Project Abstract Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder that is relentlessly progressive and has no cure. Treatment agents may slow the progress of this disease. If successful, this program could enable early diagnosis of Alzheimer’s Disease and Mild Cognitive Impairment (MCI) through ocular imaging, which could in turn permit treatment at much early stages of the disease, potentially postponing or even avoiding the dire consequences of advanced dementia. The overarching goal of this proposal is to improve the ability to detect AD and MCI. We will accomplish this using novel imaging technology that provides in-vivo, noninvasive indicators of tissue functionality. In Specific Aim 1, we will map the diagnostic and monitoring performances of commonly used Optical Coherence Tomography (OCT) parameters throughout the spectrum of AD and MCI severity. Our goal is to identify the most useful parameters at each stage of the disease. While many studies have shown the ability to detect AD using OCT, we suggest considering not only actual tissue thickness or visual field (VF) findings (which are subject to high variability) but also their interaction, even when measurements are within the supposedly normal range. A few studies suggest that structural information acquired with OCT of the optic nerve head (ONH) and macular regions provides sensitive tools for detecting AD. We will test global and localized measurements from the ONH, peripapillary, and macula regions, as well as new parameters such as pre-laminar volume, vessel density and volumetric analysis of the lamina cribrosa (LC). In Specific Aim 2, we employ a cutting-edge OCT technology - visible light (Vis-) OCT. Unlike conventional OCT technologies that use near infrared light sources, Vis-OCT utilizes a wide bandwidth light source, providing finer resolution than 1µm. Most importantly, exploiting the light absorption characteristic of oxygenated and deoxygenated hemoglobin in this wavelength range enables quantification of sO2 in retinal vessels. We will investigate the performance and applicable range of retinal oximetry measurements within AD and MCI. This will add an important objective, quantitative functional biomarker to clinical AD and MCI detection.