Subgroups of Alzheimer's Disease: Stability of Empirical Clusters Over Time

Article type: Research Article

Authors: Peter, Jessica^{a; b; c; *} | Abdulkadir, Ahmed^{b; d} | Kaller, Christoph^{a; b} | Kümmerer, Dorothee^{a; b} | Hüll, Michael^e | Vach, Werner^f | Klöppel, Stefan^{a; b; g} | for the Alzheimer's Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Neurology, University Medical Centre Freiburg, Germany | [b] Freiburg Brain Imaging, University Medical Centre Freiburg, Germany | [c] Laboratory for Biological and Personality Psychology, Department of Psychology, University of Freiburg, Germany | [d] Group of Pattern Recognition and Image Processing, Department of Computer Science, University of Freiburg, Germany | [e] Centre for Geriatric Medicine and Gerontology, University Medical Centre, Freiburg, Germany | [f] Department of Medical Biometry and Medical Informatics, University of Freiburg, Germany | [g] Department of Psychiatry and Psychotherapy, Section of Gerontopsychiatry and Neuropsychology, University Medical Centre Freiburg, Germany

Correspondence: [*] Correspondence to: Jessica Peter, Freiburg Brain Imaging, Department of Neurology, University Medical Centre Freiburg, Breisacherstraße 64, 79106 Freiburg, Germany. Tel./Fax: +49 761 270 54797/54160; E-mail: jessica.peter@uniklinik-freiburg.de.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Although episodic memory impairment is usually the earliest sign of Alzheimer's disease (AD), there are up to 15% of patients presenting with early impairment in non-memory cognitive functions (i.e., atypical AD). Stratifying patients with AD may aid clinical trials. Previous studies divided patients by cognitive profile, focusing on cross-sectional analyses without testing stability of clusters over time. We used principal component analysis followed by cluster analyses in 127 patients with AD based on 24 cognitive scores at 0, 6, 12, and 24 months follow-up. We investigated the definition of clusters and their stability over time as well as interactions of cluster assignment and disease severity. At each time point, six distinct factors and four distinct clusters were extracted that did not differ substantially between time points. Clusters were defined by cognitive profile rather than disease severity. 85% of patients fell into the same cluster twice, 42% three times, and 17% four times. Subjects with focal semantic impairment progressed significantly faster than the other cluster. Longitudinally, focal deficits increased relatively rather than tending toward average disease severity. The observed similar cluster definitions at each time point indicate the validity of the approach. Cluster-specific longitudinal increases of focal impairments and significant between-cluster differences in disease progression make this approach useful for stratified inclusion into clinical trials.

Keywords: Alzheimer's disease, atypical AD, cluster analysis, clustering, subgroups, subtypes, typical AD

DOI: 10.3233/JAD-140261

Journal: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 651-661, 2014