Project Summary/Abstract While heart disease remains as the leading cause of death in the United States, an estimated 6.7 million Americans aged 65 and older are living with Alzheimer's disease (AD) in 2023 and over 11 million American caregivers providing an estimated 18 billion hours of care valued at $339.5 billion. These astronomical numbers continue increasing as the whole population is aging. Furthermore, women are more prevalent to AD and have higher risk to cardiovascular disease at older age than men. Currently no cure of AD and very limited treatment that may slowdown AD, the best alternative care is to adapt lifestyle changes as recommended by Alzheimer's Association and CDC. Lack of exercise is one of the key lifestyle factors contributing to the risk of AD. Reducing these modifiable risk factors could reduce AD prevalence. Autopsy studies show that as many as 80% of individuals with AD also have cardiovascular disease. Exercise has been shown to have numerous benefits in both cardiac and cognitive function, and may slowdown AD. However, more mechanistic studies are needed to elucidate the effect of exercise on metabolic and vascular health of both the brain and heart in AD. Growing evidence suggests a close link between cardiovascular dysfunction and the AD progression. Cardiovascular risk factors are associated with an increased risk of developing AD. Cardiovascular health influences cerebral blood flow (CBF), and impaired blood flow to the brain can contribute to neurodegenerative processes, including AD. Reduced cardiac function can lead to decreased oxygen supply to various organs, including the brain, resulting in mitochondrial dysfunction, impaired energy production, and increased oxidative stress, which are also observed in AD. Echocardiography has been performed on 5xFAD and found a significant reduction in cardiac ejection fraction compared to wild-type controls, but no report on cardiac metabolism. There is a gap in our knowledge of the interplay between vascular and metabolic health of the brain and heart in AD, how these key functions may be improved by routine exercise to slow down AD progression, and any gender differences. In this pilot study, we will evaluate the feasibility of two non-invasive and translatable imaging techniques in 5xFAD AD model that rapidly recapitulates major features of AD amyloid pathology, with a moderate exercise remedy over time to monitor their metabolic and vascular functions of the brain and heart associated with amyloid pathogenesis. We will also investigate whether female and male mice benefit from exercise equally. The techniques and multi-modal imaging proposed in this grant will allow us to probe how MRI can yield metabolic and vascular information that may enable better classification, end points and mechanistic understanding of the effect of exercise on AD and gender differences. These studies have direct translatable value for human AD imaging research.