Biological Aging, the Proteome and Cognitive Resilience among Ischemic Stroke Survivors

Project Summary/Abstract To date, there is no effective treatment for cognitive impairment and dementia. Understanding mechanisms that promote cognitive resilience and delay vascular dementia, particularly in high-risk populations, is a complimentary approach to extend cognitive health span. Ischemic stroke survivors represent a growing population among older adults in the U.S. and a very high-risk group for Alzheimer’s disease and related dementias (ADRD). Beyond the underlying burden of brain infarction, biological factors and molecular mechanisms that elicit differences in cognitive resilience and timing of dementia onset after stroke, remain unclear. Biological aging processes at the physiological level are associated with risk of age-related diseases including cognition, stroke and dementia. However, it remains poorly understood if differences in biological aging explain variabilities in post-stroke ADRD. At the molecular level, among recognized aging biology mechanisms, the proteome plays a central role as proteins control cell functions, can help identify novel therapeutic targets and are associated with cognitive trajectories in aging. However, these associations were restricted to post-mortem assessments and have not been assessed in accessible tissue such as peripheral blood and in vulnerable populations such as ischemic stroke survivors. The immediate objective of this application is to assess the role of biological aging and molecular proteomic mechanisms in cognitive resilience and timing of onset of vascular dementia among ischemic stroke survivors. I will measure biological aging using physiological biomarkers data collected from blood tests in the Cardiovascular Health Study (CHS) and the Rotterdam Study (RS). I will then integrate these phenotypes with state-of-the art clinical ascertainment of stroke and cognition over >15 years of follow-up to assess the role of biological aging differences in cognitive resilience after stroke. I will leverage an Aptamer-based proteomic platform to identify molecular networks and cellular-level pathways of biological aging, cognitive resilience and vascular dementia among stroke survivors and healthy controls. I will evaluate algorithms of combined biological aging, proteomic and clinical stroke data for prognosis of cognitive resilience and domain-specific cognitive outcomes using supervised machine learning. I am well suited to perform this research based on 1) my prior research experience in epidemiology of stroke and aging, 2) the outstanding mentoring team to ensure this research is of highest quality; and 3) the exceptional research environment to support my career development. The proposed training and research will help me acquire substantive new skills in molecular epidemiology, high-dimensional data and machine learning to establish an independent career as a researcher at the intersection of molecular epidemiology and ADRD in vulnerable populations. This project will enable unprecedented perspectives on biological and molecular mechanisms of cognitive resilience to uncover novel biomarkers and therapeutic targets to protect cognitive health in old age among ischemic stroke survivors.