Dementia of the Alzheimer type (DAT) is a multi-factorial disease characterized by progressive loss of memory. The beta-amyloid precursor protein (bPP) has been thought to be of central importance for the pathogenesis of DAT since the deposition of its proteolytic product, b-amyloid, is found in the main pathological lesion of DAT. Moreover, all three dominant mutations responsible for early onset familial DAT appear to influence bPP processing. The cytoplasmic domain of bPP has been shown to interact with the phosphotyrosine interacting domain (PID) of a neural adaptor protein, FE65p. FE65p was hypothesized to be a regulator of bPP trafficking and processing since the region of bPP that FE65p interacts with contains the signal for bPP internalization. Overexpression of FE65 in vitro increases translocation of bPP to the cell surface, and increases of both sbPPa and secreted Ab?. The impacts of FE65 on amyloid production and deposition in vivo are unclear. To investigate the normal function(s) of FE65p and to study the effect of FE65p on amyloid production in vivo, we generated a line of transgenic FE65 deficient mice and crossed them with the Tg2576 (HuAPP695.SWE) mice, which are mouse models of DAT expressing human APP695 with the 'Swedish' mutation (K670N and M671L). In this study, we showed evidence that the deficiency of FE65p alters bPP processing and Ab production, as assayed in primary cultures from Tg2576 mice with homozygous and heterozygous deficiencies for FE65. Our FE65 knockout mice, appear normal and have normal life spans. However, these Tg2576/FE65+/- and Tg2576/FE65-/- mice have reduced survival rates as compared with littermate control (Tg2576/ FE65+/+) mice. In addition, recent behavioral studies conducted on these FE65 mice showed homozygous FE65 knock out mice have deficits in learning and memory. Our studies suggest important roles for FE65 and its potential involvement in the pathogenesis of DAT.