Taken together, in this study we found that TPFB—the total prenylflavonoids from Psoralea corylifolia L.—is a promising drug candidate preventing age-related cognitive impairments and AD-like neurobiochemical changes in SAMP8 mouse model, which effectively inhibited Aβ42 production, tau hyperphosphorylation, GSK-3β overactivation, proinflammatory cytokines production, as well as oxidative stress. This evidence concerns the gene GSK3B and Alzheimer disease.