Deficiency in brain energy metabolism has long been recognized as a prominent event in the development of Alzheimer’s disease. Recent studies provide new evidence that mitochondrial dysfunction may occur early and in proximity to amyloid deposition, a hallmark of Alzheimer’s disease. In this project, we seek to understand the spatiotemporal relationship between amyloid deposition and mitochondrial metabolic dysfunction through the development and application of first-of-a-kind dual-modal microscopy (i.e., multi-photon fluorescence microscopy of mitochondrial function and amyloid deposition at the cellular level and multi-parametric photoacoustic microscopy of oxygen metabolism at the tissue level) in a mouse model of Alzheimer’s disease. Examination of the potential reversibility of mitochondrial metabolic dysfunction following anti-amyloid therapies may lead to non-invasive imaging biomarkers that predict when such therapies can alter the course of neurodegeneration. Translation of such neuroimaging biomarkers to patients may one day guide therapeutic intervention.