Summary/Abstract Alzheimer’s disease (AD) is a degenerative brain disease and the most common form of dementia. Swallowing difficulty, called dysphagia, is an early symptom of AD, causing severe coughing, malnutrition, dehydration and/or aspiration pneumonia, all of which reduce the quality of AD patients’ lives and increase mortality of AD. Although it is unknown how muscle loss and weakness develop in early AD, a testable hypothesis is that limited food/water intake due to dysphagia leads to sarcopenia. In early AD patients, dysphagia and sarcopenia have been associated with onset of AD, yet the causative relationship between dysphagia and weight loss or sarcopenia remains to be determined. Dysphagia patients show atrophy with fibrosis of pharyngeal muscles, which are critical muscles for swallowing. Pharyngeal muscle specific pathology, such as dysphagia, has frequently been observed in several kinds of neuromuscular diseases, particularly late-onset aggregates- mediated diseases including AD. A leading hypothesis to explain of late-onset of many protein aggregates- mediated diseases is impaired autophagy with age. We found differential autophagy activity in pharyngeal muscles compared to other muscles in aged mice, implicating the role of autophagy to maintain pharyngeal muscle homeostasis. Impaired autophagy of aggregates-mediated diseases can lead to muscle degenerations and subsequent fibrosis and atrophy due to loss of myofiber integrity. Fibrosis is generated from fibrotic differentiation of fibroadipose progenitor cells by dysregulated macrophage and their cytokines in dystrophic or aged muscles. The long-term goal of this proposal is to understand the cellular and molecular pathways that control pharyngeal muscle atrophy and fibrosis, which can potentially inform the treatment for AD-related dysphagia. Our lab is well positioned to study pharyngeal muscle pathologies since we have expertise regarding mesenchymal stem cells of pharyngeal muscles in normal, aged and dystrophic conditions. We propose two aims to investigate pharyngeal muscle fibrosis and dysphagia in early AD. In aim 1, we will screen the dysphagia and pharyngeal muscle pathology of AD model mice using lick assay and histology analysis of pharyngeal muscles. In aim 2, we will investigate cytokine changes in AD pharyngeal muscles as a mechanism of fibrosis and determine the role of macrophages in regulating fibrosis using a macrophage depletion agent. By completing these aims, we expect to reveal cellular mechanisms of dysphagia in early AD.