APP and Down syndrome: Historically, it was the mapping of the APP gene to chromosome 21, together with the observation of plaques and tangles in most elderly individuals with Down's syndrome (trisomy of chromosome 21) followed by the linking of some cases of familial AD to chromosome 21 (Goate et al., 1989; St George-Hyslop et al., 1990), that lead to the identification of the first mutations in the APP gene (Chartier-Harlin et al., 1991; Goate et al., 1991; Murrell et al., 1991) (Figure 1).