Abstract: This administrative supplement is submitted in response to Notice Number: NOT-AG-20-034: Alzheimer's Disease Administrative supplements for NIH grants. This supplement outlines experiments to extend the parent U01 (UF PASS: Regulation of exercise transducers) to pursue the interaction between exercise, skeletal muscle health and progression of pathology in a mouse model of Alzheimer’s disease (AD). The parent award is part of the MoTrPAC consortium that combines well defined exercise interventions with multi-omics analysis to develop a map of molecular transducers that link exercise to systemic health. For this administrative supplement we will use a defined mouse model of AD with a treadmill training protocol based on the protocol used for MoTrPAC. We will also be in a position to analyze our outcomes data in the context of the larger multiomics data available from MoTrPAC to expand our understanding of potential cross tissue interpretations. A major challenge in the field of Alzheimer’s disease (AD) is the poor understanding of how tau pathology promotes disease. Consequently, therapeutic interventions are ineffective and clinical trials for AD have failed. The working model for this supplement is that exercise mitigates the onset and progression of AD tau pathology through impacting skeletal muscle health as well as direct effects on the brain. The rationale for this model comes from two complementary but not fully explored sub-fields: “AD and muscle/sarcopenia” and “AD and exercise”. Several clinical studies have reported that muscle weakness and loss of muscle mass occurs at a faster rate in AD patients. These muscle changes in the patients are also associated with brain atrophy and diminished cognitive performance. In addition, several studies using animal models of AD have demonstrated changes in skeletal muscle metabolism at times prior to the appearance of AD pathology in the brain. These observations are consistent with our preliminary data that found significant muscle weakness in a tauopathy mouse model of AD prior to overt signs of neurodegeneration. There are also a large number of clinical and preclinical studies showing that exercise training, primarily endurance exercise, has a positive impact on the onset and progression of AD. Thus, we propose to integrate the concepts of exercise, muscle health and brain health to define molecules and pathways that attenuate the onset and progression of AD tau pathology in the brain. We propose the following Specific Aims. Aim 1) To determine the molecular, histological and phenotypic changes in skeletal muscle and brain in an acquired tauopathy model of AD in mice. Aim 2) To use a running exercise intervention with the AD-tauopathy mouse model to identify molecular sites through which tau pathology is attenuated.