After the milestone discovery that cerebrovascular amyloid and NP are composed of Aβ (as they shared the same antigenic determinants; [85,86]) in both AD and Down syndrome [87], and that the V717I missense “London” mutation in the amyloid precursor protein gene (APP) on chromosome 21 was found to be causally related to the early-onset autosomal-dominant familial AD [88], Hardy and colleagues [89,90] proposed the “amyloid cascade hypothesis”, which has become a dominant driver of AD research ever since. This evidence concerns the gene APP and Down syndrome.