Down syndrome is the most common chromosomal disorder in humans, caused by triplication of chromosome 21, accounting for ~1/740 live births in the USA even with routine prenatal screening. In addition to mental retardation and the other classical signs of DS, 100% of people with DS will develop the pathological hallmarks of AD (plaques and tangles) by their 40s and ~80% of people with DS will eventually develop clinical dementia. The primary cause is the triplication of the APP gene on chromosome 21, resulting in 50% greater levels of both APP mRNA and protein. That the disease in DS is indeed AD is supported by pathological, molecular, in-vitro, biomarker and clinical evidence.