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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum

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Willemijn J. Jansen, Olin Janssen, Betty M. Tijms, Stephanie J.B. Vos, Rik Ossenkoppele, Pieter Jelle Visser, Dag Aarsland, Daniel Alcolea, Daniele Altomare, Christine Von Arnim, Simone Baiardi, Ines Baldeiras, Henryk Barthel, Randall J. Bateman, Bart Van Berckel, Alexa Pichet Binette, Kaj Blennow, Merce Boada, Henning Boecker, Michel Bottlaender & 162 more Anouk Den Braber, David J. Brooks, Mark A. Van Buchem, Vincent Camus, Jose Manuel Carill, Jiri Cerman, Kewei Chen, Gaël Chételat, Elena Chipi, Ann D. Cohen, Alisha Daniels, Marion Delarue, Mira Didic, Alexander Drzezga, Bruno Dubois, Marie Eckerström, Laura L. Ekblad, Sebastiaan Engelborghs, Stéphane Epelbaum, Anne M. Fagan, Yong Fan, Tormod Fladby, Adam S. Fleisher, Wiesje M. Van Der Flier, Stefan Förster, Juan Fortea, Kristian Steen Frederiksen, Yvonne Freund-Levi, Lars Frings, Giovanni B. Frisoni, Lutz Fröhlich, Tomasz Gabryelewicz, Hermann Josef Gertz, Kiran Dip Gill, Olymbia Gkatzima, Estrella Gómez-Tortosa, Timo Grimmer, Eric Guedj, Christian G. Habeck, Harald Hampel, Ron Handels, Oskar Hansson, Lucrezia Hausner, Sabine Hellwig, Michael T. Heneka, Sanna Kaisa Herukka, Helmut Hildebrandt, John Hodges, Jakub Hort, Chin Chang Huang, Ane Juaristi Iriondo, Yoshiaki Itoh, Adrian Ivanoiu, William J. Jagust, Frank Jessen, Peter Johannsen, Keith A. Johnson, Ramesh Kandimalla, Elisabeth N. Kapaki, Silke Kern, Lena Kilander, Aleksandra Klimkowicz-Mrowiec, William E. Klunk, Norman Koglin, Johannes Kornhuber, Milica G. Kramberger, Hung Chou Kuo, Koen Van Laere, Susan M. Landau, Brigitte Landeau, Dong Young Lee, Mony De Leon, Cristian E. Leyton, Kun Ju Lin, Alberto Lleó, Malin Löwenmark, Karine Madsen, Wolfgang Maier, Jan Marcusson, Marta Marquié, Pablo Martinez-Lage, Nancy Maserejian, Niklas Mattsson, Alexandre De Mendonça, Philipp T. Meyer, Bruce L. Miller, Shinobu Minatani, Mark A. Mintun, Vincent C.T. Mok, Jose Luis Molinuevo, Silvia Daniela Morbelli, John C. Morris, Barbara Mroczko, Duk L. Na, Andrew Newberg, Flavio Nobili, Agneta Nordberg, Marcel G.M. Olde Rikkert, Catarina Resende De Oliveira, Pauline Olivieri, Adela Orellana, George Paraskevas, Piero Parchi, Matteo Pardini, Lucilla Parnetti, Oliver Peters, Judes Poirier, Julius Popp, Sudesh Prabhakar, Gil D. Rabinovici, Inez H. Ramakers, Lorena Rami, Eric M. Reiman, Juha O. Rinne, Karen M. Rodrigue, Eloy Rodríguez-Rodriguez, Catherine M. Roe, Pedro Rosa-Neto, Howard J. Rosen, Uros Rot, Christopher C. Rowe, Eckart Rüther, Agustín Ruiz, Osama Sabri, Jayant Sakhardande, Pascual Sánchez-Juan, Sigrid Botne Sando, Isabel Santana, Marie Sarazin, Philip Scheltens, Johannes Schröder, Per Selnes, Sang Won Seo, Dina Silva, Ingmar Skoog, Peter J. Snyder, Hilkka Soininen, Marc Sollberger, Reisa A. Sperling, Luisa Spiru, Yaakov Stern, Erik Stomrud, Akitoshi Takeda, Marc Teichmann, Charlotte E. Teunissen, Louisa I. Thompson, Jori Tomassen, Magda Tsolaki, Rik Vandenberghe, Marcel M. Verbeek, Frans R.J. Verhey, Victor Villemagne, Sylvia Villeneuve, Jonathan Vogelgsang, Gunhild Waldemar, Anders Wallin, Åsa K. Wallin, Jens Wiltfang, David A. Wolk, Tzu Chen Yen, Marzena Zboch, Henrik Zetterberg

Original languageEnglish
Pages (from-to)228-243
Number of pages16
JournalJAMA Neurology
Volume79
Issue number3
Early online date31 Jan 2022
DOIs
Accepted/In press2022
E-pub ahead of print31 Jan 2022
PublishedMar 2022

Bibliographical note

Funding Information: Funding/Support: This study was funded by Biogen. Funding Information: from Pfizer, Avid, and MSD Avenir (paid to the institution); receiving travel funding from Eisai Inc, Functional Neuromodulation, Axovant, Eli Lilly and Company, Takeda and Zinfandel, GE Healthcare, and Oryzon Genomics; receiving consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd, Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation; participating in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai Inc, Eli Lilly and Company, Cytox Ltd, GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics; being the inventor of 11 patents (In Vitro Multiparameter Determination Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders, patent number 8916388; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases, patent number 8298784; Neurodegenerative Markers for Psychiatric Conditions, publication number 20120196300; In Vitro Multiparameter Determination Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders, publication number 20100062463; In Vitro Method for the Diagnosis and Early Diagnosis of Neurodegenerative Disorders, publication number 20100035286; In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases, publication number 20090263822; In Vitro Method for the Diagnosis of Neurodegenerative Diseases, patent number 7547553; CSF Diagnostic In Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases, publication number 20080206797; In Vitro Method for the Diagnosis of Neurodegenerative Diseases, publication number 20080199966; Neurodegenerative Markers for Psychiatric Conditions, publication number 20080131921; and Method for Diagnosis of Dementias and Neuroinflammatory Diseases Based on an Increased Level of Procalcitonin in Cerebrospinal Fluid, United States patent 10921330). Dr Jagust reported consulting for Biogen, Bioclinica, and Genentech. Dr Koglin reported being employed at Life Molecular Imaging. Dr Marquié reported receiving research funding from ISCIII Acción Estratégica en Salud, which was integrated in the Spanish National RCDCI Plan and financed by a grant from ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa). Dr Morris reported receiving grants from the National Institutes of Health (NIH). Dr Nobili reported receiving fees for teaching courses from GE Healthcare and Biogen, for advisory board participation from Roche and Biogen, and for consultation from Bial. Dr Popp reported receiving consultation and speaker honoraria from Nestle Institute of Health Sciences, Innovation Campus, EPFL, Ono Pharma, OM Pharma Suisse, and Fujirebio Europe. Dr Rowe reported receiving grants from Cerveau Technologies, Biogen, and AbbVie as well as serving on the scientific advisory committee of Cerveau Technologies and the medical education faculty of Biogen. Dr Ruiz reported receiving support from Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISCIII); the EU/European Federation of Pharmaceutical Industries and Associations (EFPIA) Innovative Medicines Initiative Joint Undertaking; grants from the EXIT (Exosomes Isolation Tool with Nanofluidic Concentration Device) project, EU Euronanomed3 Program, and PREADAPT project; grant from the Funding Information: Shatau7-Imatau studies (Sarazin, Paris) were supported by grants PHRC-0054-N 2010 and PHRC-2013-0919 from the French Health Ministry, the Institut Roche de Recherche et Medecine Translationelle (Imabio3), Service Hospitalier Frédéric Joliot, Fondation pour la Recherche sur Alzheimer, Institut de Recherches Internationales Servier, and France-Alzheimer (Shatau7-Imatau). The Nijmegen cohort was supported by the BIONIC project (grant 733050822 from ZonMW-Memorabel as part of the Dutch National Deltaplan for Dementia [zonmw.nl/dementiaresearch]), the CAFÉ project (grant 5R01NS104147-02 from the NIH), and the Selfridges Group Foundation (grant NR170024). The BIONIC project is a consortium of Radboudumc, LUMC, ADX Neurosciences, and Rhode Island University. Funding Information: Joint Program for Neurodegenerative Diseases; and research funding from ISCIII Acción Estratégica en Salud, which was integrated in the Spanish National RCDCI Plan and financed by a grant from ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER; Una manera de hacer Europa) by Fundación Bancaria La Caixa and Grífols SA (GR@ACE project). Dr Sabri reported receiving grants from Life Molecular Imaging. Dr Snyder reported being a consultant to Alzheon Inc, AlzeCure Pharma, and AlzPATH Inc outside the submitted work. Dr Soininen reported receiving personal consultation fees from AC Immune and Novo Nordisk outside the submitted work. Dr Sperling reported receiving honorarium for consulting from AC Immune, Acumen, Alnylam, Cytox, Genentech, Janssen, JOMDD, Oligomerix, Neuraly, Neurocentria, Renew, Prothena, and Shionogi; reported receiving research funding from the National Institute on Aging (NIA), Alzheimer’s Association, Eisai Inc, Eli Lilly and Company, and Janssen; and reported the following financial relationships for her spouse (Dr Keith Johnson): Cerveau, Janssen, AC Immune, and Novartis. Dr Teunissen reported receiving research support from the European Commission (Marie Curie International Training Network and Joint Program for Neurodegenerative Diseases grants), Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association, and ABOARD (A Personalized Medicine Approach for Alzheimer's Disease), which is a public-private partnership supported by ZonMW, Alzheimer Nederland, Health Holland, Gieskes-Strijbisfonds, and Edwin Bouw Fonds; having a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly and Company; performing contract research or receiving grants from AC Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai Inc, PeopleBio, Roche, Toyama, and Vivoryon; serving on editorial boards of Medidact Neurologie/ Springer, Alzheimer Research and Therapy, and Neurology: Neuroimmunology & Neuroinflammation; and being editor of a neuromethods book from Springer. Dr van der Flier reported holding the Pasman chair and receiving funding from ABOARD. Dr A. Wallin reported receiving gratuity for lectures from Lundbeck. Dr Zetterberg reported serving at scientific advisory boards and/or as a consultant for Alector, Eisai Inc, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, CogRx, and Red Abbey Labs; giving lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen; and being a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, outside the submitted work. No other disclosures were reported. Funding Information: reported participating in advisory boards from Fujirebio-Europe and Roche Diagnostics; receiving speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica SL, Zambon SAU, and Esteve Pharmaceuticals SA; and filing a patent application (WO2019175379 A1 Markers of Synaptopathy in Neurodegenerative Disease). Dr von Arnim reported receiving honoraria from serving on the scientific advisory board of Biogen, Roche, and Dr Willmar Schwabe GmbH & Co KG; funding for travel and speaker honoraria from Lilly GmbH, Daiichi Sankyo, Biogen, Roche Diagnostics AG, and Dr Willmar Schwabe GmbH & Co KG; and research support from Roche Diagnostics AG. Dr Chételat reported receiving research support from the European Union (EU)’s Horizon 2020 Research and Innovation Programme, Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation d’Entreprise MMA des Entrepreneurs du Futur, Fondation Alzheimer, Programme Hospitalier de Recherche Clinique, Région Normandie, Association France Alzheimer et Maladies Apparentées, Fondation Recherche Alzheimer, and Fondation Vaincre Alzheimer (all to INSERM), as well as personal fees from Fondation d’Entreprise MMA des Entrepreneurs du Futur. Dr Barthel reported receiving grants from Life Molecular Imaging. Dr Eckerström reported being employed as an independent reviewer at Medavante-Prophase. Dr Engelborghs reported participating in consultancy or on advisory boards of Biogen, Danone, Eisai Inc, Icometrix, Pfizer, Novartis, and Roche, and receiving unrestricted research grants (paid to his institution) from ADx Neurosciences and Janssen Pharmaceuticals. Dr Grimmer reported receiving consulting fees from AbbVie, Anavex, Biogen, Bracket, Eli Lilly and Company, Functional Neuromodulation, Iqvia/ Quintiles, Novartis, Novo Nordisk, NuiCare, Roche Pharma, Toyama, and Vivoryon; lecture fees from Actelion, B. Braun, Biogen, Eli Lilly and Company, Life Molecular Imaging, Novartis, Parexel, and Roche Pharma; and grants to his institution from Actelion and Novartis. Dr Guedj reported having a scientific collaboration on amyloid positron emission tomography (PET) imaging with Life Molecular Imaging before 2018. Dr Hampel reported being an employee of Eisai Inc; being an unpaid senior associate editor for the journal Alzheimer’s & Dementia; previously receiving lecture fees from Servier, Biogen, and Roche; receiving research grants Funding Information: HABS study was launched in 2010, is funded by the NIA, and is led by principal investigators Drs Sperling and Johnson at Massachusetts General Hospital, Harvard Medical School. A proportion of the data used in preparation of this article was obtained from the following: LEARN study, which was performed within the framework of the Center for Translational Molecular Medicine, a Dutch public-private partnership (project LEARN; grant 02 N-101 from Center for Translational Molecular Medicine); DIAN (grant UF01AG032438 from NIA), which was funded by the NIA, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, and partially by the research and development grants for dementia from Japan Agency for Medical Research and Development and Korea Health Technology Research and Development Project through the Korea Health Industry Development Institute; and PREVENT-AD program (https://douglas.research. mcgill.ca/stop-ad-centre; data release 5.0, November 30, 2017), which provided and contributed to the design and implementation of PREVENT-AD data but did not participate in the analysis or writing of this article. A complete listing of PREVENT-AD research group investigators can be found at http://preventad.loris.ca/ acknowledgements/acknowledgements.php?date= [2020=04-01]. The FACEHBI study was supported by funds from Fundació ACE Institut Català de Neurociències Aplicades, Grifols, Life Molecular Imaging, Araclon Biotech, Alkahest, Laboratorio de Análisis Echevarne and IrsiCaixa. Part of the present study was supported by the European Medical Information Framework Alzheimer's Disease (EMIF-AD), which received support from the Innovative Medicines Initiative Joint Undertaking under EMIF-AD grant agreement 115372 that comprised financial contribution from the EU’s Seventh Framework Program (FP7/2007-2013) and in kind contribution from EFPIA companies. Research of Alzheimer Centre Amsterdam was part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Centre Amsterdam was supported by Stichting Alzheimer Nederland and Stichting VUmc Fonds. The SCIENCe project was supported by research grants from Gieskes-Strijbis Fonds and Stichting Dioraphte. PET scans in the Amsterdam Dementia Cohort were obtained with research grants from GE Healthcare, Life Molecular Imaging, AVID, and ZonMW-Memorabel, the research and innovation program for dementia. The Sant Pau Memory Unit received funding from CIBERNED, ISCIII, which is jointly funded by FEDER, EU, Una manera de hacer Europa; Generalitat de Catalunya; Fundació La Marató TV3 Fundació Bancària Obra Social La Caixa; Fundación BBVA; Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica; Global Brain Health Institute; Fundació Catalana Síndrome de Down; and Fundació Víctor Grífols i Lucas. The International Mind, Activities and Urban Places (IMAP) study (Dr Chételat; Caen, France) was supported by the Programme Hospitalier de Recherche Clinique (grants PHRCN 2011-A01493-38 and PHRCN 2012 12-006-0347), the Agence Nationale de la Recherche (ANR LONGVIE 2007), Fondation Plan Alzheimer (Alzheimer Plan 2008-2012), Association France Alzheimer et Maladies Apparentées AAP 2013, the Région Basse Normandie, and INSERM. The Phoenix Arizona APOE Cohort was funded by grant R01 AG031581 from the NIA. The Imabio3 and Funding Information: Additional Information: Data used in preparation of the present article were obtained from the ADNI database (adni.loni.usc.edu). As such, ADNI investigators provided and contributed to the design and implementation of the ADNI data but did not participate in the analysis or writing of this article. 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. The ADNI was launched in 2003 as a public-private partnership, led by principal investigator Michael W. Weiner, MD. The primary goal of ADNI is to test whether serial magnetic resonance imaging, PET, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment and early Alzheimer disease. Data collection and sharing for this project was funded by grant U01 AG024904 from the NIH and award W81XWH-12-2-0012 from the US Department of Defense. The ADNI is funded by the NIA; the National Institute of Biomedical Imaging and Bioengineering; and AbbVie, Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica Inc, Biogen, Bristol-Myers Squibb Company, CereSpir Inc, Cogstate, Eisai Inc, Elan Pharmaceuticals Inc, Eli Lilly and Company, EuroImmun, F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc, Fujirebio, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research and Development LLC, Johnson & Johnson Pharmaceutical Research and Development LLC, Lumosity, Lundbeck, Merck & Co Inc, Meso Scale Diagnostics LLC, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals Corporation, Pfizer Inc, Piramal Imaging, Servier, Takeda Pharmaceutical Company, and Transition Therapeutics. The Canadian Institutes of Health Research provides support to the ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH (www. fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute (ATRI) at the University of Southern California. The ADNI data are disseminated by the Laboratory for Neuroimaging at the University of Southern California. The A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies are led by Dr Sperling at Brigham and Women’s Hospital, Harvard Medical School, and by Dr Paul Aisen at the ATRI. The A4 and LEARN studies are coordinated by the ATRI, and the data are made available through the Laboratory for Neuroimaging. The participants screening for the A4 Study provided permission to share their deidentified data to advance the objective to find a successful treatment for Alzheimer disease. The A4 Study is a secondary prevention trial in preclinical Alzheimer disease that aims to slow cognitive decline associated with brain amyloid accumulation in clinically normal older individuals. Data used in the preparation of this article were obtained from the Harvard Aging Brain Study (HABS; grant P01AG036694 from NIA). The Publisher Copyright: © 2022 American Medical Association. All rights reserved.

King's Authors

Abstract

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. Objective: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. Design, Setting, and Participants: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. Exposures: Alzheimer disease biomarkers detected on PET or in CSF. Main Outcomes and Measures: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. Results: Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P =.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P =.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P =.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P =.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P =.18). Conclusions and Relevance: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

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