This report provides data that offers the potential for a new and effective approach for the treatment of AD, based on an Aβ-lowering strategy that does not involve the inhibition of the APP secretases. Previous work from this lab demonstrated that the specific binding of APP with PS is a required initial step in the production of Aβ.In that work a specific NH2-terminal domain (residues 1–80) of PS was used to inhibit PS-APP interaction; was found to markedly inhibit Aβ production. This report builds upon these findings and aims at testing several isolated, small soluble peptides, from within the NH2-terminal domain of PS-1, for efficacy in inhibiting Aβ production. Data indicate that two small, non-overlapping water-soluble peptides ( P4 and P8) from the PS-1 NH2-terminal domain can substantially and specifically inhibit the production of total Aβ as well as Aβ40 and 42 in vitro and in vivo in the brains of mThy1-hAPP transgenic mice. These results suggest that the inhibitory activity of the entire amino terminal domain of PS-1 on Aβ production is largely focused in a few smaller sequences within that domain. The peptides that were most effective in reducing total Aβ and of Aβ 40 and 42 exhibited strong and specific binding with the ectodomain of APP 695. The reduction of Aβ by the peptides does not affect the catalytic activities of β- or γ-secretase, or the level of APP. P4 and P8 are the first reported protein site-specific small peptides to reduce Aβ production in model systems of AD. The author posits that these peptides and their derivatives offer new potential drug candidates for the treatment of AD.