Subjective Cognitive Decline and Minor Neuropsychological Deficits: Importance for Risk Stratification and Trial Recruitment in Early Alzheimer´s Disease
Year: 2025
Type: article
Abstract: BACKGROUND: The recruitment of participants with a high risk of decline is crucial for the success of clinical trials in the earliest phases of Alzheimer´s Disease (AD), where treatment benefits could be the largest. Subjective cognitive decline (SCD) and minor neuropsychological deficits (MNPD) are associated with an increased risk of cognitive decline, making them promising predictors for this risk stratification. However, the prognostic value of their interplay is understudied. METHOD: We pooled and analyzed data from cognitively unimpaired participants from the Alzheimer´s Disease Neuroimaging Initiative (N = 599), DZNE Longitudinal Cognitive Impairment and Dementia study (N = 618), and National Alzheimer's Coordinating Center (N = 11,975). SCD was measured using questionnaires or anamnestic data. MNPD was defined as a median neuropsychological test performance of z≤-0.5. We assessed the association of MNPD and SCD with the conversion to mild cognitive impairment (MCI) and dementia (cox regression) and baseline amyloid and tau positivity - measured by PET/CSF (logistic regression). We adjusted these models for the study cohorts and demographic covariates. Using power analyses, we calculated the sample sizes necessary to detect a 30% reduction in the risk of progressing to MCI over 4.5 years in amyloid positive participants. RESULT: In the overall sample (N = 13,192), the SCD-/MNPD+ (+:present, -:absent; HR=3.13[2.68-3.66]), SCD+/MNPD- (HR=1.97[1.76-2.20]), and SCD+/MNPD+ (HR=6.23[5.23-7.42]) groups had an increased risk of MCI compared to the SCD-/MNPD- group. These groups also had an increased risk of dementia. In amyloid positive participants (n = 497), this pattern persisted for the progression to MCI, while only the SCD+/MNPD+ group had an increased risk for dementia. In participants with biomarker data (n = 2,616), the SCD+/MNPD- (OR=1.47[1.20-1.81]) and SCD+/MNPD+ (OR=1.64[1.04-2.59]) groups had an increased risk of amyloid positivity. The risk of tau positivity was increased in the SCD+/MNPD+ group (OR=2.10[1.13-3.90]). In the power analyses, the required clinical trial size was reduced by approximately one third after excluding SCD-/MNPD- individuals and approximately two thirds by focusing only on SCD+/MNPD+ individuals (Figure). CONCLUSION: SCD and MNPD have a complementary prognostic value. SCD+/MNPD+ individuals are at particularly high risk of pathology and decline. These clinical symptoms should be taken into account in the recruitment for clinical trials in preclinical AD.
Source: Alzheimer s & Dementia
Authors: Melina Stark, Elizabeth Kuhn, Michael Wagner, Henning Boecker, Frederic Brosseron, Katharina Buerger, Marcel Daamen, Christoph Laske, Robert Perneczky, Oliver Peters, Josef Priller, Matthias Schmid, Anja Schneider, Annika Spottke, Stefan J. Teipel, Jens Wiltfang, Emrah Düzel, Frank Jessen, Luca Kleineidam
Institutions: University of Bonn, University Hospital Bonn, German Center for Neurodegenerative Diseases, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, Hertie Institute for Clinical Brain Research, University of Tübingen, Munich Cluster for Systems Neurology, Imperial College London, Charité - Universitätsmedizin Berlin, UK Dementia Research Institute, Stiftung Charité, Technical University of Munich, University of Edinburgh, Institut für Medizinische Biometrie, Informatik und Epidemiologie, Universitätsmedizin Rostock, Universitätsmedizin Göttingen, University of Aveiro, University of Göttingen, Otto-von-Guericke-Universität Magdeburg, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
OpenAlex ID: W7117269560
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