Numerous studies have investigated changes in protein expression at the system level using proteomic mass spectrometry, but only recently have studies explored the structure of proteins at the proteome level.We developed covalent protein painting (CPP), a protein footprinting method that quantitatively labels exposed lysine, and have now extended the method to whole intact animals to measure surface accessibility as a surrogate of in vivo protein conformations. We investigated how protein structure and protein expression change as Alzheimer's disease (AD) progresses by conducting in vivo whole animal labeling of AD mice. This allowed us to analyze broadly protein accessibility in various organs over the course of AD. We observed that structural changes of proteins related to 'energy generation,' 'carbon metabolism,' and 'metal ion homeostasis' preceded expression changes in the brain. We found that proteins in certain pathways undergoing structural changes were significantly co-regulated in the brain, kidney, muscle, and spleen.