Abstract
Introduction: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration.
Methods: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration.
Results: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE epsilon 4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage.
Discussion: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
| Original language | English |
|---|---|
| Pages (from-to) | 888-898 |
| Number of pages | 11 |
| Journal | Alzheimer's & Dementia |
| Volume | 15 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Jul 2019 |
Keywords
- Alzheimer's disease
- Disease duration
- Preclinical
- Prodromal
- Dementia
- APOE
- Clinical setting
- Progression
- Multistate model
- MILD COGNITIVE IMPAIRMENT
- BETA-AMYLOID 1-42
- ASSOCIATION WORKGROUPS
- DIAGNOSTIC GUIDELINES
- NATIONAL INSTITUTE
- RISK-FACTORS
- DECLINE
- PREVALENCE
- NEURODEGENERATION
- RECOMMENDATIONS
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In: Alzheimer's & Dementia, Vol. 15, No. 7, 07.2019, p. 888-898.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype
AU - Vermunt, Lisa
AU - Sikkes, Sietske A. M.
AU - van den Hout, Ardo
AU - Handels, Ron
AU - Bos, Isabelle
AU - van der Flier, Wiesje M.
AU - Kern, Silke
AU - Ousset, Pierre-Jean
AU - Maruff, Paul
AU - Skoog, Ingmar
AU - Verhey, Frans R. J.
AU - Freund-Levi, Yvonne
AU - Tsolaki, Magda
AU - Wallin, Asa K.
AU - Rikkert, Marcel Olde
AU - Soininen, Hilkka
AU - Spiru, Luisa
AU - Zetterberg, Henrik
AU - Blennow, Kaj
AU - Scheltens, Philip
AU - Muniz-Terrera, Graciela
AU - Visser, Pieter Jelle
AU - Vellas, B.
AU - Reynish, E.
AU - Ousset, P. J.
AU - Andrieu, S.
AU - Burns, A.
AU - Pasquier, F.
AU - Frisoni, G.
AU - Salmon, E.
AU - Michel, J. P.
AU - Zekry, D. S.
AU - Boada, M.
AU - Dartigues, J. F.
AU - Olde-Rikkert, M. G. M.
AU - Rigaud, A. S.
AU - Winblad, B.
AU - Malick, A.
AU - Sinclair, A.
AU - Froelich, L.
AU - Scheltens, P.
AU - Ribera, C.
AU - Touchon, J.
AU - Robert, P.
AU - Salva, A.
AU - Waldemar, G.
AU - Bullock, R.
AU - Tsolaki, M.
AU - Rodriguez, G.
AU - Spiru, L.
AU - Alzheimer's Disease Neuroimaging Initiative
AU - AIBL Research Group
AU - ICTUS study group
AU - DSA Study Group
N1 - Funding Information: Gothenburg H70: The Swedish Research Council (2015-02830, 2013-8717); Swedish Research Council for Health, Working Life and Welfare (No 2013-2496, 2013-2300, 2010-0870, 2012-1138); Sahlgrenska University Hospital (ALF 716681); the Alzheimer's Association Zenith Award (ZEN-01-3151); the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159); Alzheimerfonden; Hjärnfonden; and Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse. Funding Information: ICTUS/DSA: The ICTUS study was partially supported by a grant from the European Commission within the 5th framework program (QLK6-CT-2002-02645) and partially from an unrestricted equal grant from each of Eisai , Janssen , Lundbeck , and Novartis pharmaceutical companies. The pharmaceutical companies had no role in study design, data collection, data analysis, and data interpretation. Promotion of the ICTUS study was supported by the University Hospital Center of Toulouse . The data sharing activity was supported by the “ Association Monegasque pour la recherche sur la maladie d'Alzheimer ”(AMPA) and the UMR 1027 Unit INSERM–University of Toulouse III. Funding Information: Kern, Wallin, Olde Rikkert, Ousset, Spiru, Freund-Levi, Tsolaki, Muniz-Terrera, and van den Hout report no disclosures. Vermunt, Sikkes, Visser, and Handels report grants from European Brain Council (VoT project; 2017). Dr Bos has received research support from the Innovative Medicines Initiatives Joint Undertaking under resources that are composed of financial contributions from EU FP7 (FP7/2007-2013) and in-kind EFPIA. Ron Handels reports grants from BIOMARKAPD (EU JPND; 2012-2016), Actifcare (EU JPND; 2014-2017), Dutch Flutemetamol Study (2012-2017), ROADMAP (IMI2; 2016-2019), SNAC (Sweden public funding; 2016-2018), MIND-AD (EU JPND; 2017-2018), Alzheimer Association Nederland (NL fellowship; 2017-2019), Economic and Policy Implications of new treatment for AD (ARUK; 2017-2018), various ZonMw projects (NL public funding; 2017-2022), and RECAGE (EU H2020; 2018-2022) and personal fees from Piramal (advisory; 2016) and Roche (advisory; 2017). Research programs of Dr van der Flier have been funded by ZonMw , the Netherlands Organization of Scientific Research , Seventh European Framework Program, Alzheimer Nederland , Cardiovascular Onderzoek Nederland , Stichting Dioraphte , Gieskes, Strijbis fonds, Boehringer Ingelheim , Piramal Imaging, Roche BV, Janssen Stellar , and Combinostics. All funding is paid to her institution. Skoog reports consultant fee for Takeda. Dr Scheltens has acquired grant support (for the institution) from GE Healthcare , Danone Research, Piramal, and Merck . In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Lilly, GE Healthcare, Novartis, Sanofi, Nutricia, Probiodrug, Biogen, Roche, Avraham, and EIP Pharma. Paul Maruff is an employee of Cogstate Ltd. Frans RJ Verhey received grants from H2020 Induct (2016-2020), Pride Alzheimer UK (2015-2020), Actifcare (EU JPND; 2014-2017), Gieskes-Strijbis (PRECODE 2018-2022), Noaber Foundation (INPAD 2017-2021), and Interreg (SFC, 2016-202). Hilkka Soininen reports advisory board member for ACImmune and MERCK. Kaj Blennow is a advisor for Fujirebio Europe, IBL International, and Roche Diagnostics and a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures–based platform company at the University of Gothenburg. Henrik Zetterberg is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures–based platform company at the University of Gothenburg. Dr. Visser reports grants from Innovative Medicine Initiative , during the conduct of the study; nonfinancial support from GE Healthcare , other from Eli-Lilly , Janssen Pharmaceutical , grants from Biogen , and outside the submitted work. Funding Information: Funding support: Funders had no role in study design, data analysis, data interpretation, or writing of the report. The work was supported by the IALSA ( Integrative Analysis of Longitudinal Studies of Aging and Dementia ) network, which received support by NIH grant P01AG043362 (2013-2018); from the Innovative Medicines Initiative Joint Undertaking EMIF grant agreement number 115372, EPAD grant agreement number 115736, resources, and ROADMAP grant agreement number 116020 of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies' in-kind contribution; and the European Brian Council. Funding Information: AIBL: Funding for the AIBL study was provided 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 Aging Research Institute (NARI), Austin Health, CogState Ltd. , Hollywood Private Hospital , and Sir Charles Gardner Hospital ]. The study also received support from the National Health and Medical Research Council (NHMRC) and the Dementia Collaborative Research Centers program (DCRC2), as well as ongoing funding from the Science and Industry Endowment Fund (SIEF). The authors acknowledge the financial support of the Australian Government Cooperative Research Center for Mental Health . Funding Information: ADC: The VU University Medical Center (VUMC) Alzheimer Center is supported by Alzheimer Nederland and Stichting VUMC funds . This study was performed within the framework of the Dutch ABIDE project and was supported by a ZonMW-Memorabel grant (project No 733050201) in the context of the Dutch Deltaplan Dementie and through a grant of Piramal Imaging (positron emission tomography scan costs) to the Stichting Alzheimer en Neuropsychiatrie , Amsterdam. Research of the VUMC Alzheimer Center is part of the neurodegeneration research program of Amsterdam Neuroscience. The clinical database structure was developed with funding from Stichting Dioraphte. Funding Information: ADNI: 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 Defense 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: AbbVie ; Alzheimer's Association ; Alzheimer's Drug Discovery Foundation ; Araclon Biotech; BioClinica, Inc. ; Biogen ; Bristol-Myers Squibb Company ; CereSpir, Inc.; Cogstate; Eisai ; 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 & Development, LLC. ; Johnson & Johnson Pharmaceutical Research & 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 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. Funding Information: The authors are very thankful to all patients and participants in the studies included in this study, as well as to everyone involved in the data collection and data sharing. ICTUS study group refers to Vellas B. Reynish E. Ousset PJ. Andrieu S. (Toulouse), Burns A. (Manchester), Pasquier F. (Lille), Frisoni G. (Brescia), Salmon E. (Li?ge), Michel J.P. Zekry D.S. (Geneva), Boada M. (Barcelona), Dartigues J.F. (Bordeaux), Olde-Rikkert M.G.M. (Nijmegen), Rigaud A.S. (Paris), Winblad B. (Huddinge), Malick A. Sinclair A. (Warwick), Fr?lich L.(Mannheim), Scheltens P. (Amsterdam), Ribera C.(Madrid), Touchon J. (Montpellier), Robert P. (Nice), Salva A. (Barcelona), Waldemar G. (Copenhagen), Bullock R. (Swindon), Tsolaki M. (Thessaloniki), Rodriguez G. (Genoa), Spiru L. (Bucharest), Jones R.W. (Bath), Stiens G. Stoppe G. (G?ttingen), Eriksdotter J?nhagen M. (Stockholm), Cherubini A. (Perugia), Lage P.M. Gomez-Isla T. (Pamplona), Camus V. (Tours), Ag?era-Morales E. and Lopez F. (Cordoba). DSA group refers to Andrieu S. Savy S. Cantet C. and Coley N. Kern, Wallin, Olde Rikkert, Ousset, Spiru, Freund-Levi, Tsolaki, Muniz-Terrera, and van den Hout report no disclosures. Vermunt, Sikkes, Visser, and Handels report grants from European Brain Council (VoT project; 2017). Dr Bos has received research support from the Innovative Medicines Initiatives Joint Undertaking under resources that are composed of financial contributions from EU FP7 (FP7/2007-2013) and in-kind EFPIA. Ron Handels reports grants from BIOMARKAPD (EU JPND; 2012-2016), Actifcare (EU JPND; 2014-2017), Dutch Flutemetamol Study (2012-2017), ROADMAP (IMI2; 2016-2019), SNAC (Sweden public funding; 2016-2018), MIND-AD (EU JPND; 2017-2018), Alzheimer Association Nederland (NL fellowship; 2017-2019), Economic and Policy Implications of new treatment for AD (ARUK; 2017-2018), various ZonMw projects (NL public funding; 2017-2022), and RECAGE (EU H2020; 2018-2022) and personal fees from Piramal (advisory; 2016) and Roche (advisory; 2017). Research programs of Dr van der Flier have been funded by ZonMw, the Netherlands Organization of Scientific Research, Seventh European Framework Program, Alzheimer Nederland, Cardiovascular Onderzoek Nederland, Stichting Dioraphte, Gieskes, Strijbis fonds, Boehringer Ingelheim, Piramal Imaging, Roche BV, Janssen Stellar, and Combinostics. All funding is paid to her institution. Skoog reports consultant fee for Takeda. Dr Scheltens has acquired grant support (for the institution) from GE Healthcare, Danone Research, Piramal, and Merck. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Lilly, GE Healthcare, Novartis, Sanofi, Nutricia, Probiodrug, Biogen, Roche, Avraham, and EIP Pharma. Paul Maruff is an employee of Cogstate Ltd. Frans RJ Verhey received grants from H2020 Induct (2016-2020), Pride Alzheimer UK (2015-2020), Actifcare (EU JPND; 2014-2017), Gieskes-Strijbis (PRECODE 2018-2022), Noaber Foundation (INPAD 2017-2021), and Interreg (SFC, 2016-202). Hilkka Soininen reports advisory board member for ACImmune and MERCK. Kaj Blennow is a advisor for Fujirebio Europe, IBL International, and Roche Diagnostics and a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures?based platform company at the University of Gothenburg. Henrik Zetterberg is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures?based platform company at the University of Gothenburg. Dr. Visser reports grants from Innovative Medicine Initiative, during the conduct of the study; nonfinancial support from GE Healthcare, other from Eli-Lilly, Janssen Pharmaceutical, grants from Biogen, and outside the submitted work. Funding support: Funders had no role in study design, data analysis, data interpretation, or writing of the report. The work was supported by the IALSA (Integrative Analysis of Longitudinal Studies of Aging and Dementia) network, which received support by NIH grant P01AG043362 (2013-2018); from the Innovative Medicines Initiative Joint Undertaking EMIF grant agreement number 115372, EPAD grant agreement number 115736, resources, and ROADMAP grant agreement number 116020 of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies' in-kind contribution; and the European Brian Council. Funding for each of the studies. ADC: The VU University Medical Center (VUMC) Alzheimer Center is supported by Alzheimer Nederland and Stichting VUMC funds. This study was performed within the framework of the Dutch ABIDE project and was supported by a ZonMW-Memorabel grant (project No 733050201) in the context of the Dutch Deltaplan Dementie and through a grant of Piramal Imaging (positron emission tomography scan costs) to the Stichting Alzheimer en Neuropsychiatrie, Amsterdam. Research of the VUMC Alzheimer Center is part of the neurodegeneration research program of Amsterdam Neuroscience. The clinical database structure was developed with funding from Stichting Dioraphte. ADNI: 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 Defense 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: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai; 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 & Development, LLC.; Johnson & Johnson Pharmaceutical Research & 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 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. AIBL: Funding for the AIBL study was provided 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 Aging Research Institute (NARI), Austin Health, CogState Ltd., Hollywood Private Hospital, and Sir Charles Gardner Hospital]. The study also received support from the National Health and Medical Research Council (NHMRC) and the Dementia Collaborative Research Centers program (DCRC2), as well as ongoing funding from the Science and Industry Endowment Fund (SIEF). The authors acknowledge the financial support of the Australian Government Cooperative Research Center for Mental Health. DESCRIPA: The project was funded by the European Commission as part of the 5th Framework Program (QLK-6-CT-2002-02455). The center in Bucharest received support from the Ana Aslan International foundation. Gothenburg H70: The Swedish Research Council (2015-02830, 2013-8717); Swedish Research Council for Health, Working Life and Welfare (No 2013-2496, 2013-2300, 2010-0870, 2012-1138); Sahlgrenska University Hospital (ALF 716681); the Alzheimer's Association Zenith Award (ZEN-01-3151); the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159); Alzheimerfonden; Hj?rnfonden; and Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse. ICTUS/DSA: The ICTUS study was partially supported by a grant from the European Commission within the 5th framework program (QLK6-CT-2002-02645) and partially from an unrestricted equal grant from each of Eisai, Janssen, Lundbeck, and Novartis pharmaceutical companies. The pharmaceutical companies had no role in study design, data collection, data analysis, and data interpretation. Promotion of the ICTUS study was supported by the University Hospital Center of Toulouse. The data sharing activity was supported by the ?Association Monegasque pour la recherche sur la maladie d'Alzheimer?(AMPA) and the UMR 1027 Unit INSERM?University of Toulouse III. Funding Information: The authors are very thankful to all patients and participants in the studies included in this study, as well as to everyone involved in the data collection and data sharing. ICTUS study group refers to Vellas B. Reynish E. Ousset PJ. Andrieu S. (Toulouse), Burns A. (Manchester), Pasquier F. (Lille), Frisoni G. (Brescia), Salmon E. (Liège), Michel J.P. Zekry D.S. (Geneva), Boada M. (Barcelona), Dartigues J.F. (Bordeaux), Olde-Rikkert M.G.M. (Nijmegen), Rigaud A.S. (Paris), Winblad B. (Huddinge), Malick A. Sinclair A. (Warwick), Frölich L.(Mannheim), Scheltens P. (Amsterdam), Ribera C.(Madrid), Touchon J. (Montpellier), Robert P. (Nice), Salva A. (Barcelona), Waldemar G. (Copenhagen), Bullock R. (Swindon), Tsolaki M. (Thessaloniki), Rodriguez G. (Genoa), Spiru L. (Bucharest), Jones R.W. (Bath), Stiens G. Stoppe G. (Göttingen), Eriksdotter Jönhagen M. (Stockholm), Cherubini A. (Perugia), Lage P.M. Gomez-Isla T. (Pamplona), Camus V. (Tours), Agüera-Morales E. and Lopez F. (Cordoba). DSA group refers to Andrieu S. Savy S. Cantet C. and Coley N. Kern, Wallin, Olde Rikkert, Ousset, Spiru, Freund-Levi, Tsolaki, Muniz-Terrera, and van den Hout report no disclosures. Vermunt, Sikkes, Visser, and Handels report grants from European Brain Council (VoT project; 2017). Dr Bos has received research support from the Innovative Medicines Initiatives Joint Undertaking under resources that are composed of financial contributions from EU FP7 (FP7/2007-2013) and in-kind EFPIA. Ron Handels reports grants from BIOMARKAPD (EU JPND; 2012-2016), Actifcare (EU JPND; 2014-2017), Dutch Flutemetamol Study (2012-2017), ROADMAP (IMI2; 2016-2019), SNAC (Sweden public funding; 2016-2018), MIND-AD (EU JPND; 2017-2018), Alzheimer Association Nederland (NL fellowship; 2017-2019), Economic and Policy Implications of new treatment for AD (ARUK; 2017-2018), various ZonMw projects (NL public funding; 2017-2022), and RECAGE (EU H2020; 2018-2022) and personal fees from Piramal (advisory; 2016) and Roche (advisory; 2017). Research programs of Dr van der Flier have been funded by ZonMw, the Netherlands Organization of Scientific Research, Seventh European Framework Program, Alzheimer Nederland, Cardiovascular Onderzoek Nederland, Stichting Dioraphte, Gieskes, Strijbis fonds, Boehringer Ingelheim, Piramal Imaging, Roche BV, Janssen Stellar, and Combinostics. All funding is paid to her institution. Skoog reports consultant fee for Takeda. Dr Scheltens has acquired grant support (for the institution) from GE Healthcare, Danone Research, Piramal, and Merck. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Lilly, GE Healthcare, Novartis, Sanofi, Nutricia, Probiodrug, Biogen, Roche, Avraham, and EIP Pharma. Paul Maruff is an employee of Cogstate Ltd. Frans RJ Verhey received grants from H2020 Induct (2016-2020), Pride Alzheimer UK (2015-2020), Actifcare (EU JPND; 2014-2017), Gieskes-Strijbis (PRECODE 2018-2022), Noaber Foundation (INPAD 2017-2021), and Interreg (SFC, 2016-202). Hilkka Soininen reports advisory board member for ACImmune and MERCK. Kaj Blennow is a advisor for Fujirebio Europe, IBL International, and Roche Diagnostics and a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures–based platform company at the University of Gothenburg. Henrik Zetterberg is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures–based platform company at the University of Gothenburg. Dr. Visser reports grants from Innovative Medicine Initiative, during the conduct of the study; nonfinancial support from GE Healthcare, other from Eli-Lilly, Janssen Pharmaceutical, grants from Biogen, and outside the submitted work. Funding support: Funders had no role in study design, data analysis, data interpretation, or writing of the report. The work was supported by the IALSA (Integrative Analysis of Longitudinal Studies of Aging and Dementia) network, which received support by NIH grant P01AG043362 (2013-2018); from the Innovative Medicines Initiative Joint Undertaking EMIF grant agreement number 115372, EPAD grant agreement number 115736, resources, and ROADMAP grant agreement number 116020 of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and EFPIA companies' in-kind contribution; and the European Brian Council. Funding for each of the studies. ADC: The VU University Medical Center (VUMC) Alzheimer Center is supported by Alzheimer Nederland and Stichting VUMC funds. This study was performed within the framework of the Dutch ABIDE project and was supported by a ZonMW-Memorabel grant (project No 733050201) in the context of the Dutch Deltaplan Dementie and through a grant of Piramal Imaging (positron emission tomography scan costs) to the Stichting Alzheimer en Neuropsychiatrie, Amsterdam. Research of the VUMC Alzheimer Center is part of the neurodegeneration research program of Amsterdam Neuroscience. The clinical database structure was developed with funding from Stichting Dioraphte. ADNI: 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 Defense 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: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai; 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 & Development, LLC.; Johnson & Johnson Pharmaceutical Research & 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 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for NeuroImaging at the University of Southern California. AIBL: Funding for the AIBL study was provided 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 Aging Research Institute (NARI), Austin Health, CogState Ltd., Hollywood Private Hospital, and Sir Charles Gardner Hospital]. The study also received support from the National Health and Medical Research Council (NHMRC) and the Dementia Collaborative Research Centers program (DCRC2), as well as ongoing funding from the Science and Industry Endowment Fund (SIEF). The authors acknowledge the financial support of the Australian Government Cooperative Research Center for Mental Health. DESCRIPA: The project was funded by the European Commission as part of the 5th Framework Program (QLK-6-CT-2002-02455). The center in Bucharest received support from the Ana Aslan International foundation. Gothenburg H70: The Swedish Research Council (2015-02830, 2013-8717); Swedish Research Council for Health, Working Life and Welfare (No 2013-2496, 2013-2300, 2010-0870, 2012-1138); Sahlgrenska University Hospital (ALF 716681); the Alzheimer's Association Zenith Award (ZEN-01-3151); the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159); Alzheimerfonden; Hjärnfonden; and Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse. ICTUS/DSA: The ICTUS study was partially supported by a grant from the European Commission within the 5th framework program (QLK6-CT-2002-02645) and partially from an unrestricted equal grant from each of Eisai, Janssen, Lundbeck, and Novartis pharmaceutical companies. The pharmaceutical companies had no role in study design, data collection, data analysis, and data interpretation. Promotion of the ICTUS study was supported by the University Hospital Center of Toulouse. The data sharing activity was supported by the “Association Monegasque pour la recherche sur la maladie d'Alzheimer”(AMPA) and the UMR 1027 Unit INSERM–University of Toulouse III. Funding Information: DESCRIPA: The project was funded by the European Commission as part of the 5th Framework Program (QLK-6-CT-2002-02455). The center in Bucharest received support from the Ana Aslan International foundation . Publisher Copyright: © 2019 the Alzheimer's Association
PY - 2019/7
Y1 - 2019/7
N2 - Introduction: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration.Methods: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration.Results: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE epsilon 4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage.Discussion: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
AB - Introduction: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration.Methods: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration.Results: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE epsilon 4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage.Discussion: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
KW - Alzheimer's disease
KW - Disease duration
KW - Preclinical
KW - Prodromal
KW - Dementia
KW - APOE
KW - Clinical setting
KW - Progression
KW - Multistate model
KW - MILD COGNITIVE IMPAIRMENT
KW - BETA-AMYLOID 1-42
KW - ASSOCIATION WORKGROUPS
KW - DIAGNOSTIC GUIDELINES
KW - NATIONAL INSTITUTE
KW - RISK-FACTORS
KW - DECLINE
KW - PREVALENCE
KW - NEURODEGENERATION
KW - RECOMMENDATIONS
U2 - 10.1016/j.jalz.2019.04.001
DO - 10.1016/j.jalz.2019.04.001
M3 - Article
SN - 1552-5260
VL - 15
SP - 888
EP - 898
JO - Alzheimer's & Dementia
JF - Alzheimer's & Dementia
IS - 7
ER -