PROJECT SUMMARY Diabetes mellitus (DM) and Alzheimer’s disease (AD) are two major public health challenges that are anticipated to grow rapidly in the coming decades. Although these two diseases may appear unrelated, there is emerging evidence that AD is a frequent complication of DM. Indeed, the risk of developing dementia is increased by 50% to 150% in people with type-2 DM compared with the general population. Importantly, mounting evidence indicates that DM and AD share retinal neurodegeneration as a core feature. Reliable, non- invasive biomarkers of early retinal neurodegeneration are needed urgently, particularly as the DM and AD fields rapidly move towards developing therapeutics that target early-stage disease. This administrative supplement will allow us to translate our novel approaches for non-invasive measurement of retinal function that have been developed under the parent award (R01EY026004; Mechanisms of Early Functional Loss in Diabetic Eye Disease) to study abnormalities of the neural retina in AD. The overarching goals of this supplement are to apply protocols and knowledge gained from our studies of retinal neurodegeneration in DM to AD, allowing us to 1) define the cellular source of retinal abnormalities in the 5xFAD mouse model of AD; 2) determine if these abnormalities provide useful biomarkers for detecting and monitoring the progression of AD. Aim 1 will characterize the nature and extent of retinal dysfunction in the 5xFAD mouse model of AD using electroretinography. Aim 2 will quantify abnormalities in retinal thickness and vascular characteristics in the 5xFAD mouse model of AD using optical coherence tomography. These studies will provide essential new knowledge regarding retinal neurodegeneration in AD and its relationship to neurodegeneration in DM. This line of study is particularly important and timely as new therapeutic approaches for treating early-stage AD are being investigated, but biomarkers that can identify early-stage AD lag behind at present.