A role of amyloid ? (A?) peptide aggregation and deposition in Alzheimer's disease (AD) pathogenesis is widely accepted. Significantly, abnormalities induced by aggregated A? have been linked to synaptic and neuritic degeneration, consistent with the "dying-back" pattern of degeneration that characterizes neurons affected in AD. However, molecular mechanisms underlying the toxic effect of aggregated A? remain elusive. In the last 2 decades, a variety of aggregated A? species have been identified and their toxic properties demonstrated in diverse experimental systems. Concurrently, specific A? assemblies have been shown to interact and misregulate a growing number of molecular effectors with diverse physiological functions. Such pleiotropic effects of aggregated A? posit a mayor challenge for the identification of the most cardinal A? effectors relevant to AD pathology. In this review, we discuss recent experimental evidence implicating amyloid ? precursor protein (APP) as a molecular target for toxic A? assemblies. Based on a significant body of pathologic observations and experimental evidence, we propose a novel pathologic feed-forward mechanism linking A? aggregation to abnormalities in APP processing and function, which in turn would trigger the progressive loss of neuronal connectivity observed early in AD.