Characterizing Retinal Tissue Oxygenation, Structure, and Function in Alzheimer's Disease

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting approximately 5.3 million people in the US, and projected to reach 13.9 million by 2026. Progress in the management and treatment of AD is limited by lack of early diagnostics, which are critical to the development of effective therapies. AD is currently described in three stages; the preclinical, the mild cognitive impairment (MCI), and Alzheimer’s dementia. The difficulty lies in detecting the disease during the preclinical phase, when patients show no clinical symptoms of cognitive impairment but there is underlying pathology. Currently, we are limited to detecting the accumulation of amyloid plaques in the brain using expensive and invasive methods such as Positron Emission Tomography and cerebrospinal fluid assessment via lumbar puncture. The goal of this proposal is to develop a novel, non-invasive, and cost-effective retinal vascular biomarker for early AD risk detection and disease monitoring. There is increasing evidence that there are retinal manifestations of AD; the neurodegeneration in the brain of AD patients has been shown to be associated with reduced retinal nerve fiber layer (RNFL) and retinal ganglion cell (RGC) layer thickness. Thus, the human retina is an easy to examine part of the brain providing an opportunity to study and to possibly detect AD early. There is breakdown of the inner retinal blood barrier, pericyte loss, and capillary non-perfusion or dropout in AD. We have previously characterized metrics of retinal tissue oxygenation in the form of periarteriole and perivenule capillary free zones (peripheral CFZs). Building on these prior results, our central hypothesis is that the CFZ will be enlarged in older cognitively unimpaired (CU) participants at high risk for AD, MCI, and mild AD patients, and this will be associated with reduced RNFL and RGC layer thickness, reduced field of vision, and reduced sensitivity to contrast. We will test our central hypothesis by completing the following aims: AIM 1: Quantify and evaluate differences in the peripheral CFZ, structural, and functional measures between low-risk CU older adults, high-risk CU older adults, MCI, and mild AD groups. We will collect high quality optical coherence tomography angiography images, structural, and functional measures in the 4 groups with data from the low-risk CU participants serving as baseline or control data. We will compare the CFZ, structural, and functional measures in the 4 groups of participants using analysis of covariance. AIM 2: Identify associations between the peripheral CFZ, structural, and functional measures in high-risk CU, MCI, and mild AD groups. We will use multiple linear regression models to test the associations of the CFZ versus structural and functional parameters. Outputs from this proposal will identify whether CFZ measures can be used as a potential retinal biomarker of early AD risk detection and disease monitoring. Results from our studies will advance both the NIA’s goal of understanding the nature of biomedical changes associated with AD and the goal of the National Alzheimer’s Plan to prevent and effectively treat AD by 2025.