With the exception of a single reported case of an individual with an atypical DS karyotype involving a specific chromosome 21 micro-deletion in the APP gene locus [41], all subjects with Down syndrome (including the rare cases involving Robertsonian translocation, partial duplications, or trisomic mosaicism) demonstrate triplication of the APP gene locus (21q21), overexpress amyloid precursor protein (APP) in affected somatic cells, accumulate β-amyloid peptides (Aβ) in the brain, and reveal evidence of early-onset Alzheimer's disease (AD) neuropathology [18], [19], [34], [40], [42]. Here, APP is linked to Alzheimer disease.