To better understand amyloid‐β (Aβ) metabolism in vivo, we assessed the concentration of Aβ in the CSF and plasma of APP^V717F (PDAPP) transgenic mice, a model that develops age‐dependent Alzheimer's disease (AD)‐like pathology. In 3‐month‐old mice, prior to the development of Aβ deposition in the brain, there was a highly significant correlation between Aβ levels in CSF and plasma. In 9‐month‐old‐mice, an age at which some but not all mice have developed Aβ deposition, there was also a significant correlation between CSF and plasma Aβ; however, the correlation was not as strong as that present in young mice. In further exploring CSF and plasma Aβ levels in 9‐month‐old mice, levels of CSF Aβ were found to correlate highly with Aβ burden. Analysis of the CSF : plasma Aβ ratio revealed a selective two‐fold increase in plaque versus non‐plaque bearing mice, strongly suggesting a plaque‐mediated sequestration of soluble Aβ in brain. Interestingly, in 9‐month‐old mice, a significant correlation between CNS and plasma Aβ was limited to mice lacking Aβ deposition. These findings suggest that there is a dynamic equilibrium between CNS and plasma Aβ, and that plaques create a new equilibrium because soluble CNS Aβ not only enters the plasma but also deposits onto amyloid plaques in the CNS.