Project Summary / Abstract Vascular biology and white matter may be some of the key junctures that harbor early risk mechanisms that precipitate vascular contributions to cognitive impairment and Alzheimer's disease. This process may start as early as adolescence and young adulthood, and through our lifespan. While cardiovascular impacts on white matter health are well-established, our understanding of the lifetime course and the associated mechanisms are less clear. Our efforts aim to identify the earliest possible vascular biomarkers and risk factors for abnormal white matter changes for the corresponding cognitive declines. Cardiovascular-brain studies typical focus on structural imaging changes that are difficult to reverse. We hypothesize that white matter lifespan changes can be more sensitively tracked by combining standard structural imaging techniques with state-of-the-art connectome era multimodal imaging. The goal is to uncover novel vascular - white matter mechanisms and biomarkers that provide early warnings before the irreversible structural changes occur. The proposal builds upon the productivity of the Amish Connectome Project as baseline data, and leverages the collaboration between our brain imaging and cardiovascular medicine groups. The Old Order Amish/Mennonite population has a more uniform genetic profile, rural lifestyle and low alcohol and tobacco use that greatly reduce uncontrollable variability, thus providing a particularly advantageous platform to study the vascular mechanisms on white matter. Cerebral white matter will also be studied in the context of predicting white matter vulnerability to Alzheimer's disease. Tracking when the aberrant vascular – white matter coupling occurs may provide insights into the timing and mode for more effective prevention. This proposal is responsive to the new NIH Inclusion Across the Lifespan policy. If successful, the proposed study should strongly support the prevention goal highlighted in the National Alzheimer's Project Act, which supports increased public research to prevent the onset of and develop effective treatments for AD by 2025. Prevention programs can be benefited by more nuanced understanding of the pathways connecting early vascular changes to irreversible white matter changes. Therefore, we propose to use cutting-edge white matter imaging that is informative of the underlying mechanisms, combined with standard but state-of-the-art vascular assessments, to study the interaction between vascular and white matter changes across lifespan.