Alzheimer’s disease (AD) is a serious threat for the aging society.In this study,we examined the preventive effect of the total prenylflavonoids (TPFB) prepared from the driedfruits ofPsoralea corylifoliaL., using an age-related AD mouse model SAMP8. We found thatlong-term dietary TPFB at 50 mg/kg·day significantly improved cognitive performance of theSAMP8 mice in Morris water maze tests, similar to 150 mg/kg·day of resveratrol, a popularneuro-protective compound. Furthermore, TPFB treatment showed significant improvements invarious AD markers in SAMP8 brains, which were restored to near control levels of the normalmice, SAMR1. TPFB significantly reduced the level of amyloidβ-peptide 42 (Aβ42), inhibitedhyperphosphorylation of the microtubule-associated protein Tau, induced phosphorylation of Ser9of the glycogen synthase kinase 3β(GSK-3β), and decreased the expression of the proinflammatorycytokines TNFα, IL-6, and IL-1β. Finally, TPFB also markedly reduced the level of serum derivativesof reactive oxygen metabolites (d-ROMs), a biomarker of oxidative stressin vivo. These resultsshowed that dietary TPFB could effectively prevent age-related cognitive deficits and AD-likeneurobiochemical changes, and may have a potential role in the prevention of Alzheimer’s disease.