APOE-Dependent Phenotypes in Subjects with Mild Cognitive Impairment Converting to Alzheimer's Disease

Article type: Research Article

Authors: Morgen, Katrin^{a; *} | Frölich, Lutz^a | Tost, Heike^a | Plichta, Michael M.^a | Kölsch, Heike^c | Rakebrandt, Fabian^d | Rienhoff, Otto^d | Jessen, Frank^{b; c} | Peters, Oliver^e | Jahn, Holger^f | Luckhaus, Christian^g | Hüll, Michael^h | Gertz, Hermann-Josefⁱ | Schröder, Johannes^j | Hampel, Harald^k | Teipel, Stefan J.^l | Pantel, Johannes^m | Heuser, Isabella^e | Wiltfang, Jensⁿ | Rüther, Eckart^d | Kornhuber, Johannes^o | Maier, Wolfgang^{b; c} | Meyer-Lindenberg, Andreas^a

Affiliations: [a] Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany | [b] German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany | [c] Department of Psychiatry, University of Bonn, Bonn, Germany | [d] Department of Medical Informatics, University Hospital Göttingen, Göttingen, Germany | [e] Department of Psychiatry, Charité-Universitaetsmedizin Berlin, Berlin, Germany | [f] Department of Psychiatry, University Hospital Hamburg-Eppendorf, Hamburg, Germany | [g] Department of Psychiatry and Psychotherapy, Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany | [h] Section of Gerontopsychiatry and Neuropsychology, Centre of Geriatric Medicine and Gerontology Freiburg, University Hospital Freiburg, Mannheim, Germany | [i] Department of Psychiatry and Psychotherapy, University Hospital Leipzig, Leipzig, Germany | [j] Section of Geriatric Psychiatry, University of Heidelberg, Heidelberg, Germany | [k] Department of Psychiatry, Goethe University, Frankfurt, Germany | [l] University Medicine Rostock and DZNE, German Center for Neurodegenerative Diseases, Rostock, Germany | [m] Institute of General Practice, Geriatric Medicine, Goethe University, Frankfurt, Germany | [n] Klinik für Psychiatrie und Psychotherapie, LVR-Kliniken Essen, Kliniken/Institut der Universität Duisburg-Essen, Essen, Germany | [o] Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany

Correspondence: [*] Correspondence to: Katrin Morgen, MD, Central Institute of Mental Health (CIMH), J5, 68159 Mannheim, Germany. Tel.: +49 621 1703 6504; Fax: +49 621 1703 1205; E-mail: [email protected].

Abstract: Background:The E4 isoform of the APOE genotype is the most significant genetic risk factor for sporadic Alzheimer’s disease (AD) and has recently been found to modulate disease expression in patients with AD. Objective:To investigate APOE-dependent cognitive and structural phenotypes in subjects with mild cognitive impairment who converted to AD within the following three years. Methods:Subjects converting to AD (n = 63) were compared to a control group with stable mild cognitive impairment (n = 131). Clinical, neuropsychological, and MRI data were obtained by the German Dementia Competence Network. Subgroups of converting and stable APOE E4 carriers and non-carriers were investigated longitudinally with MRI to examine structural correlates of conversion. Voxel-based morphometry was applied to investigate gray matter distribution. Results:At baseline, executive performance correlated with global and bilateral prefrontal gray matter volume and predicted conversion only among non-carriers. Converting carriers and non-carriers presented distinct patterns of brain atrophy on longitudinal analysis, in line with a dissociation between more pronounced occipital atrophy in carriers and more frontoparietal volume loss in non-carriers at follow-up. Conclusions:The current findings suggest that in APOE E4 non-carriers with AD, executive dysfunction is closely linked to frontal gray matter atrophy and predictive of progression to dementia. The results are consistent with APOE genotype-dependent profiles of structural damage and cognitive decline in patients with imminent conversion to AD.

Keywords: APOE, Alzheimer's disease, magnetic resonance imaging, mild cognitive impairment, phenotypes, voxel-based morphometry

DOI: 10.3233/JAD-130326

Journal: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 389-401, 2013