Age-related cognitive decline (ARCD) exists in a continuum with more severe cognitive dysfunction that that often is a dementia prodrome and can be operationally defined as Mild Cognitive Impairment (MCI), and ultimately with dementia. ARCD is a major source of disability and reduced autonomy, to say nothing of prodromal dementia and dementia, which are of paramount public health import given projected demographics of the US population. While tremendous effort has been invested in understanding mechanisms of gray matter damage and neuron death in brain aging and neurodegenerative diseases, carefully executed studies in humans and non-human primates have shown that neuron loss is not a feature of advancing age. In contrast, numerous studies, mostly neuroimaging-based, have associated white matter changes with advancing age;however, the structural and cellular bases of this white matter damage remain enigmatic. We propose to test the hypothesis that there are specific structural and cellular vulnerabilities within cerebral white matter that contribute significantly to ARCD and MCI. Here we propose to test this hypothesis via a highly integrated multi-component R01 that pursues the following Specific Aims: (1) First, we propose to develop a unique and highly complementary resource of brain tissue from a human population-based study of brain aging and incident MCI. Tissue will be prepared to maximize investigation of white matter. Using tissue from this unique resource, we will determine associations between cognitive function and (2) magnetic resonance imaging (MRI), histological, and immunohistochemical measures of white matter damage, (3) free radical damage to myelin or axons, (4) specific subpopulations of oliogodendrocyte precursor cells (OPCs), and (5) biochemical factors that retard appropriate maturation and function of OPCs in aged brain. This project not only will develop a unique resource for the community of scientists investigating white matter injury, but also will employ this resource to answer key questions about the structural, cellular, and biochemical bases of white matter damage associated with cognitive decline in the elderly. PUBLIC HEALTH RELEVANCE: Age-related cognitive decline and prodromal dementia of paramount public health import given projected demographics of the US population. While numerous studies have associated white matter changes with advancing age, the structural and cellular bases of this white matter damage remain enigmatic. Our proposed project not only will develop a unique resource for the community of scientists investigating white matter injury, but also will employ this resource to answer key questions about the structural, cellular, and biochemical bases of white matter damage associated with cognitive decline in the elderly.