Alzheimer’s disease (AD) is a chronic, progressive, and deadly neurodegenerative disease that causes irreversible loss of mental function. There are no current medications that can delay or stop the progression of AD; thus, there is a critical need in developing novel effective drugs. The studies proposed in this project will establish new computational methodologies that will be applied towards identifying alternative binding sites (allosteric sites) in human adenosine receptor A2AR and rationally design novel target-specific chemical agents (allosteric modulators) that could be developed into viable drug candidates to treat AD and related dementias. Our in-house libraries of over 17.5 million commercially available compounds will be screened in silico by computers and the hits will be validated by experimental pharmacologists. We believe that our strategy has a high potential to achieve the goal of identification of innovative therapeutics to treat AD.