Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype

doi:10.1016/j.jalz.2019.04.001

. 2019 Jul;15(7):888-898.

doi: 10.1016/j.jalz.2019.04.001. Epub 2019 Jun 1.

Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype

Lisa Vermunt¹, Sietske A M Sikkes², Ardo van den Hout³, Ron Handels⁴, Isabelle Bos⁴, Wiesje M van der Flier⁵, Silke Kern⁶, Pierre-Jean Ousset⁷, Paul Maruff⁸, Ingmar Skoog⁶, Frans R J Verhey⁴, Yvonne Freund-Levi⁹, Magda Tsolaki¹⁰, Åsa K Wallin¹¹, Marcel Olde Rikkert¹², Hilkka Soininen¹³, Luisa Spiru¹⁴, Henrik Zetterberg¹⁵, Kaj Blennow¹⁶, Philip Scheltens¹⁷, Graciela Muniz-Terrera¹⁸, Pieter Jelle Visser¹⁹; Alzheimer Disease Neuroimaging Initiative; AIBL Research Group; ICTUS/DSA study groups

Collaborators, Affiliations

Affiliations

¹ Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. Electronic address: l.vermunt@vumc.nl.
² Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ Department of Statistical Science, University College London, London, UK.
⁴ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Alzheimer Centrum Limburg, Maastricht University, Maastricht, The Netherlands.
⁵ Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁶ Department of Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁷ CHU Toulouse, Gérontopôle and INSERM UMR 1027, Toulouse, France.
⁸ Cogstate Ltd, Florey Institute, University of Melbourne, Melbourne, Australia.
⁹ Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Old Age Psychiatry, Psychology and Neuroscience, King's College London, London, UK; School of Medical Sciences, Orebro University Campus USÖ, Örebro, Sweden.
¹⁰ 3rd Department of Neurology, Aristotle University of Thessaloniki, Memory and Dementia Center, "G Papanicolau" General Hospital, Thessaloniki, Greece.
¹¹ Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Malmö, Sweden.
¹² Department of Geriatric Medicine, Radboudumc Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
¹³ Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.
¹⁴ "Carol Davila" University of Medicine and Pharmacy, Geriatrics-Gerontology and Old Age Psychiatry Clinical Department -"Elias" University Clinical Hospital, Bucarest, Romenia; "Ana Aslan" International Academy of Aging - The Memory Clinic and Longevity Medicine, Bucarest, Romenia.
¹⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL, London, UK.
¹⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁷ Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁸ Centre for Dementia Prevention, University of Edinburgh, Edinburgh, UK.
¹⁹ Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Alzheimer Centrum Limburg, Maastricht University, Maastricht, The Netherlands.

PMID: 31164314
PMCID: PMC6646097
DOI: 10.1016/j.jalz.2019.04.001

Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype

Lisa Vermunt et al. Alzheimers Dement. 2019 Jul.

. 2019 Jul;15(7):888-898.

doi: 10.1016/j.jalz.2019.04.001. Epub 2019 Jun 1.

Authors

Affiliations

¹ Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. Electronic address: l.vermunt@vumc.nl.
² Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ Department of Statistical Science, University College London, London, UK.
⁴ Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Alzheimer Centrum Limburg, Maastricht University, Maastricht, The Netherlands.
⁵ Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁶ Department of Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
⁷ CHU Toulouse, Gérontopôle and INSERM UMR 1027, Toulouse, France.
⁸ Cogstate Ltd, Florey Institute, University of Melbourne, Melbourne, Australia.
⁹ Department of Neurobiology, Caring Sciences and Society (NVS), Karolinska University Hospital Huddinge, Stockholm, Sweden; Department of Old Age Psychiatry, Psychology and Neuroscience, King's College London, London, UK; School of Medical Sciences, Orebro University Campus USÖ, Örebro, Sweden.
¹⁰ 3rd Department of Neurology, Aristotle University of Thessaloniki, Memory and Dementia Center, "G Papanicolau" General Hospital, Thessaloniki, Greece.
¹¹ Department of Clinical Sciences, Clinical Memory Research Unit, Lund University, Malmö, Sweden.
¹² Department of Geriatric Medicine, Radboudumc Alzheimer Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
¹³ Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.
¹⁴ "Carol Davila" University of Medicine and Pharmacy, Geriatrics-Gerontology and Old Age Psychiatry Clinical Department -"Elias" University Clinical Hospital, Bucarest, Romenia; "Ana Aslan" International Academy of Aging - The Memory Clinic and Longevity Medicine, Bucarest, Romenia.
¹⁵ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL, London, UK.
¹⁶ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹⁷ Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁸ Centre for Dementia Prevention, University of Edinburgh, Edinburgh, UK.
¹⁹ Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Alzheimer Centrum Limburg, Maastricht University, Maastricht, The Netherlands.

PMID: 31164314
PMCID: PMC6646097
DOI: 10.1016/j.jalz.2019.04.001

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 ε4 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.

Keywords: APOE; Alzheimer's disease; Clinical setting; Dementia; Disease duration; Multistate model; Preclinical; Prodromal; Progression.

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Figures

**Figure 1.. Multi-state Model**
Arrows indicate fitted progression and reversion rates between stages in the multi-state model. Moderate to severe AD dementia is shortened to moderate AD dementia for readability.

**Figure 2.. Estimated Stage-specific Duration for Starting Stage Preclinical AD**
The panels show the predicted time spend in each stage stacked and stratified for (a) age (model 1); for (b) age, sex, and setting (model 3); and for (c) age, *APOE* genotype, and setting (model 4). Models include age as continues, and (b) sex or (c) *APOE*, and setting as dichotomous covariates. The age refers to the starting stage with preclinical AD and the estimated duration the predicted duration in the subsequent stages in years. The 95% confidence intervals and p-values for estimate comparison can be found for (a) in table 2, for panel (b) in suppl. table B.3, and for panel (c) in suppl. table B.4)

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References

1. Winblad B, et al., Defeating Alzheimer's disease and other dementias: a priority for European science and society. Lancet Neurol, 2016. 15(5): p. 455–532. - PubMed
1. Scheltens P, et al., Alzheimer's disease. Lancet, 2016. 388(10043): p. 505–17. - PubMed
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[1] Winblad B, et al., Defeating Alzheimer's disease and other dementias: a priority for European science and society. Lancet Neurol, 2016. 15(5): p. 455–532. - PubMed

[2] Winblad B, et al., Defeating Alzheimer's disease and other dementias: a priority for European science and society. Lancet Neurol, 2016. 15(5): p. 455–532. - PubMed

[3] Scheltens P, et al., Alzheimer's disease. Lancet, 2016. 388(10043): p. 505–17. - PubMed

[4] Scheltens P, et al., Alzheimer's disease. Lancet, 2016. 388(10043): p. 505–17. - PubMed

[5] Fargo KN, et al., 2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease. Alzheimers & Dementia, 2014. 10(5): p. S430–S452. - PubMed

[6] Fargo KN, et al., 2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease. Alzheimers & Dementia, 2014. 10(5): p. S430–S452. - PubMed

[7] Jansen WJ, et al., Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA, 2015. 313(19): p. 1924–38. - PMC - PubMed

[8] Jansen WJ, et al., Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA, 2015. 313(19): p. 1924–38. - PMC - PubMed

[9] Jack CR Jr., et al., Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol, 2013. 12(2): p. 207–16. - PMC - PubMed

[10] Jack CR Jr., et al., Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol, 2013. 12(2): p. 207–16. - PMC - PubMed

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Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype

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Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype

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