Alzheimer’s disease (AD) is an incurable neurodegenerative brain disorder that causes progressive memory loss and cognitive decline, and is the most common form of dementia. It is characterized by the coexistence of extracellular amyloid plaques, mainly formed by the amyloid beta-42 (Abeta) peptide, and intracellular neurofibrillary tangles containing aggregates of abnormal tau. Abeta and tau were considered as disconnected culprits for many years, but in view of recent studies, it is clear that they are intimately related and possess synergistic activities. Sadly, very little is known about how Abeta and tau interactions trigger AD pathogenesis, which significantly hinders the development of effective treatments. To address this, we created a new fly model of AD that genetically produces both human Abeta and tau resulting in synergistic pathology. These flies display extracellular deposits of Abeta, intracellular aggregation of pathological tau, and progressive neurodegeneration. Our preliminary data show that the robust and consistent pathology of these flies represents an ideal platform for gene discovery initiatives. Therefore, we propose to use these flies to functionally assess the first large collection of transgenic flies expressing human genes. This collection includes many AD risk genes, identified by Genome Wide Association Studies (GWAS) or Next Generation Sequencing (NGS), whose functional role in the disease is poorly understood. Thus, we will cross our Abeta+tau flies with 1,500 strains engineered to specifically activate human HA-tagged cDNAs with similar expression levels. We will first test them in the fly eye, which provides a useful and easy-to-score phenotype to assess the effect of co-expressing every human gene with Abeta and tau (Aim 1). Then, we will validate the stronger suppressors for their ability to alter the course of neuropathology in the fly brain using cellular, histological and behavioral approaches (Aim 2). We strongly believe that the screen of this new and distinctive library will lead to a rapid identification of relevant hits mediating pathological interactions between Abeta and tau, and will unveil a set of key human targets for immediate translational studies. Therefore, this work may contribute significantly to the goals of the National Plan to Address Alzheimer’s Disease.