The use of natural compounds is an interesting stratagem in the search of drugs with therapeutic potential for the treatment of Alzheimers disease (AD). We report here the effect of the hyperforin derivative (IDN5706, tetrahydrohyperforin), a semi-synthetic derivative of the St. Johns Wort, on the brain neuropathology, learning and memory in a double transgenic (APPswe, PS-1dE9) mouse model of AD. Results indicate that, IDN5706 alleviates memory decline induced by amyloid-β (Aβ) deposits as indicated by the Morris water maze paradigm. Moreover, the analysis of Aβ deposits by immunodetection and thioflavin-S staining of brain sections, only reveals a decrease in the frequency of the largersize Aβ deposits, suggesting that IDN5706 affected the turnover of amyloid plaques. Immunohistochemical analysis, using GFAP and n-Tyrosine indicated that the hyperforin derivative prevents the inflammatory astrocytic reaction and the oxidative damage triggered by high Aβ deposit levels. We conclude that the hyperforin derivative, IDN5706, has therapeutic potential for prevention and treatment of AD.