Neurovascular EV Biomarkers to Predict Cognitive and Cerebrovascular Changes in rrAD

VCID encompasses a spectrum of neurovascular changes ranging from chronic, progressive, and dementia-associated small vessel diseases (SVD) of the brain to the often-catastrophic damage following acute stroke. VCID clinically presents similar to other dementia diagnoses, but with a high prevalence of cardiovascular (CV) risk factors (e.g. hypertension, dyslipidemia). Besides drug therapies treating underlying cardiovascular disease, lifestyle interventions that increase physical activity also reduce the risk for VCID by minimizing neurovascular injury and improving cognition. Unfortunately, evidence linking CV and exercise interventions to the prevention of cognitive decline is inconclusive, nor are biomarkers available to determine the efficacy of pre-dementia lifestyle interventions. This American Heart Association Career Development Award (CDA) will utilize banked plasma and neuroimaging from subjects enrolled in the NIH-funded trial “Risk Reduction for Alzheimer’s Disease (rrAD).” This phase II randomized controlled trial will determine the independent and combined effects of Intensive pharmacological Reduction of Vascular Risk factors (IRVR; i.e. blood pressure, lipids) and aerobic exercise (Ex) on cognitive function in cognitively normal older adults with memory complaints or a family history of AD and who have hypertension/dyslipidemia. Participants were randomized into two-year interventions (IRVR, Ex, IRVR+Ex, and a control arm of standard care (SC)) with plasma and neuroimaging collected at baseline and yearly. Longitudinal rrAD samples will be used to test the hypothesis that 1) ICAM-1, GFAP, and Nfl expression in extracellular vesicles (EV) can predict changes in neuroimaging (cerebrovascular reactivity (CVR) and white matter hyperintenisities (WMH)), 2) IRVR+Ex plasma-derived EVs are protective following hypoxia, compared to S.C, in cells of the neurovascular unit, and 3) the neurobiological profile of IRVR+Ex EVs express increased markers of neuroplasticity, blood brain barrier, and growth factors compared to S.C EVs. This grant will identify biomarkers that track effective lifestyle interventions to delay dementia in high-risk individuals with CV risks prior to cognitive decline.