Processing of the beta-amyloid precursor protein (APP) plays a key role in Alzheimer's disease (AD) neuropathogenesis. APP is cleaved by beta-secretase and alpha-secretase to produce APP-C99 and APP-C83, which are further cleaved by gamma-secretase to produce Abeta and p3, respectively. APP adaptor proteins with phosphotyrosine-binding (PTB) domains, including X11alpha (MINT1; gene: APBA1) and X11beta (MINT2; gene: APBA2), can bind to the conserved YENPTY-motif in the APP C-terminus. Over-expression of X11alpha and X11beta has been previously shown to alter APP processing and Abeta production. Here, for the first time, we have described the effects of RNAi silencing of X11alpha and X11beta expression on APP processing and Abeta production. RNAi silencing of APBA1 in H4 human neuroglioma cells stably transfected to express either APP-FL or APP-C99, increased levels of APP-C-terminal fragments (APP-CTFs) and lowered Abeta levels in both cell lines by inhibiting gamma-secretase cleavage of APP. Meanwhile, RNAi silencing of APBA2 also lowered Abeta levels but apparently not via attenuation of gamma-secretase activity. The notion of attenuating gamma-secretase cleavage of APP via the APP adaptor protein, X11a, is particularly attractive with regard to therapeutic potential, given that side effects of gamma-secretase inhibition owing to impaired proteolysis of other gamma-secretase substrates, e.g. Notch, might be avoided.