This proposal is requesting a one-time renewal of a Midcareer Investigator Award in Patient-Oriented Research (K24). The candidate, Dr. Angela Jefferson, is a neuropsychologist whose interdisciplinary research program focuses on understanding the impact of cardiovascular and cerebrovascular integrity on the pathogenesis and clinical manifestation of Alzheimer's disease and small vessel disease. Dr. Jefferson is a Professor of Neurology at Vanderbilt University Medical Center and founding Director of the Vanderbilt Memory & Alzheimer's Center. Since completing her training 13 years ago, Dr. Jefferson has established herself as a productive clinical researcher with strong NIH funding and a high-impact, prolific publication record. Over the last decade, including the original K24 funding period (2013-2018), she has demonstrated a strong commitment to professional education and mentorship. This K24 renewal will be instrumental in continuing to provide protected time for Dr. Jefferson to expand her clinical research capabilities. In particular, she will expand her expertise in cerebrospinal fluid biomarkers of Alzheimer's disease to include innovative molecular biomarkers reflecting concomitant pathways, such as extracellular matrix remodeling, microglial activation, and synaptic dysfunction. She will also expand the breadth of proteomic biomarkers at her disposal by leveraging state of the art discovery-based mass spectrometry methods. These tools will substantially enrich our understanding of the mechanisms by which compromised vascular health relates to abnormal brain aging and inform strategies to prevent or delay the pathological cascade associated with cognitive impairment and dementia. Furthermore, the proposed award will allow Dr. Jefferson to continue to use her research program as a platform to mentor early career investigators, including undergraduate, graduate, and medical students; postdoctoral fellows; and early career faculty in patient-oriented research in cognitive aging, Alzheimer's disease, and small vessel disease. This proposal integrates Dr. Jefferson's interdisciplinary research team and resources available through the Vanderbilt Memory & Alzheimer's Center and Vanderbilt Institute for Clinical and Translational Research to offer a rich training environment for mentees. The training and research facilitated by this K24 mechanism renewal will not only advance knowledge regarding cardiovascular and cerebrovascular pathways contributing to the pathogenesis and clinical manifestation of Alzheimer's disease and small vessel disease, but it will also develop a cadre of next-generation cognitive aging researchers well- positioned to make meaningful contributions to the field.