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. 2018 Feb 20;10(1):23.
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  1 , Hilkka Liedes  2 , Ted Koene  3 , Afina W Lemstra  4 , Charlotte E Teunissen  5 , Frederik Barkhof  6   7   8 , Philip Scheltens  4 , Mark van Gils  2 , Jyrki Lötjönen  2   9 , Wiesje M van der Flier  4   10
Affiliations

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

Hanneke F M Rhodius-Meester et al. Alzheimers Res Ther. .

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.

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Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the local medical ethics committee. All patients provided written informed consent for their clinical data to be used for research purposes.

Consent for publication

Not applicable.

Competing interests

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.

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Figures

Fig. 1
Fig. 1
Kaplan-Meier curve, according to variables from forward selection model: age, sex, TMT-A, digit span backward, MTA, and p-tau (all except sex stratified in tertiles). Legend: Note: digit span backward: range 0-21, TMT: trail making test (no range), MTA: medial temporal lobe atrophy ranging 0-4 (average score of left and right side), p-tau: tau phosphorylated at threonine 181. Survival curves were calculated using raw data, without imputation
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