Endocytic dysfunction is an early pathological change in Alzheimer's disease (AD) and Down's syndrome (DS). Using primary fibroblasts from DS individuals , we explored the interactions among endocytic compartments that are altered in AD and assessed their functional consequences in AD pathogenesis. We found that , like neurons in both AD and DS brains , DS fibroblasts exhibit increased endocytic uptake , fusion , and recycling , and trafficking of lysosomal hydrolases to rab5-positive early endosomes. Moreover , late endosomes identified using antibodies to rab7 and lysobisphosphatidic acid increased in number and appeared as enlarged , perinuclear vacuoles , resembling those in neurons of both AD and DS brains. In control fibroblasts , similar enlargement of rab5-, rab7-, and lysobisphosphatidic acid-positive endosomes was induced when endocytosis and endosomal fusion were increased by expression of either a rab5 or an active rab5 mutant , suggesting that persistent endocytic activation results in late endocytic dysfunction. Conversely , expression of a rab5 mutant that inhibits endocytic uptake reversed early and late endosomal abnormalities in DS fibroblasts. Our results indicate that DS fibroblasts recapitulate the neuronal endocytic dysfunction of AD and DS , suggesting that increased trafficking from early endosomes can account , in part , for downstream endocytic perturbations that occur in neurons in both AD and DS brains.