Medial temporal lobe atrophy in Down syndrome along the Alzheimer's disease continuum

Medial temporal lobe structures are among the first areas impacted by neurofibrillary tangle pathology, making volumetric changes of these areas promising biomarkers for Alzheimer's disease. To date, little is known about the integrity of these regions in individuals with Down syndrome, a population which almost invariably develops Alzheimer's disease and thus offers a unique opportunity to determine the earliest structural changes related to the disease. We aimed to characterize the sequential involvement of medial temporal lobe structures with Alzheimer's disease progression, explore associations with fluid biomarkers of Alzheimer’s pathology, and assess the utility of regional volumes and cortical thickness in distinguishing Alzheimer’s disease clinical stages in Down syndrome. 138 euploid controls and 259 adults with Down syndrome underwent clinical assessment and MRI scanning, followed by automated segmentation of the medial temporal lobe on T1-weighted images. Parametric statistical tests and local regression models were used to assess the cross-sectional association between regional volumes/cortical thickness and Alzheimer’s disease clinical stage, estimated years of onset, and CSF biomarkers. Additionally, markers were assessed in their ability to distinguish clinical stages using area under the receiver-operating characteristic curves. Results showed a progressive loss of volume and cortical thickness in medial temporal lobe with advancing Alzheimer’s disease stage, showing reduced volume/thickness at the dementia stage in all subregions. The asymptomatic and prodromal groups showed significant differences in the anterior and posterior hippocampus. We identified the entorhinal cortex and posterior hippocampus as the regions showing the earliest loss in Down syndrome, starting 13-15 years before Alzheimer’s disease symptom onset. We observed non-linear structural changes with disease progression, with certain structures (e.g., the parahippocampal cortex) characterized by an initial increase in cortical thickness followed by subsequent thinning. Of all subregions, the hippocampal volumes showed the closest correlation to CSF Aβ42/40, pTau181, and neurofilament light chain levels. Further analyses demonstrated a high predictive value, similar to CSF biomarkers, of the hippocampus in differentiating between individuals with asymptomatic versus prodromal/demented Alzheimer’s disease in Down syndrome. This study provides a novel understanding of the progressive, non-linear volumetric changes of medial temporal lobe structures in relation to Alzheimer’s disease pathology in Down syndrome, which can have important implications for clinical trials monitoring neurodegeneration using MRI. We also show that MRI information can refine the prediction of clinical status in Down syndrome. This is particularly relevant in Down syndrome, where early clinical stages can be challenging to detect due to neurodevelopmental intellectual disability.