Amyloid β (Aβ) peptides are direct competitive inhibitors of insulin binding and action [25]. We demonstrate that Aβ peptides can inhibit the effect of insulin on the metabolic processing of the amyloid β protein precursor (AβPP). As evidence emerges concerning the role of insulin and insulin like growth factors (IGFs) in learning and memory, recent findings have suggested that insulin may have a significant role in the pathogenetic pathways leading to Alzheimer's disease (AD). As an example several investigators have demonstrated upregulation of insulin receptors and defective insulin receptor signal transduction in AD brains. Moreover insulin has been shown to positively modulate AβPP proteolytic processing. The fact that insulin and Aβ appear to share a common system for degradation and disposal as they are both substrates of the insulin degrading enzyme (IDE) suggested the possibility of a reciprocal interference. Here we report that Aβ can directly interfere with insulin receptor signalling inhibiting the autophosphorylation of partially purified insulin receptors. As a consequence of such interaction we also demonstrate that Aβ blocks the effect of insulin on the release of sAβPPα in chinese hamster ovaries (CHO) cells transfected with insulin receptors.