To relate levels of β-amyloid42 (Aβ42) in the cerebrospinal fluid (CSF) and brain in early Alzheimer's disease, we repeatedly measured CSF Aβ42 levels in transgenic mice carrying Swedish amyloid precursor protein and presenilin-1 mutations, at ages before and after amyloid deposition. Hippocampal Aβ42 levels were measured at the endpoints. In APPswe/PS1(A246E) mice, CSF Aβ42 levels significantly increased between 5 and 7 months of age but did not change between 8 and 13 months despite a rapid increase in brain Aβ42. Furthermore, a decline in CSF Aβ42 levels was observed between 6 and 9 months in APPswe/PS1dE9 mice with faster pathology. Interestingly, the initial CSF Aβ42 concentrations correlated more strongly with brain Aβ42 levels than the endpoint CSF Aβ42. Our results suggest that the levels of CSF Aβ42 initially reflect the rate of Aβ42 production, but after reaching a critical concentration stay in equilibrium, until plaque formation leads to decreased CSF Aβ42 levels. © 2004 Elsevier Inc. All rights reserved.