Alzheimer's disease (AD) is affecting 1 million people in France and more than 24 millions world-wide. Thus far, no disease-modifying treatments exist. Although the small peptide of 39-43 amino acids called ß-amyloid (Aß) is the major component of senile plaques, its contribution to pathological features of AD and to the synaptic and cognitive dysfunction still remains unclear. One key aspect supported by a large body of clinical and experimental evidence is that early Aß oligomers are the primary toxic species and in this respect Aß42 is more toxic than Aß40. Several compounds such as NQTrp, SEN304 and inh3 are known to reduce both fibril formation and oligomers toxicity in cells, but their success in late stage clinical trials remains to be determined. How these three small molecule or peptide-based compounds bind to Aß42 oligomers is unknown since there is no atomic structure of Aß42-drug oligomers. Our solution to this problem is the application of multi-scale state-of-the-art computational methods (from coarse-grained to all-atom models) combined with low-resolution biophysical data (Dynamic Light Scattering, DLS; Electron Microscopy, EM; Electron Paramagnetic Resonance, EPR; Electrospray Ionisation coupled to Mass Spectrometry, ESI-MS, and chemical shifts and NOE NMR) to reveal at an atomic level of detail the modes of action of the three inhibitors NQTrp, SEN304 and inh3. Building on the full spectrum of oligomeric structures of Aß42 with each inhibitor, we can screen and predict new drugs with much higher efficacy by using virtual screening, flexible docking approaches and all-atom steered and metadynamics simulations. Then, the 15 best commercially available compounds will be tested with established experimental methods such as thioflavin T (ThT) binding, MTT toxicity, LDH activity, and iFly assay based on detection of early locomotor abnormalities in a Drosophila Model of AD. Finally, the most 3 promising compounds will be tested on transgenic mice that can be tested for cognitive and behavioural performances as well as for the presence of neuropathological markers. Overall, the GRAL project, which integrates different and complementary expertises from structural biology, chemistry, biophysics, computer simulations, in silico design and screening of compounds to transgenic flies and mice, aims at discovering new therapeutic agents reducing Aß42 toxicity.