Summary/Abstract To date numerous investigators have noted similarities between many features of Age-Related Macular Degeneration (AMD) and Alzheimer Disease (AD), suggesting that they share etiologic and mechanistic attributes, and that it might thus be fruitful to adapt diagnostic and/or treatment approaches for one to the other (reviewed in(Ohno-Matsui 2011, Ashok, Singh et al. 2020)). In particular, AMD and AD share certain risk factors such as aging, inflammation, smoking, dyslipidemia, and the presence of deposits containing specific proteins including amyloid-beta, but few genetic risk factors. We discovered (Thompson, Reffatto et al. 2015) that sub-retinal pigment epithelial (sub-RPE) deposits of many types described as drusen contain microscopic spherules of hydroxyapatite (HAP; Ca5(PO4)3OH, found in bone mineral) and proposed that this mineral might nucleate the growth of drusen in the retina and promote the development of AMD. Since then, our collaborators have found that a subset of larger HAP deposits (“nodules”) is significantly associated with progression to advanced AMD within one year (odds ratio: 6.4, p = 0.001; (Tan, Pilgrim et al. 2018)). The focus of our current NEI R01 is a study of whether retinal HAP deposition presages the rate and extent of drusen formation in a non-human primate model of AMD. The study images retinal HAP in vivo in a monkey model of AMD with a novel technique: fluorescence lifetime imaging ophthalmoscopy (FLIO) using a legacy oral antibiotic as a specific stain for HAP. We have shown that aged retinas can be stained with chlortetracycline infused from the bloodstream ex vivo, and that stained drusen can be imaged by fluorescence lifetime imaging (Szmacinski, Hegde et al. 2020). Our collaborators and others have recently observed that AD patients exhibit peripheral drusen with HAP (e.g., (Csincsik, MacGillivray et al. 2018) , as well as phospho-tau-calcification in the brain, and these drusen are evidently useful for classification of AD patients in the clinic (Csincsik, Quinn et al. 2021) suggesting that widefield fluorescence imaging of calcification in the peripheral retina might be predictive of AD. With the supplement, we propose a pilot study to assess our imaging method's capability to detect peripheral HAP-containing drusen, and the correlation between them and gold standard markers of AD: deposition of beta-amyloid and phospho-tau in the brains of human donors. We have ready access to a sizable donor cohort on campus at low cost that will permit a pilot study during the term of the supplement. In addition, we will genotype the donors for the main AMD and AD risk SNPs to see if number, size, and/or radial distribution of peripheral drusen are correlated with AD risk factors. Finally, we plan to test whether we can use two photon excitation to image the stained drusen in the cadaver retina, which we believe will provide better accuracy and precision with improved safety.