The aim of this study is to adapt and validate the global deterioration scale (GDS) for the systematic tracking of Alzheimer’s disease (AD) progression in a population with Down syndrome (DS). A retrospective dual-center cohort study was conducted with 83 participants with DS (46.65 ± 5.08 years) who formed the primary diagnosis (PD) group: cognitive stability (n = 48), mild cognitive impairment (n = 24), and Alzheimer’s disease (n = 11). The proposed scale for adults with DS (GDS-DS) comprises six stages, from cognitive and/or behavioral stability to advanced AD. Two neuropsychologists placed the participants of the PD group in each stage of the GDS-DS according to cognitive, behavioral and daily living skills data. Inter-rater reliability in staging with the GDS-DS was excellent (ICC = 0.86; CI: 0.80–0.93), and the agreement with the diagnosis categories of the PD group ranged from substantial to excellent with κ values of 0.82 (95% CI: 0.73–0.92) and 0.85 (95% CI: 0.72, 0.99). Performance with regard to the CAMCOG-DS total score and orientation subtest of the Barcelona test for intellectual disability showed a slight progressive decline across all the GDS-DS stages. The GDS-DS scale is a sensitive tool for staging the progression of AD in the DS population, with special relevance in daily clinical practice.