biostudies-literatureJohnson ECBBLRD VAU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeNIA NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on AgingArizona Department of Health ServicesNINDS NIH HHSU.S. Department of Veterans AffairsADHS | Arizona Biomedical Research CommissionMichael J. Fox Foundation for Parkinson’s Research213-225https://www.ebi.ac.uk/biostudies/studies/S-EPMC8825285biostudies-literatureUnknown25(2)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 adNature neuroscienceLarge-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.PMC8825285K08AG068604R01 AG057911RF1 AG057440P30 AG066514BX005219R01AG053960U24NS072026IK4 BX005219R01AG057911K08 AG068604P30 AG019610R56 AG062633U01 AG046170U54 AG054345RF1AG057440R01 AG061800U01AG046170P30 AG010161R01 AG053960RF1 AG059319P30 AG0665112110024001, 0011, 05-901 and 1001R01 AG015819U01 AG061356P30AG19610U01 AG061357U01AG61356P30 AG072980U01AG061357P30AG10161R01AG056533RF1AG062181U24 NS072026P30 AG072975RF1 AG057470RF1 AG057471P50 AG025688RF1 AG062181R01 AG056533U54AG065187R01AG061800R01AG01581R01 AG061798U54 AG065187R01 AG017917RF1AG057470R01AG17917R01AG15819Ping LDuong DMLiu JWingo APLevey AIGaiteri CSerrano GECarter EKLiu YBetarbet RGearing MSeyfried NTWingo TSGerasimov ESBennett DAHaroutunian VDammer EBBeach TGLah JJJohnson ECBYin LZhang BPeng JDe Jager PLfalseLarge-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.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 ad2022-01-01T00:00:00Z2022 Feb2026-05-31T05:01:43.006Z2025-02-19T01:53:50.114ZS-EPMC88252853511573110.1038/s41593-021-00999-y