ArticleThe journal of prevention of Alzheimer's disease2026
Quantifying generalization error in machine learning prediction of cognitive decline.
Article in The journal of prevention of Alzheimer's disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundPredicting cognitive decline as a continuum, from healthy age-related decline to mild cognitive impairment and dementia, enables more precise individual-level predictions. However, the practical value of such models for early intervention and prevention depends on their ability to generalize to independent cohorts, a property that is often not evaluated.
objectivesThis study investigated whether adding structural magnetic resonance imaging (MRI) to non-brain data improved machine learning predictions of continuous cognitive decline and analyzed the models' generalizability.
designMulti-target random forest regression models predicted annual decline in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) using non-brain data, structural MRI data, or their combination from the Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 1237) and Open Access Series of Imaging Studies (OASIS-3; N = 662) datasets. Cross-site generalizability was evaluated.
settingData from ADNI and OASIS-3 were used for this study.
participantsA total of 1899 participants who had demographic, clinical, and brain imaging data from a baseline session and clinical data from at least 2 follow-up sessions were included. MEASUREMENTS: Baseline non-brain (demographics, clinical and neuropsychological scores, information on APOE genotype, cognitive diagnosis, health, and number of sessions before baseline) and/or structural MRI data were used to predict the yearly rate of change in CDR-SOB and MMSE scores.
resultsIncluding structural MRI data improved prediction of CDR-SOB and MMSE change, reaching respective R
conclusionsIncorporating structural MRI data enhances within-dataset prediction of continuous cognitive decline, allowing for more precise individual-level prediction and advancing towards precision medicine. Even though external validation remains limited, quantifying the generalizability gap is a crucial step towards the responsible use of ML models in clinical intervention and prevention.
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