Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer’s disease
13 affiliations
- 1Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden. [email protected]
- 2Centre de recherche de l'institut universitaire de gériatrie de Montréal (CRIUGM), Montréal, Quebec, Canada
- 3Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden
- 4Department of Physiology and Pharmacology, Université de Montréal, Montréal, Quebec, Canada
- 5Johnson & Johnson, Beerse, Belgium
- 6AbbVie, North Chicago, IL, USA
- 7Department of Clinical Sciences Malmö, SciLifeLab, Lund University, Lund, Sweden
- 8Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
- 9Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- 10Gates Ventures, Seattle, WA, USA
- 11Memory Clinic, Skåne University Hospital, Malmö, Sweden
- 12Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden. [email protected]
- 13Memory Clinic, Skåne University Hospital, Malmö, Sweden. [email protected]
Abstract
The APOE locus is the strongest genetic factor for Alzheimer’s disease, with ε4 increasing and ε2 decreasing risk, yet the basis of these opposing effects remains unclear. Here we performed a multicohort proteomic analysis across plasma and cerebrospinal fluid in GNPC, BioFINDER-2, ADNI, UK BioBank, and PPMI. APOE -associated protein alterations are detectable before amyloid pathology and remain stable across age and disease progression. APOE2 -associated proteins were enriched in pathways related to cellular maintenance and anti-inflammatory processes. By contrast, APOE4 showed a limited set of upstream mediators linked to cell-cycle and oligodendrocyte precursor cell biology, and a broader group of proteins reflecting vascular, immune, and proteostatic dysfunction shaped by downstream pathology. Comparative analyses highlighted allele-specific mediators and oppositely regulated proteins contributing to differential disease risk. Together, these findings reveal that APOE2 and APOE4 shape Alzheimer’s disease risk through distinct molecular architectures and identify candidate biomarkers and targets for allele-specific interventions.
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BibTeX
@article{lu2026proteomic,
title = {{Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer’s disease}},
author = {Lina Lu and Alexa Pichet Binette and Inès Hristovska and Shorena Janelidze and B. Smets and Irene Cumplido-Mayoral and Aparna Vasanthakumar and Britney Milkovich and Lijun An and Rik Ossenkoppele and Varsha S. Krish and Farhad B. Imam and Sebastian Palmqvist and Jacob W. Vogel and Erik Stomrud and Oskar Hansson and Niklas Mattsson},
journal = {Nature Aging},
year = {2026},
month = may,
doi = {10.1038/s43587-026-01123-0},
url = {https://doi.org/10.1038/s43587-026-01123-0},
note = {CC BY},
}
RIS
TY - JOUR
TI - Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer’s disease
AU - Lina Lu
AU - Alexa Pichet Binette
AU - Inès Hristovska
AU - Shorena Janelidze
AU - B. Smets
AU - Irene Cumplido-Mayoral
AU - Aparna Vasanthakumar
AU - Britney Milkovich
AU - Lijun An
AU - Rik Ossenkoppele
AU - Varsha S. Krish
AU - Farhad B. Imam
AU - Sebastian Palmqvist
AU - Jacob W. Vogel
AU - Erik Stomrud
AU - Oskar Hansson
AU - Niklas Mattsson
PY - 2026
DA - 2026/05/15
JO - Nature Aging
DO - 10.1038/s43587-026-01123-0
UR - https://doi.org/10.1038/s43587-026-01123-0
AB - The APOE locus is the strongest genetic factor for Alzheimer’s disease, with ε4 increasing and ε2 decreasing risk, yet the basis of these opposing effects remains unclear. Here we performed a multicohort proteomic analysis across plasma and cerebrospinal fluid in GNPC, BioFINDER-2, ADNI, UK BioBank, and PPMI. APOE -associated protein alterations are detectable before amyloid pathology and remain stable across age and disease progression. APOE2 -associated proteins were enriched in pathways related to cellular maintenance and anti-inflammatory processes. By contrast, APOE4 showed a limited set of upstream mediators linked to cell-cycle and oligodendrocyte precursor cell biology, and a broader group of proteins reflecting vascular, immune, and proteostatic dysfunction shaped by downstream pathology. Comparative analyses highlighted allele-specific mediators and oppositely regulated proteins contributing to differential disease risk. Together, these findings reveal that APOE2 and APOE4 shape Alzheimer’s disease risk through distinct molecular architectures and identify candidate biomarkers and targets for allele-specific interventions.
SN - 2662-8465
ER -