{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T16:03:34Z","timestamp":1781625814747,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,13]]},"group-title":"Neuroscience","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Post-translational modifications (PTMs) in APP and MAPT contribute to plaques and tangles in Alzheimer\u2019s disease (AD). Yet broader proteome-wide PTMs in the AD brain are relatively unexplored. Therefore, this study highlights associations between PTMs, quantified by mass spectrometry in prefrontal cortex tissue, and Alzheimer\u2019s disease neuropathology and cognition.<\/jats:p>\n                <jats:p>Leveraging PTMs quantified from prefrontal cortices in 101 Rush Memory and Aging Project participants. We assessed associations with post-mortem amyloid-\u03b2 and tau burden, global cognition, and cognitive decline. First, APP and MAPT PTM associations were assessed on these outcomes given their known relevance in AD, followed by assessment of protein-wide effects of PTMs. Then, kinase enrichment analysis was performed on each outcome to assess which kinases might contribute to the results.<\/jats:p>\n                <jats:p>We observed a novel association of APP-K687 acetylation, a known mutation hotspot driving pathology, with amyloid-\u03b2 load (\u03b2=0.44, P=3.9e-8), while confirming known MAPT PTMs with tangle burden. Further, we identified 20+ novel PTMs\u2019 associations with AD neuropathology, including ENO2-K256 ubiquitination (\u03b2=0.353, P=1.13e-6), PSMD13-K31 ubiquitination (\u03b2=0.568, P=1.34e-6), and PLXND1-K1826 ubiquitination (\u03b2=0.577, P=7.08e-8) for tangle burden and SYP-K23 ubiquitination (\u03b2=1.50, P=4.7e-8), TMEFF2-C80 cysteine oxidation (\u03b2=1.64, P=1.1e-8), and STX1B-T121 phosphorylation (\u03b2=0.898, P=3.3e-7) for amyloid-\u03b2 load. Further, kinase enrichment analyses highlight the complexity of disease-related proteome changes with some kinases like CDK5 showing expected over-enrichment (amyloid z=3.44, P=3.0e-4; tau z=4.98, P=3.3e-7) but others like PKC family kinases showing divergent enrichment between amyloid (z=8.98\u201311.55, P&lt;1.0e-18) and tau (z=-2.83\u2013-3.88, P&lt;0.006).<\/jats:p>\n                <jats:p>This study provides an atlas of brain PTMs within crucial proteins like MAPT and APP and at the proteome-wide level, that impact AD neuropathology and clinical presentation. Further, we explored what kinases might be driving phosphorylation results, emphasizing the complex proteome changes which impact AD. In sum, these results highlight robust post-translational alterations in the AD brain and provide novel targets for future mechanistic studies.<\/jats:p>","DOI":"10.64898\/2026.06.13.732018","type":"posted-content","created":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T07:55:10Z","timestamp":1781423710000},"source":"Crossref","is-referenced-by-count":0,"title":["Post-translational modifications in the brain are critical contributors to Alzheimer\u2019s disease neuropathology and cognitive decline"],"prefix":"10.64898","author":[{"given":"Julia B.","family":"Libby","sequence":"first","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2492-4350","authenticated-orcid":false,"given":"Emily R.","family":"Mahoney","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Drucker","sequence":"additional","affiliation":[{"name":"Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8057-2505","authenticated-orcid":false,"given":"Philip L.","family":"De Jager","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA"},{"name":"Cell Circuits Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilas","family":"Menon","sequence":"additional","affiliation":[{"name":"Department of Neurology, Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6841-4830","authenticated-orcid":false,"given":"Shahram","family":"Oveisgharan","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0072-9817","authenticated-orcid":false,"given":"Lisa L.","family":"Barnes","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladislav A.","family":"Petyuk","sequence":"additional","affiliation":[{"name":"Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3377-7014","authenticated-orcid":false,"given":"Timothy J.","family":"Hohman","sequence":"additional","affiliation":[{"name":"Vanderbilt Memory and Alzheimer\u2019s Center, Vanderbilt University Medical Center, Nashville, TN, USA"},{"name":"Department of Neurology, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061607300988000_2026.06.13.732018v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.261"},{"key":"2026061607300988000_2026.06.13.732018v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1066"},{"key":"2026061607300988000_2026.06.13.732018v1.3","doi-asserted-by":"crossref","unstructured":"Ren RJ , Dammer EB , Wang G , Seyfried NT , Levey AI . Proteomics of protein post-translational modifications implicated in neurodegeneration. Transl Neurodegener. 2014 Oct 30;3(23).","DOI":"10.1186\/2047-9158-3-23"},{"key":"2026061607300988000_2026.06.13.732018v1.4","doi-asserted-by":"crossref","unstructured":"Ittner LM , G\u201dtz J . Amyloid-beta and tau - toxic pas de deux in Alzheimer\u2019s disease. Nat Rev Neurosci. 12(2):67\u201372.","DOI":"10.1038\/nrn2967"},{"key":"2026061607300988000_2026.06.13.732018v1.5","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-015-1387-2"},{"key":"2026061607300988000_2026.06.13.732018v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2024.102599"},{"key":"2026061607300988000_2026.06.13.732018v1.7","doi-asserted-by":"publisher","DOI":"10.3233\/jad-170061"},{"issue":"8","key":"2026061607300988000_2026.06.13.732018v1.8","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1001\/jamaneurol.2019.1424","article-title":"Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease A Longitudinal Study","volume":"76","year":"2019","journal-title":"JAMA Neurol"},{"key":"2026061607300988000_2026.06.13.732018v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(20)80536-5"},{"key":"2026061607300988000_2026.06.13.732018v1.10","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1997.69052087.x"},{"issue":"8","key":"2026061607300988000_2026.06.13.732018v1.11","first-page":"656","article-title":"Tau in Alzheimer Disease and Related Tauopathies","volume":"7","year":"2011","journal-title":"Curr Alzheimer Res"},{"key":"2026061607300988000_2026.06.13.732018v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.02.015"},{"key":"2026061607300988000_2026.06.13.732018v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1255"},{"key":"2026061607300988000_2026.06.13.732018v1.14","doi-asserted-by":"crossref","unstructured":"Zola NKN , Balty C , Ruy SP dit , Vanparys AA , Huyghe ND , Herinckx G , et al. Specific post-translational modifications of soluble tau protein distinguishes Alzheimer\u2019s disease and primary tauopathies. Nat Commun. 2023 Jun 22;14.","DOI":"10.1038\/s41467-023-39328-1"},{"issue":"4","key":"2026061607300988000_2026.06.13.732018v1.15","doi-asserted-by":"crossref","first-page":"313","DOI":"10.2174\/1567205014666170505095109","article-title":"The Involvement of Post-Translational Modifications in Alzheimer\u2019s Disease","volume":"15","year":"2018","journal-title":"Curr Alzheimer Res"},{"key":"2026061607300988000_2026.06.13.732018v1.16","doi-asserted-by":"crossref","unstructured":"Li W , Li HL , Wang JZ , Liu R , Wang X . Abnormal protein post-translational modifications induces aggregation and abnormal deposition of protein, mediating neurodegenerative diseases. Cell Biosci. 14(22).","DOI":"10.1186\/s13578-023-01189-y"},{"key":"2026061607300988000_2026.06.13.732018v1.17","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awaa223"},{"key":"2026061607300988000_2026.06.13.732018v1.18","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-179939"},{"key":"2026061607300988000_2026.06.13.732018v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0006-9"},{"key":"2026061607300988000_2026.06.13.732018v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4256"},{"key":"2026061607300988000_2026.06.13.732018v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2022.10.300"},{"key":"2026061607300988000_2026.06.13.732018v1.22","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14094"},{"key":"2026061607300988000_2026.06.13.732018v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2013.161"},{"key":"2026061607300988000_2026.06.13.732018v1.24","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/kxj037"},{"key":"2026061607300988000_2026.06.13.732018v1.25","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001935"},{"key":"2026061607300988000_2026.06.13.732018v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2011.09.033"},{"key":"2026061607300988000_2026.06.13.732018v1.27","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x)"},{"key":"2026061607300988000_2026.06.13.732018v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2968"},{"key":"2026061607300988000_2026.06.13.732018v1.29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1267"},{"key":"2026061607300988000_2026.06.13.732018v1.30","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2003573"},{"key":"2026061607300988000_2026.06.13.732018v1.31","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx415"},{"key":"2026061607300988000_2026.06.13.732018v1.32","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.TIR118.000943"},{"key":"2026061607300988000_2026.06.13.732018v1.33","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-3224"},{"key":"2026061607300988000_2026.06.13.732018v1.34","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201200239"},{"key":"2026061607300988000_2026.06.13.732018v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2018.11.024"},{"key":"2026061607300988000_2026.06.13.732018v1.36","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-020-04342-4"},{"key":"2026061607300988000_2026.06.13.732018v1.37","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2023.1119326"},{"key":"2026061607300988000_2026.06.13.732018v1.38","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201200239"},{"key":"2026061607300988000_2026.06.13.732018v1.39","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.0c00069"},{"key":"2026061607300988000_2026.06.13.732018v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111062"},{"key":"2026061607300988000_2026.06.13.732018v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-023-00444-w"},{"key":"2026061607300988000_2026.06.13.732018v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2021.03.003"},{"key":"2026061607300988000_2026.06.13.732018v1.43","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.786353"},{"key":"2026061607300988000_2026.06.13.732018v1.44","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.10159"},{"key":"2026061607300988000_2026.06.13.732018v1.45","doi-asserted-by":"publisher","DOI":"10.1101\/2025.04.14.648858"},{"key":"2026061607300988000_2026.06.13.732018v1.46","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-018-0524-2"},{"key":"2026061607300988000_2026.06.13.732018v1.47","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.736"},{"key":"2026061607300988000_2026.06.13.732018v1.48","doi-asserted-by":"crossref","unstructured":"Le Guerroue F , Youle RJ . Ubiquitin signaling in neurodegenerative diseases: an autophagy and proteasome perspective. Cell Death Differ. 28:439\u2013545.","DOI":"10.1038\/s41418-020-00667-x"},{"key":"2026061607300988000_2026.06.13.732018v1.49","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-150318"},{"key":"2026061607300988000_2026.06.13.732018v1.50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1462003"},{"key":"2026061607300988000_2026.06.13.732018v1.51","doi-asserted-by":"publisher","DOI":"10.1101\/129551"},{"key":"2026061607300988000_2026.06.13.732018v1.52","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262010122"},{"key":"2026061607300988000_2026.06.13.732018v1.53","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2015.00426"},{"key":"2026061607300988000_2026.06.13.732018v1.54","doi-asserted-by":"publisher","DOI":"10.1111\/NAN.12742"},{"key":"2026061607300988000_2026.06.13.732018v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/0925-4439(93)90023-t"},{"key":"2026061607300988000_2026.06.13.732018v1.56","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5273"},{"key":"2026061607300988000_2026.06.13.732018v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(87)80670-1"},{"key":"2026061607300988000_2026.06.13.732018v1.58","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.2926"},{"key":"2026061607300988000_2026.06.13.732018v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-394816-8.00008-8"},{"issue":"22","key":"2026061607300988000_2026.06.13.732018v1.60","doi-asserted-by":"crossref","first-page":"15721","DOI":"10.1016\/S0021-9258(19)49595-1","article-title":"Microtubule-associated protein tau is phosphorylated by protein kinase C on its tubulin binding domain","volume":"267","year":"1992","journal-title":"J Biol Chem"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.13.732018","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T14:53:13Z","timestamp":1781621593000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.13.732018"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,13]]},"references-count":60,"URL":"https:\/\/doi.org\/10.64898\/2026.06.13.732018","relation":{},"subject":[],"published":{"date-parts":[[2026,6,13]]},"subtype":"preprint"}}