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

Lisa Vermunt, Sietske A M Sikkes, Ardo van den Hout, Ron Handels, Isabelle Bos, Wiesje M van der Flier, Silke Kern, Pierre-Jean Ousset, Paul Maruff, Ingmar Skoog, Frans R J Verhey, Yvonne Freund-Levi, Magda Tsolaki, Åsa K Wallin, Marcel Olde Rikkert, Hilkka Soininen, Luisa Spiru, Henrik Zetterberg, Kaj Blennow, Philip Scheltens, Graciela Muniz-Terrera, Pieter Jelle Visser, Alzheimer Disease Neuroimaging Initiative, AIBL Research Group, ICTUS/DSA study groups, B Vellas, E Reynish, P J Ousset, S Andrieu, A Burns, F Pasquier, G Frisoni, E Salmon, J P Michel, D S Zekry, M Boada, J F Dartigues, M G M Olde-Rikkert, A S Rigaud, B Winblad, A Malick, A Sinclair, L Frölich, P Scheltens, C Ribera, J Touchon, P Robert, A Salva, G Waldemar, R Bullock, M Tsolaki, G Rodriguez, L Spiru, R W Jones, G Stiens, G Stoppe, M Eriksdotter Jönhagen, A Cherubini, P M Lage, T Gomez-Isla, V Camus, E Agüera-Morales, F Lopez, S Andrieu, S Savy, C Cantet, N Coley, Lisa Vermunt, Sietske A M Sikkes, Ardo van den Hout, Ron Handels, Isabelle Bos, Wiesje M van der Flier, Silke Kern, Pierre-Jean Ousset, Paul Maruff, Ingmar Skoog, Frans R J Verhey, Yvonne Freund-Levi, Magda Tsolaki, Åsa K Wallin, Marcel Olde Rikkert, Hilkka Soininen, Luisa Spiru, Henrik Zetterberg, Kaj Blennow, Philip Scheltens, Graciela Muniz-Terrera, Pieter Jelle Visser, Alzheimer Disease Neuroimaging Initiative, AIBL Research Group, ICTUS/DSA study groups, B Vellas, E Reynish, P J Ousset, S Andrieu, A Burns, F Pasquier, G Frisoni, E Salmon, J P Michel, D S Zekry, M Boada, J F Dartigues, M G M Olde-Rikkert, A S Rigaud, B Winblad, A Malick, A Sinclair, L Frölich, P Scheltens, C Ribera, J Touchon, P Robert, A Salva, G Waldemar, R Bullock, M Tsolaki, G Rodriguez, L Spiru, R W Jones, G Stiens, G Stoppe, M Eriksdotter Jönhagen, A Cherubini, P M Lage, T Gomez-Isla, V Camus, E Agüera-Morales, F Lopez, S Andrieu, S Savy, C Cantet, N Coley

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.

Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Multi-state Model
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…
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)

Source: PubMed

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