Background: Alzheimer's disease (AD) is a neurodegenerative disease featured by memory loss, neuroinflammation and oxidative stress. Overproduction or insufficient clearance of A beta leads to its pathological aggregation and deposition, which is considered the predominant neuropathological hallmark of AD. Therefore, reducing A beta levels and inhibiting A beta-induced neurotoxicity are feasible therapeutic strategies for AD treatment. Wolfberry has been traditionally used as a natural antioxidant and anti-aging product. However, whether wolfberry species has therapeutic potential on AD remains unknown. Method: The effects of fruitless wolfberry-sprout extract (FWE) on A beta fibrillation and fibril disaggregation was measured by thioflavin T fluorescence and transmission electron microscope imaging; A beta oligomer level was determined by dot-blot; Cell viability and apoptosis was assessed by MTT and TUNEL assay. The levels of A beta 40/42, oxidative stress biomarkers and inflammatory cytokines were detected by corresponding kits. 8-month-old male APP/PSI mice and their age-matched WT littermates were treated with FWE or vehicle by oral administration (gavage) once a day for 4 weeks. Then the cognitive performance was determined using object recognition test and Y-maze test. The A beta burden and gliosis was evaluated by immunostaining and immunoblotting, respectively. Results: FWE significantly inhibited A beta fibrillation and disaggregated the formed A beta fibrils, lowered A beta oligomer level and A beta-induced neuro-cytotoxicity, and attenuated oxidative stress in vitro. Oral administration of FWE remarkably improved cognitive function, reduced A beta burden, decreased gliosis and inflammatory cytokines release, and ameliorated oxidative stress in the brains of APP/PS1 mice. Conclusion: These findings indicate that FWE is a promising natural agent for AD treatment.