funding source for the Chandigarh study is the Indian Council of Medical Research (ICMR), India. Funding for the St Louis contribution was provided by the National Institute on Aging (P50 AG005681, P01 AG003991, and P01 AG026276); Fred Simmons and Olga Mohan, and the Charles and Joanne Knight Alzheimer’s Research Initiative of the Washington University Knight Alzheimer’s Disease Research Center. The Tours study received financial support of the French Ministry of Health grant PHRC-N 2008 1004 and the EC-FP6-project DiMI, LSHB-CT-2005-512146. The Caen study was funded by Agence Nationale de la Recherche, Programme Hospitalier de Recherche Clinique, Région Basse Normandie, and Institut National de la Santé et de la Recherche Médicale (Inserm). The research leading to the Munich contribution to the Mattsson multicenter study has received funding from the program “Investissements d’avenir” (ANR-10-IAIHU-06). The study from Pittsburgh was supported by National Institutes of Health grants (P50 AG005133, R37 AG025516, P01 AG025204). The New York contributions to the Mattsson multicenter study were in part supported by P30 AG008051, R01 AG13616, R01 AG022374, and R01 AG12101. Data from Brescia in this article were collected by Translational Outpatient Memory Clinic (TOMC) working group at IRCCS Fatebenefratelli in Brescia, Italy. Contributors to the TOMC are G. Amicucci, S. Archetti, L. Benussi, G. Binetti, L. Bocchio-Chiavetto, C. Bonvicini, E. Canu, F. Caobelli, E. Cavedo, E. Chittò, M. Cotelli, M. Gennarelli, S. Galluzzi, C. Geroldi, R. Ghidoni, R. Giubbini, U. P. Guerra, G. Kuffenschin, G. Lussignoli, D. Moretti, B. Paghera, M. Parapini, C. Porteri, M. Romano, S. Rosini, I. Villa, R. Zanardini, and O. Zanetti. The JPND Project is supported in Italy by the Italian Ministry of Health. The assembling of the TU Munich data set was supported in part by the German research foundation (Deutsche Forschungsgemeinschaft) (HE 4560/1-2, DR 445/3-1 and DR 445/4-1 to A.D.), and by a KKF grant for clinical research of the Technische Universität München (to A.D. and T.G.). The Florbetaben phase 2 study from which data were derived for this multicenter evaluation was sponsored by Bayer Healthcare/Piramal Imaging (Berlin, Germany). This work was supported by the University of Antwerp Research Fund; the Alzheimer Research Foundation (SAO-FRA); the Research Foundation Flanders (FWO); the Agency for Innovation by Science and Technology (IWT); the Belgian Science Policy Office Interuniversity Attraction Poles (IAP) program; and the Flemish Government–initiated Methusalem excellence grant.
Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors’ respective organizations were given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.
Disclaimer: Any views expressed in this publication represent the personal opinions of the authors and not those of their respective employers.
Additional Contributions: We acknowledge Gabriel Miltenberger-Miltényi and André Janeiro (Institute of Molecular Medicine, Lisbon) for quantification of CSF biomarkers assembled in the Lisbon contribution. Neither individual was compensated for the contribution besides salary. Multicenter studies involved in this project included the following: European Medical Information Framework–Alzheimer Disease (EMIF-AD); Biomarkers for Alzheimer Disease and Parkinson Disease (BIOMARKAPD); Alzheimer’s Disease Neuroimaging Initiative (ADNI); Australian Imaging, Biomarkers & Lifestyle (AIBL) study; Avid Pharmaceuticals multicenter study for the AV45-A17 Study Group; Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) study; German Dementia Competence Network (DCN); European Beta Amyloid Oligomers in the Early Diagnosis of AD and as Marker for Treatment Response (EDAR) study; Florbetaben (FBB) Phase 2 multicenter study; Leiden Alzheimer-Research Nederland (LeARN) project; Mattsson et al (2009) multicenter study; Multicenter study by UK Hospitals and University Hospital of Turku. Part of the data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://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/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. Additional information is available in the Supplement.
Correction: This article was corrected online May 19, 2015, to fix curves in Figure 3C.