The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment

Article type: Research Article

Authors: Koppara, Alexander^{a; b; 1; *} | Wolfsgruber, Steffen^{a; b; 1} | Kleineidam, Luca^{a; b; 1} | Schmidtke, Klaus^c | Frölich, Lutz^d | Kurz, Alexander^e | Schulz, Stefanie^f | Hampel, Harald^h | Heuser, Isabellaⁱ | Peters, Oliverⁱ | Reischies, Friedel M.ⁱ | Jahn, Holger^j | Luckhaus, Christian^k | Hüll, Michael^l | Gertz, Hermann-Josef^m | Schröder, Johannesⁿ | Pantel, Johannes^o | Rienhoff, Otto^p | Rüther, Eckart^g | Henn, Fritz^q | Wiltfang, Jens^g | Maier, Wolfgang^{a; b} | Jessen, Frank^{a; b; s} | Kornhuber, Johannes^r | Wagner, Michael^{a; b}

Affiliations: [a] Department of Psychiatry, University of Bonn, Germany | [b] German Center for Neurodegenerative Diseases, Bonn, Germany | [c] Center for Geriatric Medicine, Ortenau Klinikum, Offenburg-Gengenbach, Germany | [d] Department of Gerontopsychiatry, Central Institute of Mental Health, Mannheim, Germany | [e] Department of Psychiatry, Technical University of Munich, Germany | [f] Department of Neurology, University of Aachen, Germany | [g] Department of Psychiatry and Psychotherapy, University of Göttingen, Germany | [h] Department of Neurology, Université Pierre et Marie Curie (Sorbonne), and AXA Research Fund & UPMC Chair, Paris, France | [i] Department of Psychiatry, Charité Berlin, Campus Benjamin Franklin, Berlin, Germany | [j] Department of Psychiatry, University of Hamburg, Germany | [k] Department of Psychiatry, University of Düsseldorf, Germany | [l] Center for Psychiatry, Clinic for Geronto- and Neuropsychiatry Emmendingen and Dep. of Psychiatry, University of Freiburg, Germany | [m] Department of Psychiatry, University of Leipzig, Germany | [n] Section for Geriatric Psychiatry/Institute of Gerontology, University of Heidelberg, Germany | [o] Institute of General Medicine University of Frankfurt, Frankfurt am Main, Germany | [p] Department of Medical Informatics, University of Göttingen, Germany | [q] Ichan School of Medicine at Mt. Sinai, New York, USA | [r] Department of Psychiatry, Friedrich-Alexander-University Erlangen, Germany | [s] Department of Psychiatry, Medical Faculty University of Cologne, Germany

Correspondence: [*] Correspondence to: Dipl.-Psych. Alexander Koppara, Department of Psychiatry and Psychotherapy, Rheinische-Friedrich-Wilhelms University, Sigmund-Freud-Straße 25, 53105 Bonn, Germany. Tel.: +49 228 287 16946; Fax: +49 228 287 16097; E-mail: [email protected]

Note: [1] These authors contributed equally to this work.

Abstract: Background:The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer’s disease (AD) research and clinical trials. Objective:To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). Methods:Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. Results:In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1–3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects. Conclusion:These findings support the interpretation of δ as a construct capturing the disease-related “essence” of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.

Keywords: CSF AD biomarker signature, delta model, incident dementia, mild cognitive impairment

DOI: 10.3233/JAD-150257

Journal: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 547-560, 2016