Proteomic profiling was performed using isobaric tandem mass tag (TMT) peptide labeling and analyzed by liquid chromatography coupled to mass spectrometry as described in detail previously13. Prior to TMT labeling, samples were randomized by co-variates (age, sex, post-mortem interval, cognitive diagnosis, and pathologies) into 50 total batches (8 samples per batch). Peptides from each individual sample (N=400) and the global internal standard (GIS; N=100) were labeled using the TMT 10-plex kit (ThermoFisher). High pH fractionation was performed as previously described with slight modifications51. Database searches and protein quantification have been described in detail here13. Briefly, all raw files were analyzed using the Proteome Discoverer suite (version 2.3 ThermoFisher Scientific) and MS2 spectra were searched against the canonical UniProtKB Human proteome database downloaded in February 2019 with 20,338 total sequences. Percolator was used to filter peptide spectral matches (PSM) and peptides to a false discovery rate (FDR) of less than 1%. Following spectral assignment, peptides were assembled into proteins, which were further filtered based on the combined probabilities of their constituent peptides to a final FDR of 1%. In cases of
