Project Summary: Abnormalities in cognition and mobility are common accompaniments of aging that often precede the development of Alzheimer's disease. Among their many etiologies, these abnormalities are associated with alterations in the regulation of cerebral blood flow to frontal regions of the brain that subserve executive functions and gait speed. We have previously shown that treatment with cocoa flavanols can improve blood flow in response to a cognitive task (neurovascular coupling [NVC]), as well as executive function in older people with impaired NVC. These compounds can also reduce the number of senescent cells and their toxic secretory products (SASP) in a variety of tissues. In mice, “senolytic” compounds such as flavanols and tyrosine kinase inhibitors, have been shown to reduce neurofibrillary tangle density, neuron loss, and ventricular enlargement, and in humans with idiopathic pulmonary fibrosis, improve gait speed and other functional abilities. Based on these findings, we hypothesize that the flavanol, Quercetin, and tyrosine kinase inhibitor, Dasatinib, (Q+D) will improve NVC in response to an executive task, reduce circulating SASP components, and in so doing, improve cognition and mobility in older adults who are at risk of Alzheimer's disease.

Project Narrative: The long-term goal of this study is to prevent common age-related impairments in cognition and mobility that lead to the development of Alzheimer's disease by interrupting one of the fundamental mechanisms of aging, namely the accumulation of senescent cells and their damaging products. We will determine the feasibility of administering Quercetin and Dasatinib to eliminate these cells from the body, and test whether their elimination can improve brain blood flow, cognition, and mobility in older adults at risk of developing Alzheimer's disease.