Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease

Hanneke F.M. Rhodius-Meester; Hilkka Liedes; Ted Koene; Afina W. Lemstra; Charlotte E. Teunissen; Frederik Barkhof; Philip Scheltens; Mark Van Gils; Jyrki Lötjönen; Wiesje M. Van Der Flier

doi:10.1186/s13195-018-0348-0

Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease

Hanneke F.M. Rhodius-Meester, Hilkka Liedes, Ted Koene, Afina W. Lemstra, Charlotte E. Teunissen, Frederik Barkhof, Philip Scheltens, Mark Van Gils, Jyrki Lötjönen, Wiesje M. Van Der Flier

Research output: Contribution to journal › Article › Scientific › peer-review

21 Citations (Scopus)

Abstract

Background: Survival after dementia diagnosis varies considerably. Previous studies were focused mainly on factors related to demographics and comorbidity rather than on Alzheimer's disease (AD)-related determinants. We set out to answer the question whether markers with proven diagnostic value also have prognostic value. We aimed to identify disease-related determinants associated with mortality in patients with AD. Methods: We included 616 patients (50% female; age 67 ± 8 years; mean Mini Mental State Examination score 22 ± 3) with dementia due to AD from the Amsterdam Dementia Cohort. Information on mortality was obtained from the Dutch Municipal Register. We used age- and sex-adjusted Cox proportional hazards analysis to study associations of baseline demographics, comorbidity, neuropsychology, magnetic resonance imaging (MRI) (medial temporal lobe, global cortical and parietal atrophy, and measures of small vessel disease), and cerebrospinal fluid (CSF) (β-amyloid 1-42, total tau, and tau phosphorylated at threonine 181 [p-tau]) with mortality (outcome). In addition, we built a multivariate model using forward selection. Results: After an average of 4.9 ± 2.0 years, 213 (35%) patients had died. Age- and sex-adjusted Cox models showed that older age (HR 1.29 [95% CI 1.12-1.48]), male sex (HR 1.60 [95% CI 1.22-2.11]), worse scores on cognitive functioning (HR 1.14 [95% CI 1.01-1.30] to 1.31 [95% CI 1.13-1.52]), and more global and hippocampal atrophy on MRI (HR 1.18 [95% CI 1.01-1.37] and HR 1.18 [95% CI 1.02-1.37]) were associated with increased risk of mortality. There were no associations with comorbidity, level of activities of daily living, apolipoprotein E (APOE) ϵ4 status, or duration of disease. Using forward selection, the multivariate model included a panel of age, sex, cognitive tests, atrophy of the medial temporal lobe, and CSF p-tau. Conclusions: In this relatively young sample of patients with AD, disease-related determinants were associated with an increased risk of mortality, whereas neither comorbidity nor APOE genotype had any prognostic value.

Original language	English
Article number	23
Journal	Alzheimer's Research And Therapy
Volume	10
Issue number	1
DOIs	https://doi.org/10.1186/s13195-018-0348-0
Publication status	Published - 20 Feb 2018
Externally published	Yes
Publication type	A1 Journal article-refereed

Funding

Research done at the VUmc Alzheimer Center is part of the neurodegeneration research program of Amsterdam Neuroscience. The VUmc Alzheimer Center is supported by Alzheimer Nederland and Stichting VUmc Fonds. The clinical database structure was developed with funding from Stichting Dioraphte. HFMRM is appointed on a grant from the European Union Seventh Framework Program project PredictND under grant agreement 611005. CET is a member of the Innogenetics International Advisory Boards of Fujirebio/ Innogenetics and Roche. FB serves/has served on the advisory boards of Bayer-Schering Pharma, Sanofi-Aventis, Biogen-Idec, Teva Pharmaceutical Industries, Merck-Serono, Novartis, Roche, Synthon BV, Jansen Research, and Genzyme. FB has received funding from the Dutch MS Society and the European Union Seventh Framework Program (EU-FP7) and has been a speaker at symposia organized by the Serono Symposia Foundation and Medscape. PS has served as a consultant for Wyeth-Elan, Genentech, Danone, and Novartis and has received funding for travel from Pfizer, Elan, Janssen, and Danone Research. JL reports that Combinostics Oy owns the following intellectual property rights related to this paper: (1) J. Koikkalainen and J. Lotjonen. Method for inferring the state of a system. Publication number US 7840510 B2; application number PCT/ FI2007/050277; (2) J. Lotjonen, J. Koikkalainen, and J. Mattila. State inference in a heterogeneous system. Application number PCT/FI2010/050545; FI20125177. JL is a shareholder in Combinostics Oy. WMvdF performs contract research for Boehringer Ingelheim. Research programs of WMvdF have been funded by ZonMw, the Netherlands Organization for Scientific Research (now), EU-FP7, Alzheimer Nederland, Cardiovascular Onderzoek Nederland, Stichting Dioraphte, Gieskes-Strijbis Fonds, Boehringer Ingelheim, Piramal Neuroimaging, Roche BV, and Janssen Stellar. All funding is paid to WMvdF’s institution. The other authors declare that they have no competing interests.

Keywords

Alzheimer's disease
Diagnostic test assessment
Mortality
Prognosis

ASJC Scopus subject areas

Neurology
Clinical Neurology
Cognitive Neuroscience

Access to Document

10.1186/s13195-018-0348-0

Cite this

@article{be29a1897a1b445794acb1dc6a56250e,

title = "Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease",

abstract = "Background: Survival after dementia diagnosis varies considerably. Previous studies were focused mainly on factors related to demographics and comorbidity rather than on Alzheimer's disease (AD)-related determinants. We set out to answer the question whether markers with proven diagnostic value also have prognostic value. We aimed to identify disease-related determinants associated with mortality in patients with AD. Methods: We included 616 patients (50% female; age 67 ± 8 years; mean Mini Mental State Examination score 22 ± 3) with dementia due to AD from the Amsterdam Dementia Cohort. Information on mortality was obtained from the Dutch Municipal Register. We used age- and sex-adjusted Cox proportional hazards analysis to study associations of baseline demographics, comorbidity, neuropsychology, magnetic resonance imaging (MRI) (medial temporal lobe, global cortical and parietal atrophy, and measures of small vessel disease), and cerebrospinal fluid (CSF) (β-amyloid 1-42, total tau, and tau phosphorylated at threonine 181 [p-tau]) with mortality (outcome). In addition, we built a multivariate model using forward selection. Results: After an average of 4.9 ± 2.0 years, 213 (35%) patients had died. Age- and sex-adjusted Cox models showed that older age (HR 1.29 [95% CI 1.12-1.48]), male sex (HR 1.60 [95% CI 1.22-2.11]), worse scores on cognitive functioning (HR 1.14 [95% CI 1.01-1.30] to 1.31 [95% CI 1.13-1.52]), and more global and hippocampal atrophy on MRI (HR 1.18 [95% CI 1.01-1.37] and HR 1.18 [95% CI 1.02-1.37]) were associated with increased risk of mortality. There were no associations with comorbidity, level of activities of daily living, apolipoprotein E (APOE) ϵ4 status, or duration of disease. Using forward selection, the multivariate model included a panel of age, sex, cognitive tests, atrophy of the medial temporal lobe, and CSF p-tau. Conclusions: In this relatively young sample of patients with AD, disease-related determinants were associated with an increased risk of mortality, whereas neither comorbidity nor APOE genotype had any prognostic value.",

keywords = "Alzheimer's disease, Diagnostic test assessment, Mortality, Prognosis",

author = "Rhodius-Meester, {Hanneke F.M.} and Hilkka Liedes and Ted Koene and Lemstra, {Afina W.} and Teunissen, {Charlotte E.} and Frederik Barkhof and Philip Scheltens and {Van Gils}, Mark and Jyrki L{\"o}tj{\"o}nen and {Van Der Flier}, {Wiesje M.}",

note = "Funding Information: Research done at the VUmc Alzheimer Center is part of the neurodegeneration research program of Amsterdam Neuroscience. The VUmc Alzheimer Center is supported by Alzheimer Nederland and Stichting VUmc Fonds. The clinical database structure was developed with funding from Stichting Dioraphte. HFMRM is appointed on a grant from the European Union Seventh Framework Program project PredictND under grant agreement 611005. Funding Information: CET is a member of the Innogenetics International Advisory Boards of Fujirebio/ Innogenetics and Roche. FB serves/has served on the advisory boards of Bayer-Schering Pharma, Sanofi-Aventis, Biogen-Idec, Teva Pharmaceutical Industries, Merck-Serono, Novartis, Roche, Synthon BV, Jansen Research, and Genzyme. FB has received funding from the Dutch MS Society and the European Union Seventh Framework Program (EU-FP7) and has been a speaker at symposia organized by the Serono Symposia Foundation and Medscape. PS has served as a consultant for Wyeth-Elan, Genentech, Danone, and Novartis and has received funding for travel from Pfizer, Elan, Janssen, and Danone Research. JL reports that Combinostics Oy owns the following intellectual property rights related to this paper: (1) J. Koikkalainen and J. Lotjonen. Method for inferring the state of a system. Publication number US 7840510 B2; application number PCT/ FI2007/050277; (2) J. Lotjonen, J. Koikkalainen, and J. Mattila. State inference in a heterogeneous system. Application number PCT/FI2010/050545; FI20125177. JL is a shareholder in Combinostics Oy. WMvdF performs contract research for Boehringer Ingelheim. Research programs of WMvdF have been funded by ZonMw, the Netherlands Organization for Scientific Research (now), EU-FP7, Alzheimer Nederland, Cardiovascular Onderzoek Nederland, Stichting Dioraphte, Gieskes-Strijbis Fonds, Boehringer Ingelheim, Piramal Neuroimaging, Roche BV, and Janssen Stellar. All funding is paid to WMvdF{\textquoteright}s institution. The other authors declare that they have no competing interests. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = feb,

day = "20",

doi = "10.1186/s13195-018-0348-0",

language = "English",

volume = "10",

number = "1",

}

TY - JOUR

T1 - Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease

AU - Rhodius-Meester, Hanneke F.M.

AU - Liedes, Hilkka

AU - Koene, Ted

AU - Lemstra, Afina W.

AU - Teunissen, Charlotte E.

AU - Barkhof, Frederik

AU - Scheltens, Philip

AU - Van Gils, Mark

AU - Lötjönen, Jyrki

AU - Van Der Flier, Wiesje M.

N1 - Funding Information: Research done at the VUmc Alzheimer Center is part of the neurodegeneration research program of Amsterdam Neuroscience. The VUmc Alzheimer Center is supported by Alzheimer Nederland and Stichting VUmc Fonds. The clinical database structure was developed with funding from Stichting Dioraphte. HFMRM is appointed on a grant from the European Union Seventh Framework Program project PredictND under grant agreement 611005. Funding Information: CET is a member of the Innogenetics International Advisory Boards of Fujirebio/ Innogenetics and Roche. FB serves/has served on the advisory boards of Bayer-Schering Pharma, Sanofi-Aventis, Biogen-Idec, Teva Pharmaceutical Industries, Merck-Serono, Novartis, Roche, Synthon BV, Jansen Research, and Genzyme. FB has received funding from the Dutch MS Society and the European Union Seventh Framework Program (EU-FP7) and has been a speaker at symposia organized by the Serono Symposia Foundation and Medscape. PS has served as a consultant for Wyeth-Elan, Genentech, Danone, and Novartis and has received funding for travel from Pfizer, Elan, Janssen, and Danone Research. JL reports that Combinostics Oy owns the following intellectual property rights related to this paper: (1) J. Koikkalainen and J. Lotjonen. Method for inferring the state of a system. Publication number US 7840510 B2; application number PCT/ FI2007/050277; (2) J. Lotjonen, J. Koikkalainen, and J. Mattila. State inference in a heterogeneous system. Application number PCT/FI2010/050545; FI20125177. JL is a shareholder in Combinostics Oy. WMvdF performs contract research for Boehringer Ingelheim. Research programs of WMvdF have been funded by ZonMw, the Netherlands Organization for Scientific Research (now), EU-FP7, Alzheimer Nederland, Cardiovascular Onderzoek Nederland, Stichting Dioraphte, Gieskes-Strijbis Fonds, Boehringer Ingelheim, Piramal Neuroimaging, Roche BV, and Janssen Stellar. All funding is paid to WMvdF’s institution. The other authors declare that they have no competing interests. Publisher Copyright: © 2018 The Author(s).

PY - 2018/2/20

Y1 - 2018/2/20

N2 - Background: Survival after dementia diagnosis varies considerably. Previous studies were focused mainly on factors related to demographics and comorbidity rather than on Alzheimer's disease (AD)-related determinants. We set out to answer the question whether markers with proven diagnostic value also have prognostic value. We aimed to identify disease-related determinants associated with mortality in patients with AD. Methods: We included 616 patients (50% female; age 67 ± 8 years; mean Mini Mental State Examination score 22 ± 3) with dementia due to AD from the Amsterdam Dementia Cohort. Information on mortality was obtained from the Dutch Municipal Register. We used age- and sex-adjusted Cox proportional hazards analysis to study associations of baseline demographics, comorbidity, neuropsychology, magnetic resonance imaging (MRI) (medial temporal lobe, global cortical and parietal atrophy, and measures of small vessel disease), and cerebrospinal fluid (CSF) (β-amyloid 1-42, total tau, and tau phosphorylated at threonine 181 [p-tau]) with mortality (outcome). In addition, we built a multivariate model using forward selection. Results: After an average of 4.9 ± 2.0 years, 213 (35%) patients had died. Age- and sex-adjusted Cox models showed that older age (HR 1.29 [95% CI 1.12-1.48]), male sex (HR 1.60 [95% CI 1.22-2.11]), worse scores on cognitive functioning (HR 1.14 [95% CI 1.01-1.30] to 1.31 [95% CI 1.13-1.52]), and more global and hippocampal atrophy on MRI (HR 1.18 [95% CI 1.01-1.37] and HR 1.18 [95% CI 1.02-1.37]) were associated with increased risk of mortality. There were no associations with comorbidity, level of activities of daily living, apolipoprotein E (APOE) ϵ4 status, or duration of disease. Using forward selection, the multivariate model included a panel of age, sex, cognitive tests, atrophy of the medial temporal lobe, and CSF p-tau. Conclusions: In this relatively young sample of patients with AD, disease-related determinants were associated with an increased risk of mortality, whereas neither comorbidity nor APOE genotype had any prognostic value.

AB - Background: Survival after dementia diagnosis varies considerably. Previous studies were focused mainly on factors related to demographics and comorbidity rather than on Alzheimer's disease (AD)-related determinants. We set out to answer the question whether markers with proven diagnostic value also have prognostic value. We aimed to identify disease-related determinants associated with mortality in patients with AD. Methods: We included 616 patients (50% female; age 67 ± 8 years; mean Mini Mental State Examination score 22 ± 3) with dementia due to AD from the Amsterdam Dementia Cohort. Information on mortality was obtained from the Dutch Municipal Register. We used age- and sex-adjusted Cox proportional hazards analysis to study associations of baseline demographics, comorbidity, neuropsychology, magnetic resonance imaging (MRI) (medial temporal lobe, global cortical and parietal atrophy, and measures of small vessel disease), and cerebrospinal fluid (CSF) (β-amyloid 1-42, total tau, and tau phosphorylated at threonine 181 [p-tau]) with mortality (outcome). In addition, we built a multivariate model using forward selection. Results: After an average of 4.9 ± 2.0 years, 213 (35%) patients had died. Age- and sex-adjusted Cox models showed that older age (HR 1.29 [95% CI 1.12-1.48]), male sex (HR 1.60 [95% CI 1.22-2.11]), worse scores on cognitive functioning (HR 1.14 [95% CI 1.01-1.30] to 1.31 [95% CI 1.13-1.52]), and more global and hippocampal atrophy on MRI (HR 1.18 [95% CI 1.01-1.37] and HR 1.18 [95% CI 1.02-1.37]) were associated with increased risk of mortality. There were no associations with comorbidity, level of activities of daily living, apolipoprotein E (APOE) ϵ4 status, or duration of disease. Using forward selection, the multivariate model included a panel of age, sex, cognitive tests, atrophy of the medial temporal lobe, and CSF p-tau. Conclusions: In this relatively young sample of patients with AD, disease-related determinants were associated with an increased risk of mortality, whereas neither comorbidity nor APOE genotype had any prognostic value.

KW - Alzheimer's disease

KW - Diagnostic test assessment

KW - Mortality

KW - Prognosis

U2 - 10.1186/s13195-018-0348-0

DO - 10.1186/s13195-018-0348-0

M3 - Article

C2 - 29458426

AN - SCOPUS:85042278602

SN - 1758-9193

VL - 10

JO - Alzheimer's Research And Therapy

JF - Alzheimer's Research And Therapy

IS - 1

M1 - 23

ER -

Disease-related determinants are associated with mortality in dementia due to Alzheimer's disease

Abstract

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