BRIEF RESEARCH REPORT article
Front. Neurosci.
Sec. Neurodegeneration
Volume 19 - 2025 | doi: 10.3389/fnins.2025.1653261
This article is part of the Research TopicBiomarkers for the identification of effective treatments for neurodegenerative diseaseView all 3 articles
Biomarkers of Alzheimer's Disease Modification using Adaptive Cognitive Assessments to Improve Responsiveness - A Simulation Study
Provisionally accepted
Antobio Rodríguez-Romero
Shibeshih Belachew*Emmanuel BartholoméClaudia MazzàÓscar ReyesCarlos Luque
Corrado Bernasconi- Indivi AG, Basel, Switzerland
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Introduction Clinical studies assessing cognition in Alzheimer's and other neurodegenerative diseases require endpoints that are sensitive to treatment response across a broad range of cognitive abilities. However, responsiveness of conventional cognitive assessments typically varies with the performance level, especially due to non-linearities such as floor or ceiling effects. Here, we evaluate 6 newly developed smartphone-based and gamified Adaptive Cognitive Assessments (ACAs) entailing a system of dynamic difficulty adaptation to individual performance, which is expected to improve adherence but also measurement properties. Deployment of such ACAs to maximize their discriminative ability in comparative studies requires exploration of many free parameters and complex dynamics. Methods In simulations of cohorts of patients with cognitive impairment, we compared two ACAs paradigms: after 14 daily tests allowing performance-based difficulty adaptation, the difficulty level was either (1) fixed or (2) kept adaptive for a period of 4 years with weekly testing. Sensitivity to between-group effects was assessed in cohorts characterized by cognitive decline observed in neurodegenerative diseases. Results The discriminative ability of the two paradigms depends on features of the study design and subjects. At study end, the adaptive difficulty paradigm clearly outperformed the fixed-difficulty paradigm in terms of responsiveness for cognitive decline rates >2.5% per year. Discussion ACA can increase biomarker responsiveness to treatment effects over fixed difficulty. ACA deployment should be guided by study and assessment features, including duration, expected cognitive decline rates and effect size. In the high-dimensional parameter space of ACA instruments, study simulations are indispensable to identify suitable deployment strategies.
Keywords: Cognition, Neurodegenerative Diseases, Adaptive test (AT), biomarker, Endpoint, simulation – computers, responsiveness, Digital Health
Received: 24 Jun 2025; Accepted: 08 Sep 2025.
Copyright: © 2025 Rodríguez-Romero, Belachew, Bartholomé, Mazzà, Reyes, Luque and Bernasconi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Shibeshih Belachew, Indivi AG, Basel, Switzerland
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