Aggregation of the amyloid-β (Aβ) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Aβ aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Aβ levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Aβ levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Aβ metabolism and ultimately region-specific Aβ deposition. The findings also have important implications for treatment development.