The biological processes that are disrupted in the Alzheimer’s disease (AD) brain remain incompletely understood. In this study, we analyzed the proteomes of more than 1,000 brain tissues to reveal new AD-related protein co-expression modules that were highly preserved across cohorts and brain regions. Nearly half of the protein co-expression modules, including modules significantly altered in AD, were not observed in RNA networks from the same cohorts and brain regions, highlighting the proteopathic nature of AD. Two such AD-associated modules unique to the proteomic network included a module related to MAPK signaling and metabolism and a module related to the matrisome. The matrisome module was influenced by the APOE ε4 allele but was not related to the rate of cognitive decline after adjustment for neuropathology. By contrast, the MAPK/metabolism module was strongly associated with the rate of cognitive decline. Disease-associated modules unique to the proteome are sources of promising therapeutic targets and biomarkers for AD.

Here, we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer's disease (AD). Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation. Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome, consistent with their causal role in AD. This multi-network analysis reveals protein- and disease-specific pathways involved in the etiology, initiation, and progression of AD.

Integrative proteomic analysis identifies CSF biomarker panels linked to brain-based pathophysiologies in Alzheimer’s disease.

Patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD) often have overlap in clinical presentation and brain neuropathology suggesting that these two diseases share common underlying mechanisms. Currently, the molecular pathways linking AD and PD are incompletely understood. Utilizing Tandem Mass Tag (TMT) isobaric labeling and synchronous precursor selection-based MS3 (SPS-MS3) mass spectrometry, we performed an unbiased quantitative proteomic analysis of post-mortem human brain tissues (n=80) from four different groups defined as 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- 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 disease-specific protein signatures and molecular pathways that are common in AD and PD.