Research on the multiple aspects of cognitive impairment in Down syndrome (DS), from genes to behavior to treatment, has made tremendous progress in the last decade as reflected in current clinical trials to improve learning and memory. Congenital intellectual disabilities such as DS originate from the earliest stages of development and both the acquisition of cognitive skills and neurodegenerative pathologies are cumulative. Comorbidities such as cardiac malformations, sleep apnea, diabetes, and dementia are frequent in the DS population, as well, and their increased risk in this genetically sensitized population provides a means of assessing early stages of these pathologies that affect the entire population.