Project Summary There are approximately 46 million people worldwide living with dementia according to the 2015 World Alzheimer Report, and it is estimated to increase to 131.5 million by 2050. It has been estimated that the total worldwide dementia-related healthcare cost is $818 billion, rising to $2 trillion by 2030. The most common progressive cause of dementia in the elderly is Alzheimer's Disease (AD), which is in the top ten leading causes of death in America and has no proven preventative or curative interventions. The goal of Alzheimer's research is to improve and simplify diagnosis, characterizing testing parameters that identify the earliest pathological changes in the patient, while ideally being inexpensive, non-invasive, and widely distributable to health care providers. Cognitive decline and neurological damage displaying anatomical losses are often preceded by functional and molecular changes that are harder to detect. The eye and brain are anatomically, embryologically, and physiologically linked. The retinal ganglion cells (RGCs) are like the cerebral cortex neurons but the synaptic layers of the retina are beautifully laid out, easing examination of histopathology and functional testing. There is strong evidence of retinal manifestations of AD in both post- mortem human tissue samples and the APP/PS1 rodent model of Alzheimer's disease. Functional testing like the electroretinogram (ERG) can and has identified early neurological losses in Alzheimer's models and can be immediately transferable as a technique to human subjects, Alzheimer's patients, and preclinical Alzheimer's subjects. Here we will pursue retinal testing for AD in 1) the APP/PS1 mouse model of AD to track the earliest disease indicators, 2) in young and old human subjects to define a range of normal function, and 3) in preclinical and mild cognitively impaired humans to control for early AD onset to determine specificity and sensitivity of the tests. We will use novel combinations of pattern size and contrast sensitivity as visual stimuli, and use identical ERG tests on a well-defined animal model of AD and human subjects with varying degrees of cognitive impairment. We will also investigate the structure of the unique glutamatergic ribbon synapses of the two retinal synaptic layers with the goal of identifying a mechanism behind the retinal sensitivity declines.