PROJECT SUMMARY Alzheimer’s disease (AD) is an age-related disease clinically diagnosed by the onset of dementia. This disease is defined by the formation of amyloid-beta (A) plaques and NFTs composed of tau aggregates. Although tau pathology has been considered secondary to A accumulation, it has been proposed that it may correlate more accurately to disease progression and cognitive changes. Abnormal tau aggregation occurs not only in the Alzheimer’s disease, but also in a family of protein-misfolding diseases called tauopathies. Currently, diagnosis of AD in individuals showing symptoms of cognitive decline is a lengthy and costly process, requiring multiple modes of testing over months to years. Early, pre-symptomatic diagnosis is even more challenging, if not impossible, with currently available technology. The only definitive way to diagnose AD is through post-mortem analysis. An ante-mortem diagnostic is needed that can reliably identify AD at the early, asymptomatic stages, enabling patients to get under the guidance of neurologist before the disease is at an advanced stage to maximize the opportunity for therapeutic intervention. Furthermore, a useful and affordable outcome marker is needed for clinical trials focused on therapies for AD/tauopathies that could stop or reverse progression of the disease. Amydis’ goal is to address these unmet needs by identifying tau in the eye, as a window to the brain, for early detection of AD/tauopathies. This proposal aims to develop small molecule fluorescent retinal tracers as a novel diagnostic for Alzheimer’s disease and tauopathies.