Objective: Alzheimer's disease (AD) is a major health concern for aging adults with Down syndrome (DS), but conventional diagnostic techniques are less reliable in those with severe baseline disability. Likewise, acquisition of magnetic resonance imaging to evaluate cerebral atrophy is not straightforward, as prolonged scanning times are less tolerated in this population. Computed tomography (CT) scans can be obtained faster, but poor contrast resolution limits its function for morphometric analysis. We implemented an automated analysis of CT scans to characterize differences across dementia stages in a cross-sectional study of an adult DS cohort. Methods: CT scans of 98 individuals were analyzed using an automatic algorithm. Voxel-based correlations with clinical dementia stages and AD plasma biomarkers (phosphorylated tau-181 and neurofilament light chain) were identified, and their dysconnectomic patterns delineated. Results: Dementia severity was negatively correlated with gray (GM) and white matter (WM) volumes in temporal lobe regions, including parahippocampal gyri. Dysconnectome analysis revealed an association between WM loss and temporal lobe GM volume reduction. AD biomarkers were negatively associated with GM volume in hippocampal and cingulate gyri. Interpretation: Our automated algorithm and novel dysconnectomic analysis of CT scans successfully described brain morphometric differences related to AD in adults with DS, providing a new avenue for neuroimaging analysis in populations for whom magnetic resonance imaging is difficult to obtainThe Adult Down Syndrome Outpatient unit at Hospital Universitario de La Princesa is grateful to Licenciado Don Jesús Coronado Hinojosa for his financial support of the research endeavors of our unit. BSM is supported by the Foundation Jérôme Lejeune (grant no. 2021b/2088). DRA is partially supported by the Fondo de Investigaciones Sanitarias (FIS grant PI19/00634, from the Ministerio de Economía y Competitividad (Instituto de Salud Carlos III) and co-funded by The European Regional Development Fund (ERDF) “A way to make Europe”) and the Foundation Jérôme Lejeune (grant no. 2021a/2069). FM is partially supported by the Spanish Society of Internal Medicine (FEMI grant 2018
