Down syndrome (DS) is a high-incidence (1:750–1000) genetic condition [93] caused by an extra copy of chromosome 21 (Chr21; HSA21) [211]. Among the various DS-linked traits, such as cardiac abnormalities and gastrointestinal disorders [49], intellectual disability (ID), which is defined by an intelligence quotient <70, is a fully penetrant phenotype [23, 223, 409] and a source of major concern to parents and relatives. In children with DS, IQ score is usually in the moderately to severely retarded range (IQ = 25–55) and decreases progressively with age [371]. Children and adults with DS exhibit deficits in a constellation of brain functions, such as memory, executive functions, language, and verbal and motor skills [62, 86, 133, 370, 371]. Understanding the nature of cognitive deficits in DS is important for understanding their biological bases, timing, and approaches to treatment. While using standardized tests, there is evidence of progressive decline, and a different pattern emerges when raw scores are examined longitudinally [133]. For example, Couzens et al. (2011), assessing raw scores for different cognitive functions, show clear increases with increasing age. Though the measures in all tests in 4-year-old children with DS were lower than in cognitively normal subjects, tests of vocabulary, comprehension, and quantitative function (so-called crystallized abilities) showed increases in performance from ages 4 through ~20 years, with apparent stabilization, or relatively modest decrements, through age 25. Interestingly, raw scores of vocabulary were stable through age ~30. In contrast, raw scores for pattern analysis (a measure of fluid ability) showed progressive improvements that continued beyond age 20. The findings show that cognitive deficits in DS are not fixed but pursue a different developmental trajectory with lesser gains relative to cognitive normals. Marked decrements linked to dementia ensue only later. Indeed, after age 40, adults with DS are at a high risk of developing Alzheimer’s disease (AD) [410]. During the past 20 years, research has made great strides in defining how trisomy of HSA21 affects cognition in early and later life. Yet, despite increasing knowledge, there are no treatments for ID or AD in DS. Herein, we discuss the efforts made to address this topic and neurobiological discoveries and insights that may lead to effective treatments.