OSCR

Cross-tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease.

Overview

Authors: Artur Shvetcov1,2, Shannon Thomson1,2, Mark E Graham3, Brittany Hauger4, Jessica E Keller4, Christine J Smoyer5, Sarah E Tague5, Ann‐Na Cho6, Farhad B Imam7, Varsha Krish7, Global Neurodegeneration Proteomics Consortium (GNPC), Matthew K Taylor4, Jonathan D Mahnken4, Debra K Sullivan4, Joanne H Reed2,8, Jeffrey M Burns4,9, Chad Slawson4,10,11, Russell H Swerdlow4,9,11,12, Heather M Wilkins4,9,11, Caitlin A Finney1,2
ORCID iDs: Ann‐Na Cho, Caitlin A Finney
  1. Neurodegeneration and Disease Modelling Laboratory, Westmead Institute for Medical Research, The University of Sydney, Westmead, New South Wales, Australia
  2. School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
  3. Biomedical Proteomics, Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales, Australia
  4. University of Kansas Alzheimer's Disease Research Centre, University of Kansas Medical Center, Kansas City, Kansas, USA
  5. Integrative Imaging Core, University of Kansas Medical Center, Kansas City, Kansas, USA
  6. Human Brain Microphysiology Systems Group, School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, Sydney, New South Wales, Australia
  7. Gates Ventures, Seattle, Washington, USA
  8. Autoimmunity and Amyloidosis Research Group, Westmead Institute for Medical Research, The University of Sydney, Westmead, New South Wales, Australia
  9. Department of Neurology, University of Kansas School of Medicine, Kansas City, Kansas, USA
  10. University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kansas, USA
  11. Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
  12. Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA
Institutions: The University of Sydney (Australia); Westmead Institute for Medical Research (Australia); Children's Medical Research Institute (Australia); University of Kansas (United States); University of Kansas Medical Center (United States); Gates Ventures (United States); The University of Kansas Cancer Center (United States)
Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association, volume 22, issue 9, article e71714
Dates: received 4 March 2026; accepted 28 June 2026; published online 31 August 2026; in print September 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1002/alz.71714 · PMID 42671246 · PMCID PMC13528450 · OpenAlex W7204760097
Open access: hybrid, a free copy (OpenAlex)
Status: dead link
Categories: genetics / omics (modality), human (organism), Alzheimer's / dementia (population), systems (subfield)
Methods: Statistics, Smoothing, state filtering, decompositions, Machine learning, Connectivity
Keywords: apolipoprotein E ε4, (APOE ε4), cerebrospinal fluid, cortical organoid, dorsolateral prefrontal cortex, inflammation, machine learning, plasma, proteomics, superior temporal gyrus
MeSH: Alzheimer Disease*, Apolipoprotein E4*, Aged, Female, Genotype, Humans, Male, Prefrontal Cortex, Proteomics, Temporal Lobe (* major topic)
Topic: Alzheimer's disease research and treatments (Physiology, Medicine), according to OpenAlex
Funding: NCATS NIH HHS (R21 TR003589); NIA NIH HHS (U19 AG068054, P30 AG072973, U01 AG046139, U01 AG061357, U01 AG061359, R01 AG060733, U01 AG046170, U01 AG061356, R01 AG064227, R01 AG067025); Hillcrest Foundation; National Health and Medical Research Council; NIH HHS (S10 OD032207); Perpetual Foundation John Williams Endowment; Australian Government's Medical Research Future Fund; Neil and Norma Hill Foundation; Paul & Valeria Ainsworth Family; Alzheimer's Association; Dementia Australia Research Foundation; Annemarie & Arturo Gandioli-Fumagali Foundation; John & Anne Leece Family; University of Kansas Alzheimer's Disease Research Center
Citations: not cited yet (Europe PMC); 79 references in the paper

Abstract

INTRODUCTION: Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for late‐onset Alzheimer's disease (AD), but its contribution to disease pathogenesis remains incompletely understood.

METHODS: Here, we integrate proteomic profiling of plasma (n = 9028), cerebrospinal fluid (n = 1099), dorsolateral prefrontal cortex (n = 720), and superior temporal gyrus (n = 105) to define the immune phenotype associated with APOE ε4.

RESULTS: We identify a conserved, allele dose‐dependent pro‐inflammatory immune protein signature across peripheral and central tissues independent of AD diagnosis. This signature also emerges in patient‐derived cortical organoids prior to amyloid beta and tau pathology, supporting a genotype‐driven mechanism. Cross‐tissue comparisons reveal shared innate and antiviral responses alongside tissue‐specific immune signaling. Notably, a 12‐week medical ketogenic diet partially reversed the APOE ε4 immune signature.

DISCUSSION: These findings position immune dysregulation as an early and tractable driver of AD risk in APOE ε4 carriers with direct implications for targeted prevention strategies.

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.

Art83/AD_apoe

License: none: the authors keep all their rights
State: the link is dead, verified on 26 September 2026
Evidence: found in the paper
Software Heritage: not archived
Found in: “Code availability”
Not found: README, license file, CITATION.cff, environment file, tests, continuous integration, documentation
Availability: 1 check, the latest on 26 September 2026: the link is dead
  • 26 September 2026: the link is dead
At the source: github.com/Art83/AD_apoe

Code availability

All code used in this study is publicly available at https://github.com/Art83/AD_apoe.

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 harmonized GNPC data used to generate these findings were provided to consortium members in June 2024 and will be made available to the public upon request by the AD Data Initiative by July 1, 2025. Members of the global research community will be able to access the metadata and submit a data use request via the AD Discovery Portal (https://discover.alzheimersdata.org/). Access is contingent on adherence to the GNPC Data Use Agreement and the Publication Policies.

The AMP‐AD Diverse Cohorts study data are available through the AD Knowledge Portal (https://adknowledgeportal.synapse.org/). Researchers who wish to access this controlled dataset are required to submit a Data Use Agreement. More information can be found here: https://adknowledgeportal.synapse.org/Data%20Access (https://adknowledgeportal.synapse.org/Data Access).

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, 10 keywords, 10 MeSH terms, 14 funders, 77 references.

Cite

This paper

Shvetcov, A., Thomson, S., Graham, M. E., Hauger, B., Keller, J. E., Smoyer, C. J., Tague, S. E., Cho, A., Imam, F. B., Krish, V., Global Neurodegeneration Proteomics Consortium (GNPC), Taylor, M. K., Mahnken, J. D., Sullivan, D. K., Reed, J. H., Burns, J. M., Slawson, C., Swerdlow, R. H., Wilkins, H. M., & Finney, C. A. (2026). Cross-tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association, 22(9), e71714. https://doi.org/10.1002/alz.71714

BibTeX

@article{shvetcov2026cross,
author = {Shvetcov, Artur and Thomson, Shannon and Graham, Mark E and Hauger, Brittany and Keller, Jessica E and Smoyer, Christine J and Tague, Sarah E and Cho, Ann‐Na and Imam, Farhad B and Krish, Varsha and {Global Neurodegeneration Proteomics Consortium (GNPC)} and Taylor, Matthew K and Mahnken, Jonathan D and Sullivan, Debra K and Reed, Joanne H and Burns, Jeffrey M and Slawson, Chad and Swerdlow, Russell H and Wilkins, Heather M and Finney, Caitlin A},
title = {{Cross-tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease}},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2026},
month = sep,
volume = {22},
number = {9},
pages = {e71714},
publisher = {Wiley},
issn = {1552-5260},
doi = {10.1002/alz.71714},
url = {https://doi.org/10.1002/alz.71714},
pmid = {42671246},
pmcid = {PMC13528450}
}

RIS

TY - JOUR
AU - Shvetcov, Artur
AU - Thomson, Shannon
AU - Graham, Mark E
AU - Hauger, Brittany
AU - Keller, Jessica E
AU - Smoyer, Christine J
AU - Tague, Sarah E
AU - Cho, Ann‐Na
AU - Imam, Farhad B
AU - Krish, Varsha
AU - Global Neurodegeneration Proteomics Consortium (GNPC)
AU - Taylor, Matthew K
AU - Mahnken, Jonathan D
AU - Sullivan, Debra K
AU - Reed, Joanne H
AU - Burns, Jeffrey M
AU - Slawson, Chad
AU - Swerdlow, Russell H
AU - Wilkins, Heather M
AU - Finney, Caitlin A
TI - Cross-tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease
T2 - Alzheimer's & dementia : the journal of the Alzheimer's Association
J2 - Alzheimers Dement
PY - 2026
DA - 2026/09/01
VL - 22
IS - 9
SP - e71714
SN - 1552-5260
PB - Wiley
DO - 10.1002/alz.71714
UR - https://doi.org/10.1002/alz.71714
LA - en
ER -

CSL-JSON

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

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