Peer-reviewedCC BYAlzheimer s & Dementia
Cross‐tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease
12 affiliations
- 1Neurodegeneration and Disease Modelling Laboratory Westmead Institute for Medical Research, The University of Sydney Westmead New South Wales Australia
- 2School of Medical Sciences, Faculty of Medicine and Health The University of Sydney Sydney New South Wales Australia
- 3Biomedical Proteomics Children's Medical Research Institute, The University of Sydney Westmead New South Wales Australia
- 4University of Kansas Alzheimer's Disease Research Centre University of Kansas Medical Center Kansas City Kansas USA
- 5Integrative Imaging Core University of Kansas Medical Center Kansas City Kansas USA
- 6Human Brain Microphysiology Systems Group, School of Biomedical Engineering, Faculty of Engineering The University of Sydney Sydney New South Wales Australia
- 7Gates Ventures Seattle Washington USA
- 8Autoimmunity and Amyloidosis Research Group Westmead Institute for Medical Research, The University of Sydney Westmead New South Wales Australia
- 9Department of Neurology University of Kansas School of Medicine Kansas City Kansas USA
- 10Department of Biochemistry and Molecular Biology University of Kansas Medical Center Kansas City Kansas USA
- 11University of Kansas Cancer Center University of Kansas Medical Center Kansas City Kansas USA
- 12Department of Cell Biology and Physiology University of Kansas Medical Center Kansas City Kansas USA
Abstract
APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), but its contribution to disease pathogenesis remains incompletely understood. Here, we integrate proteomic profiling of plasma, cerebrospinal fluid (CSF), and brain tissue from over 10,000 individuals to define the immune phenotype associated with APOE ε4. We identify a conserved, allele dose-dependent pro-inflammatory immune signature across peripheral and central tissues independent of AD diagnosis. This signature is enriched in adaptive immune cells and white matter-resident glial and vascular cells. It also emerges in patient-derived cortical organoids prior to amyloid-β and tau pathology, supporting a causal, 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. 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.
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BibTeX
@article{shvetcov2026crosstissue,
title = {{Cross‐tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease}},
author = {Artur Shvetcov and Shannon Thomson and Mark E. Graham and Brittany M Hauger and Jessica E. Keller and Christine J. Smoyer and Sarah E. Tague and Ann‐Na Cho and Farhad B. Imam and Varsha S. Krish and Matthew K. Taylor and Jonathan D. Mahnken and Debra K. Sullivan and Joanne H. Reed and Jeffrey Murray Burns and Chad M Slawson and Russell Howard Swerdlow and Heather Wilkins and Caitlin A. Finney},
journal = {Alzheimer s \& Dementia},
year = {2026},
month = aug,
doi = {10.1002/alz.71714},
url = {https://doi.org/10.1002/alz.71714},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cross‐tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease
AU - Artur Shvetcov
AU - Shannon Thomson
AU - Mark E. Graham
AU - Brittany M Hauger
AU - Jessica E. Keller
AU - Christine J. Smoyer
AU - Sarah E. Tague
AU - Ann‐Na Cho
AU - Farhad B. Imam
AU - Varsha S. Krish
AU - Matthew K. Taylor
AU - Jonathan D. Mahnken
AU - Debra K. Sullivan
AU - Joanne H. Reed
AU - Jeffrey Murray Burns
AU - Chad M Slawson
AU - Russell Howard Swerdlow
AU - Heather Wilkins
AU - Caitlin A. Finney
PY - 2026
DA - 2026/08/31
JO - Alzheimer s & Dementia
DO - 10.1002/alz.71714
UR - https://doi.org/10.1002/alz.71714
AB - APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), but its contribution to disease pathogenesis remains incompletely understood. Here, we integrate proteomic profiling of plasma, cerebrospinal fluid (CSF), and brain tissue from over 10,000 individuals to define the immune phenotype associated with APOE ε4. We identify a conserved, allele dose-dependent pro-inflammatory immune signature across peripheral and central tissues independent of AD diagnosis. This signature is enriched in adaptive immune cells and white matter-resident glial and vascular cells. It also emerges in patient-derived cortical organoids prior to amyloid-β and tau pathology, supporting a causal, 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. 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.
SN - 1552-5260
SN - 1552-5279
ER -