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Nonetheless, there is still limited understanding of how gene expression dysregulation underpins specific proteinopathies core to Alzheimer\u2019s disease. Here, we investigate brain transcriptomic changes in a well-characterized cohort of Alzheimer\u2019s disease donors to identify genes and networks that associate with Alzheimer\u2019s disease endophenotypes, including neuropathology measures (Braak stage, Thal phase and cerebral amyloid angiopathy score) and Alzheimer\u2019s disease-related brain protein levels (Apolipoprotein E, Amyloid-\u03b2 40, Amyloid-\u03b2 42, tau and phospho-Tau). Bulk transcriptome measures were collected from the temporal cortex tissue of 477 Alzheimer\u2019s disease donors. Following quality control, transcriptome-wide association studies were performed for each endophenotype. We used weighted gene co-expression network analysis to build co-expression networks and integrated transcriptome with epigenetic and genetic data from the same donors. We detected a total of 5740 Bonferroni-significant temporal cortex gene associations with Alzheimer\u2019s disease endophenotypes, most of which were with brain tau levels. We discovered tau-associated co-expression modules enriched in known and novel Alzheimer\u2019s disease pathways. We found that a beneficial (or neutral) brain biochemical state of higher total tau and lower phospho-Tau is associated with increased levels of synaptic, DNA damage\/repair, nucleic acid metabolism and myelin processes. In contrast, in a detrimental state with lower total and higher phospho-Tau, there is upregulation of vascular and immune, and downregulation of mitochondrial and myelin pathways. There are brain gene expression perturbations that are associated with Alzheimer\u2019s disease endophenotypes. While some of these associations are common across multiple endophenotypes, many are distinct for different Alzheimer\u2019s disease-related proteins. Based on these findings, we propose a hypothetical model of dynamic brain gene expression changes that track with progressive Alzheimer\u2019s disease proteostasis. These expression changes hold potential to serve as dynamic, precision biomarkers of brain Alzheimer\u2019s disease progression. This study demonstrates the potential of integrative multi-omics and deep Alzheimer\u2019s disease endophenotypes in well-characterized brain tissues to precisely uncover the complex biology of Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag326","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T20:41:22Z","timestamp":1787863282000},"source":"Crossref","is-referenced-by-count":0,"title":["Brain multiomic profiling identifies tau-related transcriptomic dysregulation in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"8","author":[{"given":"Stephanie R","family":"Oatman","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary S","family":"Quicksall","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremiah","family":"Bergman","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph S","family":"Reddy","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floor","family":"Vanelderen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuy","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Malphrus","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J","family":"Lincoln","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka A","family":"Martens","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yamazaki","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"DeTure","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7379-2545","authenticated-orcid":false,"given":"Melissa E","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Bu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6751-9374","authenticated-orcid":false,"given":"Takahisa","family":"Kanekiyo","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7189-7917","authenticated-orcid":false,"given":"Dennis W","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariet","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4436-8889","authenticated-orcid":false,"given":"Nil\u00fcfer","family":"Ertekin-Taner","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]},{"name":"Department of Neurology, Mayo Clinic , Jacksonville, FL 32224 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"issue":"3","key":"2026090803363768700_fcag326-B1","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.jalz.2017.09.012","article-title":"Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases","volume":"14","author":"Allen","year":"2018","journal-title":"Alzheimers Dement"},{"issue":"1","key":"2026090803363768700_fcag326-B2","doi-asserted-by":"crossref","first-page":"4758","DOI":"10.1038\/s41467-024-48926-6","article-title":"Gliovascular transcriptional perturbations in Alzheimer\u2019s disease reveal molecular mechanisms of blood brain barrier dysfunction","volume":"15","author":"\u0130\u015f","year":"2024","journal-title":"Nat Commun."},{"issue":"1","key":"2026090803363768700_fcag326-B3","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s40478-021-01199-2","article-title":"Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer\u2019s disease","volume":"9","author":"Reddy","year":"2021","journal-title":"Acta Neuropathol 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Invest"},{"issue":"3","key":"2026090803363768700_fcag326-B7","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2013.03.030","article-title":"Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer\u2019s disease","volume":"153","author":"Zhang","year":"2013","journal-title":"Cell"},{"issue":"6","key":"2026090803363768700_fcag326-B8","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/s41593-018-0154-9","article-title":"A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer\u2019s disease","volume":"21","author":"Mostafavi","year":"2018","journal-title":"Nat Neurosci."},{"issue":"6","key":"2026090803363768700_fcag326-B9","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.tig.2018.02.007","article-title":"Understanding Alzheimer disease at the interface between genetics and 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