Updated project metadata. Patients with Alzheimer’s disease (AD) and Parkinson disease (PD) often have overlap in brain neuropathology and clinical presentation suggesting that these two diseases share common underlying mechanisms. Currently, the molecular events linking AD and PD are incompletely understood. Utilizing 10-plex Tandem Mass Tag (TMT) assays and MultiNotch MS3 mass spectrometry, we performed an unbiased quantitative proteomic analysis of post-mortem human brain tissues (n=80) from four different groups defined as healthy controls, AD, PD, and co-morbid AD/PD cases across two brain regions (frontal cortex and anterior cingulate gyrus). In total, we identified 11,840 protein groups representing 10,230 gene symbols, which map to ~65% of the protein coding genes in brain. The utility of including two reference standards in each TMT 10-plex assay to assess intra-batch and inter-batch variance is also described. Ultimately, this comprehensive human brain proteomic dataset serves as a valuable resource for various research endeavors including, but not limited to, the identification of protein signatures and neuro-centric signaling pathways that are common or distinct in AD and PD.