Purpose: Accumulation of amyloid-β (Aβ) correlates significantly with progressive cognitive deficits, a main symptom of Alzheimer’s disease (AD). Although treadmill exercise reduces Aβ levels, the molecular mechanisms underlying the effects are not fully understood. We hypothesize that treadmill exercise decreases Aβ production and alleviates cognitive deficits by activating the non-amyloidogenic pathway via SIRT-1 signaling. Method: NSE/AβPPsw Tg mice and their control non-Tg mice at 12 months of age were divided into three groups: non-Tg sedentary mice (NTS, n=8), Tg sedentary mice (TS, n=8) and Tg exercise mice (TE, n=8). TE mice group was subjected to treadmill exercise on a treadmill for 12 weeks (15 m/min, 60 min/day, 5 day/week). And then, brain cortex was evaluated to determine whether any changes in the Aβ expression, non-amyloidogenesis (SIRT-1, ROCK-1, RARβ, ADAM-10), amyloidogenesis (PGC-1a, BACE-1, C-99), and neuronal cell survival-related proteins. Result: Treadmill exercise improved cognitive deficits and alleviated neurotoxicity. Most importantly, treadmill exercise increased SIRT-1 level, which subsequently resulted in increased ADAM-10 level by down-regulation of ROCK-1 and upregulation of RARβ, ultimately facilitating the non-amyloidogenic pathway. Treadmill exercise-induced activation in SIRT-1 level also elevated PGC-1a level and reduced BACE-1 and C-99 level, resulting in inhibition of the amyloidogenic pathway. Conclusion: In summary, our study is the first to report that treadmill exercise might reduce Aβ production and improve cognitive deficits by increasing ADAM-10 and decreasing BACE-1 via activation of SIRT-1/PGC-1a signaling, ultimately facilitating the non-amyloidogenic pathway. This study provides new insight into the mechanisms of treadmill exercise-induced Aβ reduction, which represents a potential therapeutic strategy for AD.