Accumulation of the amyloid beta (Aβ) peptide in the brain is the hallmark of Alzheimer's disease (AD), with evidence indicating that oligomeric forms of Aβ are toxic to neurons, but the exact mechanisms are still unclear. Aβ is generated from its precursor APP in the secretory pathway and reaches the extracellular space, where it interacts with the plasma membrane and undergoes endocytosis and vesicular trafficking. Genetic studies have pointed to endocytic pathway factors as risk factors for sporadic AD, but whether such effects are linked to Aβ was unknown. Using the power of yeast genetics, Lindquist and colleagues screened for factors that modify the toxicity of Aβ. To mimic the fate of Aβ in neurons, the authors fused Aβ to a signal sequence, resulting in cleavage within the endoplasmic reticulum and secretion. Aβ then interacted with the plasma membrane and was endocytosed. Importantly, the secreted Aβ caused cellular toxicity. This approach uncovered 12 modifiers of Aβ toxicity with clear human orthologs. Of these, three are involved in clathrin-mediated endocytosis, and their human orthologs are known risk factors for AD. Seven are associated with cytoskeleton functions, and reexamination of previous clinical studies revealed a suggestive association of three of them with susceptibility to AD. Furthermore, the secreted Aβ increased the number of clathrin foci and perturbed the localization of a plasma membrane protein that is normally endocytosed and trafficked to the vacuole. Finally, the authors validated the effects of some of these factors on Aβ neurotoxicity using Caenorhabditis elegans and rat cortical neurons. Altogether, their work indicates that Aβ can exert toxicity by disturbing neuronal endocytic homeostasis and highlights the value of yeast as a model system to identify novel players and provide mechanistic insights into a complex human disease. (Science doi:10.1126/science.1213210, published online 27 October 2011)