Abstract: A? (beta-amyloid peptide) is an important contributor to Alzheimer's disease (AD). We modeled A? toxicity in yeast by directing the peptide to the secretory pathway. A genome-wide screen for toxicity modifiers identified the yeast homolog of phosphatidylinositol binding clathrin assembly protein (PICALM) and other endocytic factors connected to AD whose relationship to A? was previously unknown. The factors identified in yeast modified A? toxicity in glutamatergic neurons of Caenorhabditis elegans and in primary rat cortical neurons. In yeast, A? impaired the endocytic trafficking of a plasma membrane receptor, which was ameliorated by endocytic pathway factors identified in the yeast screen. Thus, links between A?, endocytosis, and human AD risk factors can be ascertained with yeast as a model system.