ALSTAR2 (R01EY029595) is a prospective cohort study of older adults in normal retinal health and those with early and intermediate age-related macular degeneration (AMD). AMD is the leading cause of irreversible vision impairment in older adults in the US and affects about 170 million people worldwide. The retina has the same embryological origin and development as the brain, providing a unique, non-invasive approach for evaluating brain conditions including Alzheimer’s disease and mild cognitive impairment (MCI). Associations between AMD and Alzheimer’s disease have been shown in several epidemiologic studies to date. AMD and Alzheimer’s disease both are characterized by neurodegeneration and share advanced age and smoking as risk factors. In addition, Alzheimer’s disease and AMD have common features such as microangiopathy, chronic inflammation, and amyloidß. However, the shared mechanistic pathways between these two prevalent diseases remain unknown. Most studies on retinal biomarkers for MCI and Alzheimer’s disease have excluded persons with concurrent retinal disease including AMD. There has never been a large, well-powered, prospective study on Alzheimer’s disease that has explicitly by design included people with AMD. In ALSTAR2, we are examining the structural biomarkers of early AMD associated with visual function decline. These same participants are also at risk for Alzheimer’s disease and MCI due to advanced age. We just completed baseline ALSTAR2 enrollment (N=546), with large numbers of persons with early AMD, intermediate AMD, and those in normal retinal health. The three-year follow-up will begin in early 2023, repeating the entire baseline ALSTAR2 protocol. At that follow-up visit we will leverage ALSTAR2’s unique dataset by adding cognitive testing and neuroimaging through an R01 application we will submit in 2022. Thus we will not only have retinal microscopic structure and microvasculature imaging through multimodalities and visual functional biomarkers, but we will also have a simultaneous examination of neuroimaging of cerebral structure and vasculature and cognitive function. We will be well-positioned to identify structural abnormalities (e.g., lipidic depositions) and vascular characteristics in retina and brain as a function of cognitive function (e.g., MCI). To prepare for this R01 application, which will also add a six-year follow-up, we plan this supplement to study 60 new participants from normal macular health to intermediate AMD, many of whom have MCI. The goal of this supplement is to develop pilot data on neuroimaging, cognitive function, retinal imaging, AMD disease severity, and functional biomarkers for AMD to generate guidance on statistical power for the R01 submission and to establish neuroimaging and cognitive testing feasibility. In this supplemental study we will examine the associations of (1) structural abnormalities in retina and brain with cognitive dysfunction, (2) retinal and cerebral microvasculatu...