Unravelling pathological ageing with brain age gap estimation in Alzheimer's disease, diabetes and schizophrenia.

Brain age gap estimation (BrainAGE), the difference between predicted brain age and chronological age, might be a putative biomarker aiming to detect the transition from healthy to pathological brain ageing. The biomarker primarily models healthy ageing with machine learning models trained with structural magnetic resonance imaging (MRI) data. BrainAGE is expected to translate the deviations in neural ageing trajectory and has been shown to be increased in multiple pathologies, such as Alzheimer's disease (AD), schizophrenia and Type 2 diabetes (T2D). Thus, accelerated ageing seems to be a general feature of neuropathological processes. However, neurobiological constraints remain to be identified to provide specificity to this biomarker. Explainability might be the key to uncovering age predictions and understanding which brain regions lead to an elevated predicted age on a given pathology compared to healthy controls. This is highly relevant to understanding the similarities and differences in neurodegeneration in AD and T2D, which remains an outstanding biological question. Sensitivity maps explain models by computing the importance of each voxel on the final prediction, thereby contributing to the interpretability of deep learning approaches. This paper assesses whether sensitivity maps yield different results across three conditions related to pathological neural ageing: AD, schizophrenia and T2D. Five deep learning models were considered, each model trained with different MRI data types: minimally processed T-weighted brain scans, and corresponding grey matter, white matter, cerebrospinal fluid tissue segmentation and deformation fields (after spatial normalization). Our results revealed an increased BrainAGE in all pathologies, with a different mean, which is the smallest in schizophrenia; this is in line with the observation that neural loss is secondary in this early-onset condition. Importantly, our findings suggest that the sensitivity, indexing regional weights, for all models varies with age. A set of regions were shown to yield statistical differences across conditions. These sensitivity results suggest that mechanisms of neurodegeneration are quite distinct in AD and T2D. For further validation, the sensitivity and the morphometric maps were compared. The findings outlined a high congruence between the sensitivity and morphometry maps for age and clinical group conditions. Our evidence outlines that the biological explanation of model predictions is vital in adding specificity to the BrainAGE and understanding the pathophysiology of chronic conditions affecting the brain.