@article{a842d3288eb14a7b82dcd1fa728b0068,
title = "Large-scale deep multi-layer analysis of Alzheimer{\textquoteright}s disease brain reveals strong proteomic disease-related changes not observed at the RNA level",
abstract = "The biological processes that are disrupted in the Alzheimer{\textquoteright}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.",
author = "Johnson, {Erik C.B.} and Carter, {E. Kathleen} and Dammer, {Eric B.} and Duong, {Duc M.} and Gerasimov, {Ekaterina S.} and Yue Liu and Jiaqi Liu and Ranjita Betarbet and Lingyan Ping and Luming Yin and Serrano, {Geidy E.} and Beach, {Thomas G.} and Junmin Peng and {De Jager}, {Philip L.} and Vahram Haroutunian and Bin Zhang and Chris Gaiteri and Bennett, {David A.} and Marla Gearing and Wingo, {Thomas S.} and Wingo, {Aliza P.} and Lah, {James J.} and Levey, {Allan I.} and Seyfried, {Nicholas T.}",
note = "Funding Information: We are grateful to those who agreed to donate their brains for research and who participated in the described observational studies. This study was supported by the following National Institutes of Health funding mechanisms: RF1AG057471 (A.I.L.), RF1AG057470 (N.T.S.), R01AG01581 (N.T.S.), U54AG065187 (A.I.L.), U01AG061357 (A.I.L.), R01AG057911 (C.G.), R01AG061800 (N.T.S.), R01AG053960 (N.T.S.), RF1AG062181 (N.T.S.), P30AG10161 (D.A.B.), R01AG15819 (D.A.B.), R01AG17917 (D.A.B.), U01AG61356 (D.A.B.), RF1AG057440 (B.Z.), U01AG046170 (B.Z.), K08AG068604 (E.C.B.J.), U24NS072026 (T.G.B.), P30AG19610 (T.G.B.) and R01AG056533 (T.S.W.). The study was also supported by VA Administration BX005219 (A.P.W.), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer{\textquoteright}s Research Center) (T.G.B.), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson{\textquoteright}s Disease Consortium) (T.G.B.) and the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research (N.T.S.). We thank K. Yu for contributions to this study. We also thank the Neuropathology Core of the Emory Center for Neurodegenerative Disease Core Facilities for their assistance. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = feb,
doi = "10.1038/s41593-021-00999-y",
language = "English",
volume = "25",
pages = "213--225",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "2",
}