Alzheimer’s disease (AD), which is the most common type of dementia, is characterized by the deposition of extracellular amyloid plaques. To understand the pathophysiology of the AD brain, the assessment of global proteomic dynamics is required. Since the hippocampus is a major region affected in the AD brain, we performed hippocampal analysis and identified proteins that are differentially expressed between wild-type and 5XFAD model mice via LC-MS methods. To reveal the relationship between proteomic changes and the progression of amyloid plaque deposition in the hippocampus, we analyzed the hippocampal proteome at two ages (5 and 10 months). We identified 9,313 total proteins and 1411 differentially expressed proteins (DEPs) in 5- and 10-month-old wild-type and 5XFAD mice. We designated a group of proteins showing the same pattern of changes as amyloid beta (Aβ) as the Aβ-responsive proteome. In addition, we examined potential biomarkers by investigating secretory proteins from the Aβ-responsive proteome. Consequently, we identified vitamin K-dependent protein S (PROS1) as a novel microglia-derived biomarker candidate in the hippocampus of 5XFAD mice. Moreover, we confirmed that the PROS1 level in the serum of 5XFAD mice increases as the disease progresses. An increase in PROS1 is also observed in the sera of AD patients and shows a close correlation with AD neuroimaging markers in humans. Therefore, our quantitative proteome data obtained from 5XFAD model mice successfully predicted AD-related biological alterations and suggested a novel protein biomarker for AD.