Combining several drugs to target different aspects of a disease is a very common strategy in medicine and pharmacy. Widespread diseases like hypertension and cardiac failure are now treated this way with relatively good success. Research evidence suggests that this same strategy might be beneficial for AlzheimerÕs disease (AD) too. Indeed, a wide range of molecular players are involved in AD and many of them seem to be necessary for the development of the disease. Most current therapeutic approaches in clinical trials focus only on one feature of the disease and this might explain why no efficient treatment has been developed yet. In other words, if you block one only of the AD pathological players, the others might continue their dirty job and you get no therapeutic effect. Thus, we hypothesize that by combining drugs with synergistic mechanisms of action, we can achieve the best effect against AD pathology. A difficult part is to choose the right drugs to combine. We have selected three drugs that have: 1) striking disease-modifying effects in preclinical studies and 2) very good safety profiles in human. The first is docosahexaenoic acid (DHA), which is a part of our regular diet since it is found in fish. During his postdoctoral stay in the laboratory of Greg Cole (UCLA), the principal applicant has shown that DHA protected against AD pathology and cognitive deficit in a mouse model of AD. The second is resveratrol, which is a natural compound found in red wine that has been consumed by humans for thousands of years. Many positive effects of resveratrol have been demonstrated in animal models of other diseases but, more specifically, in cultured cells modeling AD cellular processes. The third is R-flurbiprofen, which is a safer version of a compound available on the market for years under the brand name of Ansaid¨. Convincing beneficial effects of R-flurbiprofen have been shown in animal models of AD. DHA and R-flurbiprofen are already undergoing separate clinical trials. To study these promising drugs we will use a recent triple-transgenic mouse that models most neuropathological signs of AD including neuritic plaques and neurofibrillary tangles. The effect of the three drugs on neuropathological signs of AD (neuritic plaques, neurofibrillary tangles, oxidative damage, synapse health, etc.) will be investigated alone and in combination to evidence their synergistic effect against AD. If successful, our research project could identify potential synergistic treatment(s) for AD that could lead to new clinical trials in humans.