Oxygen delivery requires that Red Blood Cells (RBCs) must be deformable to pass through the microcirculation. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by abnormal extracellular deposition of beta-amyloid peptide (Abeta) and neuronal loss. We have analyzed RBC morphology in blood from subjects with AD and found that > 15% of the RBCs are elongated as compared to 5.9% in normal controls (p < 0.0001). To determine whether these morphology changes can be associated with the greater exposure of RBCs to AP in AD subjects, we investigated the in vitro effect of Abeta fibrils on blood. Morphological analysis of RBCs treated with Abeta1-40 or Abeta1-42 fibrils show 8.6% or 11.1% elongated cells, respectively. In contrast, only 2.9% or 1.3% of RBCs are elongated when blood is treated with buffer or mock fibrils generated from Abeta42-1. Elongated RBCs are expected to be less deformable. This prediction is consistent with our earlier studies showing impaired deformability of RBCs treated with Abeta fibrils. An additional factor previously reported by us, expected to impair the flow of RBCs through the microcirculation is their adherence to endothelial cells (ECs) when Abeta1-40 fibrils are bound to either RBCs or ECs. This factor would be more pronounced in AD subjects with elevated levels of Abeta on the vasculature. These results suggest that Abeta interactions with RBCs in AD subjects can result in impaired oxygen transport and delivery, which will have important implications for AD.