Project Summary Alzheimer's disease (AD) is the most common cause of dementia. Current clinical standard-of-care for assessing metabolic dysfunction in AD is 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), based on a temporoparietal pattern of hypometabolism. However, 1) PET is impractical as a longitudinal assessment tool because it requires injection of a radioactive tracer, is expensive, and has poorer spatial resolution and availability compared to MRI; and 2) FDG-PET may not be an accurate measure of neuronal metabolism, because FDG signal can reflect glucose uptake by microglia and astrocytes for glycolysis, as well as glucose uptake for oxidative phosphorylation by neurons. The cerebral metabolic rate of oxygen (CMRO2), reflective of oxidative phosphorylation in neuronal mitochondria, may more directly measure the abnormal metabolism seen in patients with MCI and AD. Moreover, an MRI-based tool for mapping neuronal metabolism would allow for longitudinal monitoring both clinically and in therapeutic trials. Therefore, the objective of this proposal is to develop and optimize an MR-based CMRO2 mapping technique. Aim 1 will be to develop a multi- echo gradient echo acquisition, integrated with arterial spin labeling to construct oxygen extraction fraction, cerebral blood flow, and CMRO2 maps using sparsity fingerprinting. Aim 2 will investigate whether this CMRO2 mapping demonstrates regional correlation with well-established measures of AD pathology, including A, tau, and FDG hypometabolism, the “ATN” stages of AD per the 2018 NIA-Alzheimer's Association research framework. Aim 3 will investigate the value of our CMRO2 mapping in predicting longitudinal gray matter degeneration and cognitive decline. If successful, this proposal will develop and validate a noninvasive, quantitative MR-based tool to diagnose and longitudinally assess cerebral hypometabolism in AD.