A role of amyloid I2 (AI2) peptide aggregation and deposition in Alzheimer's disease (AD) pathogenesis is widely accepted. Significantly, abnormalities induced by aggregated AI2 have been linked to synaptic and neuritic degeneration, consistent with the adying-backa pattern of degeneration that characterizes neurons affected in AD. However, molecular mechanisms underlying the toxic effect of aggregated AI2 remain elusive. In the last 2 decades, a variety of aggregated AI2 species have been identified and their toxic properties demonstrated in diverse experimental systems. Concurrently, specific AI2 assemblies have been shown to interact and misregulate a growing number of molecular effectors with diverse physiological functions. Such pleiotropic effects of aggregated AI2 posit a mayor challenge for the identification of the most cardinal AI2 effectors relevant to AD pathology. In this review, we discuss recent experimental evidence implicating amyloid I2 precursor protein (APP) as a molecular target for toxic AI2 assemblies. Based on a significant body of pathologic observations and experimental evidence, we propose a novel pathologic feed-forward mechanism linking AI2 aggregation to abnormalities in APP processing and function, which in turn would trigger the progressive loss of neuronal connectivity observed early in AD.