APP and Down syndrome: Other mutations generate more Aβ overall by: 1) providing more APP substrates (e.g., APP duplications (Rovelet-Lecrux et al., 2006) and Down's syndrome (Wisniewski et al., 1985)); 2) rendering APP more accessible to BACE (e.g., the APP KM670/671NL Swedish APP mutation (Haass et al., 1995)); or 3) increasing the aggregation propensity of Aβ peptides (e.g., APP E693G Arctic mutation (Nilsberth et al., 2001)).