PROJECT SUMMARY/ABSTRACT Visual impairment (VI) and cognitive impairment are chronic conditions that disproportionately affect older adults. Research has revealed a consistent relationship between VI and cognitive impairment and dementia in older adults. VI is a risk factor for Alzheimer disease (AD) and is associated with future cognitive decline. However, the extent to which VI is associated with the characteristics of the longitudinal cognitive trajectory of aging adult remains unclear, particularly how VI status in midlife affects the cognitive trajectory in older life. Additionally, the mechanisms through which VI affects cognitive functioning have not been well elucidated. VI and cognitive decline could both be the result of a common underlying cause such as brain neurodegeneration. Alternatively, VI may reduce older adults’ ability to participate in activities and engage socially, which become risk factors for cognitive decline. Cardiovascular diseases (CVD) risk factors influence the risk of both VI and cognitive outcomes which may serve as important etiologic pathways underlying cognitive impairment. Important genetic factors such as APOE ε4 which is positively associated with AD has been demonstrated to be related to certain cerebrovascular diseases and visual disorders. These important and complex associations among VI, CVD risk factors, brain neurodegeneration, APOE ε4 genotype and cognitive decline have not been studied in a systematic and comprehensive manner. The current proposal leverages two large epidemiological cohort (The Health ABC Study and UK Biobank) and presents an unprecedented opportunity to employ sophisticated and novel application of Structure Equation Modeling techniques to investigate the complex associations between VI, brain neurodegeneration, CVD risk factors, APOE ε4 genotype, and sociopsychological factors as they relate to the longitudinal trajectories of cognitive decline and the linking mechanisms between VI and cognitive decline. The research in this career development award is complemented by training activities that build on the candidate’s strong background in statistics and provides new trainings on 1) cognitive neurosciences and clinical assessment of normal aging, cognitive impairment and AD; 2) cerebrovascular disease and risk factors and their relevant disease mechanisms and consequences; 3) neuroimaging and markers of brain neurodegeneration; 4) clinical aspects of VI and conducting ocular epidemiological study. This sophisticated research and training plan combined with a highly experienced and committed mentorship team will facilitate acquisition of meaningful skills and foster the applicant’s development into an independent investigator. This research will answer the important question of whether VI is associated with accelerated downward trajectories of cognitive decline and will elucidate critical underlying mechanisms linking VI with cognitive decline. The treatment for AD and ADRD is curren...