Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by intracellular formation of neurofibrillary tangles and extracellular deposition of β-amyloid protein (Aβ) in the extracellular matrix. The pathogenesis of AD has not yet been fully elucidated and little is known about global alterations in the brain proteome that are related to AD. To identify and quantify such AD-related changes in the brain, we employed a tandem mass tags approach coupled to high-resolution mass spectrometry. We compared the proteomes of frontal cortex from AD patients with corresponding age-matched brain samples. Liquid chromatography–mass spectrometry/MS analysis carried out on an Orbitrap Fusion Lumos Tribrid mass spectrometer led to identification of 8,066 proteins. Of these, 432 proteins were observed to be significantly altered (>1.5 fold) in their expression in AD brains. Proteins whose abundance was previously known to be altered in AD were identified including secreted phosphoprotein 1 (SPP1), somatostatin (SST), SPARC-related modular calcium binding 1 (SMOC1), dual specificity phosphatase 26 (DUSP26), and neuronal pentraxin 2 (NPTX2). In addition, we identified several novel candidates whose association with AD has not been previously described. Of the novel molecules, we validated chromogranin A (CHGA), inner membrane mitochondrial protein (IMMT) and RAS like proto-oncogene A (RALA) in an additional set of 20 independent brain samples using targeted parallel reaction monitoring mass spectrometry assays. The differentially expressed proteins discovered in our study, once validated in larger cohorts, should help discern the pathogenesis of AD. (Figure presented.).