Evolving evidence suggests that cerebrovascular disease may interact with the Alzheimer's disease process to increase the likelihood of dementia during life. However, many of these factors exert considerable effect on brain structure and function beginning in middle life. By design, the Framingham Heart Study offers a wealth lifetime cerebrovascular risk factor data to study these relationships. In the current cycle of this grant, we focused on developing methods for intensive cognitive surveillance. Moreover, we combined efforts with the Boston University Alzheimer's Disease Center to assure accurate clinical diagnoses and clinical-pathological confirmation. Clinical diagnosis and the assessment of concomitant cerebrovascular disease was improved by the addition of quantitative MRI. Employment of these methods resulted in the successful identification of homocysteine as a novel risk factor for incident dementia and confirmed the significance of incident stroke as another risk factor. In addition, we have identified a group of cognitively normal oldest old to which the presence or absence of these factors can be compared. In the next five years, we propose to expand these efforts to older members of the FHS Offspring and multi-ethnic OMNI cohorts permitting us to examine familial occurrence of AD and dementia and to relate mid-life habits and risk factors to incidence of AD and other types of dementia. Risk factor data is available on these nearly 4,000 subjects since 1971 by means of 7 periodic examinations. More than 420 of these offspring and OMNI subjects have volunteered as brain donors, and we plan to continue to recruit more donors. We will relate vascular pathology in the brain at autopsy to mid-life vascular risk factors measured over several decades. In addition to subjects determined to fulfill standard criteria for Alzheimer's disease and other dementia, a substantial proportion of brain donors coming to postmortem examination have been documented to have normal cognition within months of death. This will provide an opportunity to compare the neuro-pathology (and particularly the vascular neuropathoiogy) in subjects with normal, minimally impaired cognition and clinically demented subjects. Taken together, this design will permit us to address a key question of whether vascular risk factors, especially those present at midlife, increase the risk of dementia generally, and AD specifically. And if so, do these risk factors promote AD via a nonvascular mechanism or "add" to brain injury thereby leading to earlier age of onset and/or accelerated.