Abstract: Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) have different underlying pathophysiological substrates. It follows, then, that these disorders may affect the visual system in different ways. Structural and functional changes in the visual system are critical to understanding and treating symptoms and impairments that impact quality of life. Structure, as revealed by imaging of the retina, an outgrowth of the brain that is amenable to direct visualization, can provide potential biomarkers to aid in the monitoring of disease progression. Advances in in vivo optical coherence tomography (OCT) imaging over the past few decades have shown that eyes of patients with AD and PD have generalized thinning of inner retinal layers associated with the ganglion cells, and microvascular changes. However, such changes likely do not directly reflect the primary pathology across the spectrum of neurodegenerative diseases. Deciphering different manifestations of the ocular component to neurodegenerative disease requires a clear step forward in the level of detail provided by approaches to image the retina. To achieve this, we propose to develop and optimize the next generation of visible light optical coherence tomography (OCT), with 1 micrometer depth resolution, and associated machine learning tools, for imaging and quantifying ocular neurodegeneration. Our visible light OCT instrument achieves 3-5x better resolution than commercial near-infrared OCT systems. The improved resolution provides a uniquely stratified view of cellular architecture in the inner nuclear layer (INL) and of synapses in the inner plexiform layer (IPL), potentially providing in vivo insights into circuit- or cell-specific retinal changes that have been reported in both AD and PD. Performing OCT in the visible light range is also significant because macular pigments, which are associated with cognition, are detectable and quantifiable through novel approaches. In addition, hyperspectral information in the visible light range purportedly detects protein deposits in the retina. In fact, our preliminary results suggest the ability to both localize hyper-reflective features in an amyloid AD mouse model and to decipher their hyperspectral signatures. Guided by basic studies in mice that verify the relationship of imaging features to disease pathophysiology, we will investigate the potential for visible light OCT measures and markers to distinguish eyes of persons with MCI (AD) and PD, both between disorders and with comparison to cognitively and neurologically normal controls of similar age. Based on the premise that oculomics is enhanced by placing the eye in the context of the entire visual pathway, our research plan, supported by our team’s expertise, will integrate advanced imaging with visual function testing and quality of life measures.