Aguila, Ana Lawry; Lorenzini, Luigi; Janahi, Mohammed; Barkhof, Frederik; Altmann, Andre; (2025) Deep normative modelling reveals insights into early-stage Alzheimer's disease using multi-modal neuroimaging data. Alzheimer's Research & Therapy , 17 (1) , Article 107. 10.1186/s13195-025-01753-3.

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Abstract

Background: Exploring the early stages of Alzheimer's disease (AD) is crucial for timely intervention to help manage symptoms and set expectations for affected individuals and their families. However, the study of the early stages of AD involves analysing heterogeneous disease cohorts which may present challenges for some modelling techniques. This heterogeneity stems from the diverse nature of AD itself, as well as the inclusion of undiagnosed or ‘at-risk’ AD individuals or the presence of comorbidities which differentially affect AD biomarkers within the cohort. Normative modelling is an emerging technique for studying heterogeneous disorders that can quantify how brain imaging-based measures of individuals deviate from a healthy population. The normative model provides a statistical description of the ‘normal’ range that can be used at subject level to detect deviations, which may relate to pathological effects. Methods: In this work, we applied a deep learning-based normative model, pre-trained on MRI scans in the UK Biobank, to investigate ageing and identify abnormal age-related decline. We calculated deviations, relative to the healthy population, in multi-modal MRI data of non-demented individuals in the external EPAD (ep-ad.org) cohort and explored these deviations with the aim of determining whether normative modelling could detect AD-relevant subtle differences between individuals. Results: We found that aggregate measures of deviation based on the entire brain correlated with measures of cognitive ability and biological phenotypes, indicating the effectiveness of a general deviation metric in identifying AD-related differences among individuals. We then explored deviations in individual imaging features, stratified by cognitive performance and genetic risk, across different brain regions and found that the brain regions showing deviations corresponded to those affected by AD such as the hippocampus. Finally, we found that ‘at-risk’ individuals in the EPAD cohort exhibited increasing deviation over time, with an approximately 6.4 times greater t-statistic in a pairwise t-test compared to a ‘super-healthy’ cohort. Conclusion: This study highlights the capability of deep normative modelling approaches to detect subtle differences in brain morphology among individuals at risk of developing AD in a non-demented population. Our findings allude to the potential utility of normative deviation metrics in monitoring disease progression.

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