Alzheimer's disease (AD), the most prevalent of neurodegenerative diseases, is growing increasingly common in the elderly, gradually depriving them of memory and cognitive function. Hallmarks of the disease include severe dementia, seemingly associated with amyloid plaques and neurofibrillary tangles in the CNS. However, the mechanisms that cause AD are not completely understood. Currently, there are no treatments that effectively ameliorate or abate disease progression, although many candidates are in clinic trials. Over the past decade, the fruit fly, Drosophila melanogaster, has been used as a vehicle for AD research, typically as an implement for identification and validation of targets. More recently, Drosophila have been used to test potential therapeutics for efficacy. Vitruvean, LLC has developed a Drosophila-based, medium-throughput behavioral screening platform for discovery and validation of compound treatments for neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases. Vitruvean uses this automated system to screen compounds for modification of progressively degenerating climbing phenotypes. We are currently investigating multiple models of AD, generated by overexpressing derivatives and variations of human APP and human tau transgenes in the fly CNS. Using the PhenoScreen system, we were able to identify histone deacetylase inhibitors (TSA, SAHA), gamma-secretase inhibitors (Compound E), aggregation inhibitors (Methylene Blue), and cholinesterase inhibitors (Physostigmine, Tacrine) as being positive in one or more of our AD models. Such compounds have been previously shown to have positive effects in other AD model systems. Furthermore, we have been able to profile compound effects on behavior over multiple Drosophila AD models, providing us with information regarding which pathway they may affect. We were also able to assess some of these compounds in a Huntington's disease line in hopes of further understanding their mechanisms. We demonstrate the utility of different Drosophila models of AD that are amenable to use in the PhenoScreen platform for drug discovery and validation. We have shown that potentially therapeutic compound classes can be used to reverse the degenerating behavior in multiple AD models highlighting different aspects of the disease. We believe that this screening system and this battery of fly models can be used to facilitate drug discovery for Alzheimer's disease.