Project Summary Amyloid accumulation in the brain is a universal feature of Alzheimer’s disease (AD) and many other related dementias and precedes clinical symptoms by several years. Methods for antemortem detection of amyloid species may, therefore, aid in diagnosing and monitoring neurodegeneration, providing critical information that can be used to devise a proper plan for patient management. While a number of clinical tools for detecting amyloid in the brain or cerebral spinal fluid have been developed to help diagnose AD, methods to differentiate AD from non-AD neuropathology in living patients are limited. We have recently developed two new families of fluorescent probes that can selectively detect aggregated forms of tau or alpha-synuclein, which could address an unmet need by extending the available toolbox for aiding in detection of amyloid or amyloid-like aggregates associated with non-AD diseases such as Frontotemporal Dementia (FTD), Parkinson’s disease (PD), and other tauopathies and synucleinopathies. The proposed research seeks to uncover new and reliable design principles for developing such selective amyloid-responsive probes and will seek to evaluate their utility for detection of amyloid species in emerging platforms for antemortem diagnostics. The Specific Aims of this proposal are to: 1) Develop fluorescent probes that exhibit selective enhancement of fluorescence upon binding to aggregated alpha-synuclein or tau versus ABeta in solution and in tissue; 2) Develop a method to characterize the distribution of aggregates of amyloidogenic proteins in biofluids; and 3) Evaluate whether selective amyloid-responsive fluorescent probes can be used to image specific amyloid deposits in the retina.