ßThe amyloid-beta protein precursor (AbPP) is a type I transmembrane molecule which undergoes regulated cleavage events. The physio-pathological relevance of AbPP derives from the fact that its aberrant processing correlates with the onset of Alzheimer’s Disease (AD). AD is a neuro-degenerative disorder characterized by neuronal cell death, loss of synapses and deposition of misfolded protein plaques in the brain: these plaques are the pathological hallmark for AD diagnosis and their main constituent is the Amyloid-b peptide, a 40-42 aminoacid long protein fragment derived by AbPP upon two sequential processing events. Mutations in the genes encoding for AbPP and some of the enzymes responsible for its processing cause Familial forms of AD (FAD): the elucidation of the mechanisms underlying AbPP metabolism appears therefore crucial in order to understand the basis for the onset of AD. Apart from Ab, upon processing of AbPP other fragments are generated: the long extracellular domain is released in the extracellular space, while the short cytoplasmic tail, named AbPP Intracellular Domain (AID) is released intracellularly. AID appears be involved in several cellular processes: it acts as a pro-apoptotic molecule and as a regulator of intracellular calcium homeostasis. However the mechanisms through which AID serves its functions have yet to be elucidated. A large number of adaptor molecules interact with AID and are able to modulate its function. We have recently characterized AID Associated protein-1 (AIDA-1), a novel AID binding protein. Different isoforms of AIDA-1, derived from alternative splicing of the same messenger RNA, have been described. Here we further analyze the interaction between several AIDA-1 isoforms and the cytoplasmic tail of AbPP: our data demonstrate that the interaction between the two molecules is regulated by alternative splicing of the AIDA-1 proteins. Furthermore, we provide data supporting a possible function for AIDA-1a as a modulator of AbPP processing.