OSCR

Brain multiomic profiling identifies tau-related transcriptomic dysregulation in Alzheimer's disease.

Overview

Authors: Stephanie R Oatman1, Zachary S Quicksall2, Xue Wang2, Jeremiah Bergman1, Joseph S Reddy2, Floor Vanelderen1, Thuy Nguyen1, Kimberly Malphrus1, Sarah J Lincoln1, Yuka A Martens1, Na Zhao1, Yu Yamazaki1, Michael DeTure1, Melissa E Murray1, Chia-Chen Liu1, Guojun Bu1, Takahisa Kanekiyo1, Dennis W Dickson1, Mariet Allen1, Nilüfer Ertekin-Taner1,3
ORCID iDs: Melissa E Murray, Takahisa Kanekiyo, Dennis W Dickson, Nilüfer Ertekin-Taner
  1. Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
  2. Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, USA
  3. Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
Institutions: Mayo Clinic (United States); Mayo Clinic in Florida (United States)
Journal: Brain communications, volume 8, issue 5, article fcag326
Dates: received 9 September 2025; accepted 4 August 2026; published online 27 August 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1093/braincomms/fcag326 · PMID 42712681 · PMCID PMC13550776 · OpenAlex W7204473389
Open access: gold, a free copy (OpenAlex)
Status: code verified
Categories: genetics / omics (modality), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Preprocessing, Connectivity, Spectral & time-frequency
Keywords: transcriptome, expression, tau, amyloid, APOE
Topic: Alzheimer's disease research and treatments (Physiology, Medicine), according to OpenAlex
Funding: National Institute on Aging (RF1 AG051504, U01 AG046139, R01 AG061796, U19 AG074879); U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (R01 NS080820); CurePSP; Alzheimer’s Association Zenith Fellow Award (ZEN-22-969810, P30 AG062677, R01 AG032990, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949); Rainwater Charitable Foundation; Mayo Foundation for Medical Education and Research
Citations: not cited yet (Europe PMC); 74 references in the paper

Abstract

Identification of gene expression changes in postmortem brain tissue of Alzheimer’s disease donors compared to controls has implicated numerous biological pathways for Alzheimer’s disease pathophysiology. Nonetheless, there is still limited understanding of how gene expression dysregulation underpins specific proteinopathies core to Alzheimer’s disease. Here, we investigate brain transcriptomic changes in a well-characterized cohort of Alzheimer’s disease donors to identify genes and networks that associate with Alzheimer’s disease endophenotypes, including neuropathology measures (Braak stage, Thal phase and cerebral amyloid angiopathy score) and Alzheimer’s disease-related brain protein levels (Apolipoprotein E, Amyloid-β 40, Amyloid-β 42, tau and phospho-Tau). Bulk transcriptome measures were collected from the temporal cortex tissue of 477 Alzheimer’s 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’s disease endophenotypes, most of which were with brain tau levels. We discovered tau-associated co-expression modules enriched in known and novel Alzheimer’s 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’s disease endophenotypes. While some of these associations are common across multiple endophenotypes, many are distinct for different Alzheimer’s disease-related proteins. Based on these findings, we propose a hypothetical model of dynamic brain gene expression changes that track with progressive Alzheimer’s disease proteostasis. These expression changes hold potential to serve as dynamic, precision biomarkers of brain Alzheimer’s disease progression. This study demonstrates the potential of integrative multi-omics and deep Alzheimer’s disease endophenotypes in well-characterized brain tissues to precisely uncover the complex biology of Alzheimer’s disease.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

No file of the authors' code could be read here: it is described below, and read at its source.

synapse.org/synapse:syn75046458

License: none: the authors keep all their rights
State: the link answers, verified on 27 September 2026
Evidence: the link answers
Software Heritage: not checked
Found in: “Code availability”
Not found: README, license file, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 27 September 2026: the link answers (HTTP 200)
  • 27 September 2026: the link answers (HTTP 200)
At the source: synapse.org/Synapse:syn75046458

Code availability

Code used in this manuscript for data analyses can be accessed via the AD Knowledge Portal: https://www.synapse.org/Synapse:syn75046458.

Reproduced under the paper's license (CC BY), from the paper cited above.

Tracing map

Proposed by the machine: these links were found in the paper and verified at the source, without human review. The map will receive a Zenodo DOI once one of the paper's authors has validated it with their ORCID.

What the map holds:

  • 1 repository of the authors' code, each at its verified commit, with its license and how the link was found in the paper;
  • 0 scripts, each with its path and the digest of its content;
  • no match between paragraphs and code yet;
  • neither the text of the paper nor the code itself.

Its JSON (tracing-map.json) is deposited on Zenodo with its DOI once the map is validated.

Data

Datasets cited

Data availability

The data in this manuscript, including full results for TWAS, gene enrichment analysis and multi-omics integration, are available via the AD Knowledge Portal (https://adknowledgeportal.synapse.org). The AD Knowledge Portal is a platform for accessing data, analyses and tools generated by the Accelerating Medicines Partnership (AMP-AD) Target Discovery Program and other National Institute on Aging (NIA)-supported programs to enable open- science practices and accelerate translational learning. The data, analyses and tools are shared early in the research cycle without a publication embargo on secondary use. Data are available for general research use according to the following requirements for data access and data attribution (https://adknowledgeportal.synapse.org/DataAccess/Instructions). For access to content described in this manuscript see the manuscript landing page: https://www.synapse.org/Synapse:syn64679963/datasets/.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 20 authors, 5 keywords, 6 funders, 72 references.

Cite

This paper

Oatman, S. R., Quicksall, Z. S., Wang, X., Bergman, J., Reddy, J. S., Vanelderen, F., Nguyen, T., Malphrus, K., Lincoln, S. J., Martens, Y. A., Zhao, N., Yamazaki, Y., DeTure, M., Murray, M. E., Liu, C.-C., Bu, G., Kanekiyo, T., Dickson, D. W., Allen, M., & Ertekin-Taner, N. (2026). Brain multiomic profiling identifies tau-related transcriptomic dysregulation in Alzheimer's disease. Brain communications, 8(5), fcag326. https://doi.org/10.1093/braincomms/fcag326

BibTeX

@article{oatman2026brain,
author = {Oatman, Stephanie R and Quicksall, Zachary S and Wang, Xue and Bergman, Jeremiah and Reddy, Joseph S and Vanelderen, Floor and Nguyen, Thuy and Malphrus, Kimberly and Lincoln, Sarah J and Martens, Yuka A and Zhao, Na and Yamazaki, Yu and DeTure, Michael and Murray, Melissa E and Liu, Chia-Chen and Bu, Guojun and Kanekiyo, Takahisa and Dickson, Dennis W and Allen, Mariet and Ertekin-Taner, Nilüfer},
title = {{Brain multiomic profiling identifies tau-related transcriptomic dysregulation in Alzheimer's disease}},
journal = {Brain communications},
year = {2026},
month = aug,
volume = {8},
number = {5},
pages = {fcag326},
publisher = {Oxford University Press},
issn = {2632-1297},
doi = {10.1093/braincomms/fcag326},
url = {https://doi.org/10.1093/braincomms/fcag326},
pmid = {42712681},
pmcid = {PMC13550776}
}

RIS

TY - JOUR
AU - Oatman, Stephanie R
AU - Quicksall, Zachary S
AU - Wang, Xue
AU - Bergman, Jeremiah
AU - Reddy, Joseph S
AU - Vanelderen, Floor
AU - Nguyen, Thuy
AU - Malphrus, Kimberly
AU - Lincoln, Sarah J
AU - Martens, Yuka A
AU - Zhao, Na
AU - Yamazaki, Yu
AU - DeTure, Michael
AU - Murray, Melissa E
AU - Liu, Chia-Chen
AU - Bu, Guojun
AU - Kanekiyo, Takahisa
AU - Dickson, Dennis W
AU - Allen, Mariet
AU - Ertekin-Taner, Nilüfer
TI - Brain multiomic profiling identifies tau-related transcriptomic dysregulation in Alzheimer's disease
T2 - Brain communications
J2 - Brain Commun
PY - 2026
DA - 2026/08/27
VL - 8
IS - 5
SP - fcag326
SN - 2632-1297
PB - Oxford University Press
DO - 10.1093/braincomms/fcag326
UR - https://doi.org/10.1093/braincomms/fcag326
LA - en
ER -

CSL-JSON

{
"id": "10.1093/braincomms/fcag326",
"type": "article-journal",
"title": "Brain multiomic profiling identifies tau-related transcriptomic dysregulation in Alzheimer's disease",
"container-title": "Brain communications",
"author": [
{
"family": "Oatman",
"given": "Stephanie R"
},
{
"family": "Quicksall",
"given": "Zachary S"
},
{
"family": "Wang",
"given": "Xue"
},
{
"family": "Bergman",
"given": "Jeremiah"
},
{
"family": "Reddy",
"given": "Joseph S"
},
{
"family": "Vanelderen",
"given": "Floor"
},
{
"family": "Nguyen",
"given": "Thuy"
},
{
"family": "Malphrus",
"given": "Kimberly"
},
{
"family": "Lincoln",
"given": "Sarah J"
},
{
"family": "Martens",
"given": "Yuka A"
},
{
"family": "Zhao",
"given": "Na"
},
{
"family": "Yamazaki",
"given": "Yu"
},
{
"family": "DeTure",
"given": "Michael"
},
{
"family": "Murray",
"given": "Melissa E"
},
{
"family": "Liu",
"given": "Chia-Chen"
},
{
"family": "Bu",
"given": "Guojun"
},
{
"family": "Kanekiyo",
"given": "Takahisa"
},
{
"family": "Dickson",
"given": "Dennis W"
},
{
"family": "Allen",
"given": "Mariet"
},
{
"family": "Ertekin-Taner",
"given": "Nilüfer"
}
],
"container-title-short": "Brain Commun",
"volume": "8",
"issue": "5",
"page": "fcag326",
"DOI": "10.1093/braincomms/fcag326",
"PMID": "42712681",
"PMCID": "PMC13550776",
"ISSN": "2632-1297",
"publisher": "Oxford University Press",
"URL": "https://doi.org/10.1093/braincomms/fcag326",
"language": "en",
"issued": {
"date-parts": [
[
2026,
8,
27
]
]
}
}

The tracing map gets a citation of its own once an author has validated it and it has a DOI.

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1016/j.isci.2026.117038 [code]
Multi-region brain transcriptomes uncover two subtypes of aging individuals with differences in Alzheimer risk and the impact of <i>APOEε4</i>.
Journal: iScience
In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, 9 references
[2] doi:10.1038/s43587-026-01204-0
Fibronectin mediates APOE4-driven blood-brain barrier dysfunction in Alzheimer's disease.
Journal: Nature aging
In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, 5 references, author Nilüfer Ertekin-Taner
[3] doi:10.1038/s41380-026-03686-1 [code]
Early oligodendrocyte dysfunction signature in Alzheimer's disease: Insights from DNA methylomics and transcriptomics.
Journal: Molecular psychiatry
In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, 7 references
[4] doi:10.1002/alz.71804
A meta-refined human Alzheimer's disease-associated gene subset shows partial mouse-model pathway correspondence and limited cross-cohort machine-learning transportability.
Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association
In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, 7 references
[5] doi:10.1038/s41586-026-10793-0
Cell-type signatures of Alzheimer's disease shared across population groups.
Journal: Nature
In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, 8 references
[6] doi:10.1016/j.celrep.2026.117235 [code]
Integration of aged brain multi-omics reveals cross-system mechanisms underlying Alzheimer's disease heterogeneity.
Journal: Cell reports
In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, 6 references
[7] doi:10.34133/csbj.0108 [code]
Latent Factor Modeling Reveals Unexpected Spatial Heterogeneity in Human Alzheimer's Disease Brain Transcriptomes.
Journal: Computational and structural biotechnology journal
In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, 6 references
[8] doi:10.1002/alz.71558 [code]
Allele specific expression in Alzheimer's disease.
Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association
In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, 6 references
[9] doi:10.1186/s13195-026-02081-w [code]
Cellular state heterogeneity underlying sex differences in Alzheimer's disease based on single-cell transcriptome.
Journal: Alzheimer's research & therapy
In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, 6 references
[10] doi:10.34133/csbj.0134 [code]
Integrated Multi-Tissue Transcriptomics Reveals Antagonistic Pleiotropy in Aging and Alzheimer's Disease.
Journal: Computational and structural biotechnology journal
In common: Alzheimer's / dementia, genetics / omics, cellular / molecular, 6 references

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Sign in with ORCID to claim this paper as one of its authors, correct its record or validate its tracing map: when the paper's metadata lists your ORCID iD, you are recognized at once. Maintainers of its code: sign in with GitHub, then claim the repository on your account page.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion, reproductions, activity

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.