Volumetric Characterization of Medial Temporal Lobe in Down Syndrome Along the Alzheimer's Disease Continuum

Background Individuals with Down Syndrome (DS) almost invariably develop Alzheimer's Disease (AD), but detecting early clinical changes is challenging due to comorbid intellectual disability, highlighting the importance of non‐invasive biomarkers. Neuroimaging of the medial temporal lobe (MTL), a key site of tau pathology, shows promise as an early AD biomarker. Here, we aimed to characterise volumetric patterns of the MTL in DS across the AD clinical continuum, and define associations with AD cerebrospinal fluid (CSF) biomarkers. Method 253 adults with DS and 190 euploid controls from the Down Alzheimer Barcelona Neuroimaging Initiative underwent a 3T‐MRI protocol, and a comprehensive clinical assessment. T1‐weighted images were used to parse the medial temporal lobe using the Automated Segmentation of Hippocampal Subfields (ASHS) pipeline. Segmentation quality was visually inspected and W‐scores were computed for MTL subregions (anterior and posterior hippocampus, entorhinal cortex (ERC), parahippocampal cortex (PHC), and Brodmann areas Br35 and Br36) to adjust volumes for total intracranial volume, age and MRI scanner. Non‐parametric statistical tests were employed to assess volumes by AD clinical stage, age, and CSF biomarkers of AD. Result Hippocampal and Br36 volumes gradually decreased with AD clinical stage, and all subregions were decreased at the dementia stage (dDS) compared to asymptomatic (aDS) and prodromal (pDS) stages (Fig. 1). Surprisingly, significantly larger ERC, PHC and Br35 volumes were found at the asymptomatic DS stage compared to controls. All subregions had decreased volumes with age, with inflexion points around 40y for the hippocampus, ERC and Br36, 45y for Br35 and 50y for PHC (Fig. 2). Most subregions exhibited significant correlations with CSF Aß42/40 ratio, p‐tau‐181 and neurofilament light chain, and the strongest associations were found with anterior and posterior hippocampus (Fig. 3). Conclusion AD clinical stage and age are associated with progressive decreasing MTL volumes. Among all subregions, the hippocampus correlated best with CSF measures and appears particularly sensitive to detect early disease processes. These results indicate effectiveness of MTL volumes as a biomarker of early AD pathological changes in DS. Further studies are required to determine the pathological substrate of MTL atrophy and understand the increased volumes in some subregions.