Project Summary Alzheimer's disease (AD) is a devastating, irreversible neurodegenerative disorder that affects over 5 million individuals in the US alone. Unfortunately, currently there is no cure or effective treatment for AD, and the lack of tools to accurately assess an individual's susceptibility and predict one's future development of AD adds another layer of complexity. Today, doctors are relying on several biomarkers to diagnose individuals with AD, but there are serious limitations with current assessment methods such as the use of radioactive isotopes, high-risk lumbar puncture, and the high cost. Clearly, more reliable, less-invasive, and patient-friendly biomarkers that can predict and/or diagnose the onset of AD is highly desired. Our preliminary data show that branched-chain amino acids (BCAAs) and their metabolites are elevated in humans with AD as well as a transgenic mouse model of AD mice compared to healthy controls. In line with these findings, BCAAs are identified as a significant composite predictor of AD in our predictive model (Figs. 1 and 2). Furthermore, a number of studies suggest that excess BCAAs can induce neural oxidative stress and apoptosis, trigger insulin resistance in the brain, and offset the balance of those neurotransmitters. Interestingly, all of these represent the pathophysiological hallmarks of AD, indicating a potential causative role of BCAAs in the pathogenesis of AD. Our pilot data show that BCAA supplementation in mature hippocampal neurons induces features of neuronal dysfunctions commonly observed in AD (Fig. 3), making BCAAs an attractive interventional target to treat AD. Experiments in the proposed study will utilize transgenic, molecular, integrative physiology, and behavioral approaches to examine 1) BCAA metabolism before and after the onset of AD-like symptoms and brain pathologies in a well-established transgenic mouse model (APP/PS1) to determine if plasma BCAAs and their metabolites can serve as a predictive and/or diagnostic biomarker for AD; and 2) whether dietary BCAA manipulation alters the progression of AD in vivo. The findings will identify novel biomarkers for prediction and detection of AD and provide new insights into the impact of BCAAs and their metabolism in the development of AD.