Acute, s.c. administration of a gamma-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), to young PDAPP mice dose dependently decreases cortical amyloid-beta (A beta). The present studies replicated these findings in Tg2576 mice and examined further whether DAPT would reduce cerebrospinal fluid (CSF) A beta comparably in young (plaque-free) and aged (plaque-bearing) mice. In the first study, vehicle or DAPT (10, 30, or 100 mg/kg s.c.) administered to young Tg2576 mice (6 months old) dose dependently reduced A beta peptide levels in the cortex as seen previously in the PDAPP mice. Additionally, a dose-dependent decrease in plasma A beta levels was evident. The same dosing regime was applied next to aged mice (17 months old) to assess A beta changes in the CSF in addition to plasma and brains. DAPT dose dependently reduced A beta levels in the CSF and plasma, but not in the brain wherein A beta levels were 400 to 500 times higher than those in young mice, consistent with a large pool of A beta extracted from amyloid deposits. In subsequent studies, effects of oral DAPT (100 or 200 mg/kg) were examined concurrently in young and aged mice. DAPT reduced A beta levels in CSF and plasma to a similar extent at both ages. In contrast, DAPT reduced brain A beta levels primarily in young mice, with minimal effects in aged mice. These results demonstrate that A beta levels in CSF and plasma decrease dose dependently after gamma-secretase inhibition, and this response is not affected by amyloid plaque burden. We conclude that CSF and plasma A beta may offer a clinically applicable, mechanism-based biomarker for inhibitors of A beta production.