PROJECT SUMMARY/ABSTRACT: Alzheimer disease is expected to affect over 13 million Americans by 2050. There is ample evidence that relates vascular disease to Alzheimer disease, and the vascular contributions to cognitive decline and dementia are a national research priority. Data from our group and others have demonstrated that brain large artery disease is an important determinant of cerebrovascular health and, consequently, of cognitive function. For example, narrowing of the brain arteries due to atherosclerosis has been associated with an increased risk of Alzheimer disease and vascular dementia. The field has long focused on atherosclerosis and stenosis as the sole contributors to cerebrovascular health, however. We believe that brain arterial dilatation may also be deleterious to brain health. Consequently, we propose a change in the paradigm of brain large artery disease that goes beyond atherosclerosis and/or stenosis, and incorporates brain arterial dilatation as a distinct pathological phenotype. We postulated that, as with many anthropomorphic measurements, the diameters of brain arteries are normally distributed and that the extremes of this distribution are pathological. We have confirmed this hypothesis. We reported that among individuals with the largest or the smallest brain arterial diameters, the risk of vascular event is higher. The increased risk of vascular events among these individuals with extreme cerebral phenotypes is partially explained by the co-existence of systemic but not necessarily cerebral atherosclerosis. We have also demonstrated that non-atherosclerotic brain arterial aging relates to Alzheimer pathology independent of atherosclerosis and brain infarcts. We have gathered preliminary data showing that brain arterial diameters are associated non-linearly with cognition, so that individuals with narrowed or dilated brain arteries have poorer cognitive performance compared with those with average arterial diameters. Because brain arterial dilatation is understudied, it will be the focus of our proposal. Brain arterial dilatation may occur among patients with genetic syndromes predisposing to weaker connective tissue, but it is unclear whether genetic predisposing factors exist in the general population. It is plausible that the mechanical effects of brain arterial dilatation over the distal arteriolar and capillary flow may disrupt cerebral autoregulation, and explain the relationship with parenchymal functions such as cognition. It remains unclear whether these genetic factors are effect modifiers or direct contributors to cognition. This proposal aims to address these uncertainties. In Aim 1, we will define genetic loci that relate to brain arterial dilatation in >5,000 participants of four well-characterized, population-based studies with longitudinal follow-up who also have neuroimaging and cognitive assessments. In Aim 2, we will establish the hemodynamic consequences of brain arterial dilatation by relating ...