The proposal has been revised to respond to the concerns raised by the reviewers. The overarching aim of the studies proposed in this application is to continue to define some of the major neurobiological and cognitive features associated with early dementia and early (prodromal) Alzheimer's disease (AD) by examining the influence of cardiovascular risk factors (CvRF) in the initiation of cognitive impairment and progression of dementia and its neurobiology. The long-term objectives of the program are to provide a solid neurobiological basis for the consideration of certain CvRF as risk factors for AD and dementia in order to improve future identification and treatment of persons at risk for dementia. The projects in this application therefore continue the theme of exploring the cognitive and neurobiological bases of cognitive compromise and early AD established previously by examining the role of prominent CvRFs and their relationships to cognitive and neurobiological features of AD. The studies proposed combine exploration of CvRF influences on early dementia and its neurobiology in animal model systems with studies in well-defined elderly subjects. The study of elderly veterans allows diversification of characterization and risk-factor assessment to a well defined and relatively homogeneous population. The contribution of a common set of known or hypothesized CvRF to the onset of cognitive impairment and progression to dementia will be evaluated and related to neurobiological indices of AD. The neurobiological mechanisms through which prevalent CvRFs may influence cognitive impairment and dementia are studied. One project explores the extent of micro-cerebrovascular pathology. The studies of animal model systems focuses on the role of two known and well documented CvRF; hypercholesterolemia and high fat diet induced insulin resistance, and explore their influences on neurobiological indices of AD and on micro-cerebrovascular and neuronal pathology.
The aims of the proposed cores are to support the specific studies and to provide and maintain a rich research infrastructure to sustain these projects and their derivatives in the future. The subjects participating in will be initially recruited and characterized by the Clinical Diagnosis and Assessment Core. These extensive medical and diagnostic assessments that are repeated yearly include CvRF assessment and neuroimaging studies where appropriate. The results derived from these core assessments and diagnoses, including neuropathological findings from study cases who come to autopsy are integrated by the Data management and Statistics Core with the data generated by the projects and are made available to all projects and cores. The Administrative Core provides the administrative oversight and governance infrastructure to maintain and enhance this tight integration.
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