The position of the APP gene on chromosome 21 led to an interest in the connection of the presenile cognitive decline and amyloid plaque pathology seen in Trisomy 21,45, 83, 84, 85, 86, 87 however, subsequent work has demonstrated the limitations of applying the pathophysiology of this form of cognitive decline to the later‐onset, sporadic form of AD.79, 88, 89. Here, APP is linked to Alzheimer disease.