Symptomatic Clusters Related to Amyloid Positivity in Cognitively Unimpaired Individuals

Article type: Research Article

Authors: Sannemann, Lena^{a; *} | Bartels, Claudia^b | Brosseron, Frederic^c | Buerger, Katharina^{d; e} | Fliessbach, Klaus^{c; f} | Freiesleben, Silka Dawn^{g; h} | Frommann, Ingo^{c; f} | Glanz, Wenzelⁱ | Heneka, Michael T.^j | Janowitz, Daniel^e | Kilimann, Ingo^{k; l} | Kleineidam, Luca^{c; f} | Lammerding, Dominik^h | Laske, Christoph^{m; n} | Munk, Matthias H.J.^{m; o} | Perneczky, Robert^{d; p; q; r} | Peters, Oliver^{g; h} | Priller, Josef^{g; s; t; u} | Rauchmann, Boris-Stephan^{p; v; w} | Rostamzadeh, Ayda^a | Roy-Kluth, Nina^c | Schild, Ann-Katrin^a | Schneider, Anja^{c; f} | Schneider, Luisa-Sophie^h | Spottke, Annika^{c; x} | Spruth, Eike Jakob^{g; s} | Teipel, Stefan^{k; l} | Wagner, Michael^{c; f} | Wiltfang, Jens^{b; y; z} | Wolfsgruber, Steffen^{c; f} | Duezel, Emrah^{i; aa} | Jessen, Frank^{a; c; bb} | for the DELCODE Study Group

Affiliations: [a] Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany | [b] Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Göttingen, Germany | [c] German Center for Neurodegenerative Diseases – DZNE, Bonn, Germany | [d] German Center for Neurodegenerative Diseases – DZNE, Munich, Germany | [e] Institute for Stroke and Dementia Research – ISD, University Hospital, LMU Munich, Munich, Germany | [f] Department of Neurodegenerative Disease and Geriatric Psychiatry/Psychiatry, University of Bonn Medical Center, Bonn, Germany | [g] German Center for Neurodegenerative Diseases – DZNE, Berlin, Germany | [h] Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin-Department of Psychiatry and Neurosciences, Berlin, Germany | [i] German Center for Neurodegenerative Diseases – DZNE, Magdeburg, Germany | [j] Luxembourg Centre for Systems Biomedicine – LCSB, University of Luxembourg, Belvaux, Luxembourg | [k] German Center for Neurodegenerative Diseases – DZNE, Rostock, Germany | [l] Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany | [m] German Center for Neurodegenerative Diseases – DZNE, Tübingen, Germany | [n] Department of Psychiatry and Psychotherapy, Section for Dementia Research, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany | [o] Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany | [p] Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany | [q] Munich Cluster for Systems Neurology – SyNergy, Munich, Munich, Germany | [r] Ageing Epidemiology Research Unit – AGE, School of Public Health, Imperial College London, London, UK | [s] Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, Berlin, Germany | [t] Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Munich, Germany | [u] University of Edinburgh and UK DRI, Edinburgh, UK | [v] Sheffield Institute for Translational Neuroscience – SITraN, University of Sheffield, Sheffield, UK | [w] Department of Neuroradiology, University Hospital LMU, Munich, Germany | [x] Department of Neurology, University of Bonn, Bonn, Germany | [y] German Center for Neurodegenerative Diseases – DZNE, Göttingen, Germany | [z] Department of Medical Sciences, Neurosciences and Signaling Group, Institute of Biomedicine – iBiMED, University of Aveiro, Aveiro, Portugal | [aa] Institute of Cognitive Neurology and Dementia Research – IKND, Otto-von-Guericke University, Magdeburg, Germany | [bb] Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases – CECAD, University of Cologne, Cologne, Germany

Correspondence: [*] Correspondence to: Lena Sannemann, Department of Psychiatry and Psychotherapy, University Cologne, Kerpener Str. 62, 50937 Cologne, Germany. Tel.: +49 221 478 98910; Fax: +49 221 478 36858; E-mail: lena.sannemann@uk-koeln.de.

Abstract: Background:The NIA-AA Research Framework on Alzheimer’s disease (AD) proposes a transitional stage (stage 2) characterized by subtle cognitive decline, subjective cognitive decline (SCD) and mild neurobehavioral symptoms (NPS). Objective:To identify participant clusters based on stage 2 features and assess their association with amyloid positivity in cognitively unimpaired individuals. Methods:We included baseline data of N = 338 cognitively unimpaired participants from the DELCODE cohort with data on cerebrospinal fluid biomarkers for AD. Classification into the AD continuum (i.e., amyloid positivity, A+) was based on Aβ42/40 status. Neuropsychological test data were used to assess subtle objective cognitive dysfunction (OBJ), the subjective cognitive decline interview (SCD-I) was used to detect SCD, and the Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess NPS. A two-step cluster analysis was carried out and differences in AD biomarkers between clusters were analyzed. Results:We identified three distinct participant clusters based on presented symptoms. The highest rate of A+ participants (47.6%) was found in a cluster characterized by both OBJ and SCD. A cluster of participants that presented with SCD and NPS (A+:26.6%) and a cluster of participants with overall few symptoms (A+:19.7%) showed amyloid positivity in a range that was not higher than the expected A+ rate for the age group. Across the full sample, participants with a combination of SCD and OBJ in the memory domain showed a lower Aβ42/ptau181 ratio compared to those with neither SCD nor OBJ. Conclusions:The cluster characterized by participants with OBJ and concomitant SCD was enriched for amyloid pathology.

Keywords: Alzheimer’s disease, Alzheimer’s disease continuum, amyloid, cerebrospinal fluid biomarkers, NIA-AA stage 2, neuropsychiatric symptoms, preclinical Alzheimer’s disease, subjective cognitive decline

DOI: 10.3233/JAD-231335

Journal: Journal of Alzheimer's Disease, vol. 100, no. 1, pp. 193-205, 2024