Investigators at Stanford University have created a panel of isogenic iPSC-derived neurons with various mutations of amyloid precursor protein (APP) and presenilin (PSEN), and used it to demonstrate that accumulation of APP beta C-terminal fragments (beta-CTFs), but not of amyloid beta, correlated with endosomal dysfunction and could be improved by inhibiting beta-secretase (BACE-1). Genetic evidence clearly implicates APP misprocessing in Alzheimer's disease (AD), and amyloid beta plaques are the disease's major anatomical calling card, which has led to a focus on therapeutic targeting of the latter. However, that therapeutic targeting has failed multiple times, and the evidence linking amyloid beta to AD is weaker than that for APP. Recently, endosomal dysfunction has been proposed as "another plausible underlying pathological mechanism," leading the authors to investigate the causes of endosomal dysfunction in their cell lines. They showed that endosomal dysfunction, which leads to deficits in intracellular transport, was correlated with changes in beta-CTF but not amyloid beta.