The identification of duplications of the APP locus (mapping to the chromosome 21) causing autosomal-dominant EOAD (early-onset Alzheimer’s disease, onset before 65 years) without Down syndrome [149] was of major importance to confirm the amyloid hypothesis stating that the Aβ peptide aggregation, produced following the processing of the APP protein, has a key role in AD pathophysiology. The gene discussed is APP; the disease is Down syndrome.