| Title: | Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer's disease |
| Journal: | Nature Aging |
| Published: | 15 May 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42141098/ |
| DOI: | https://doi.org/10.1038/s43587-026-01123-0 |
Publication 20018
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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.</p>
14 Keywords
- Aged
- Aged, 80 and over
- Alleles
- Alzheimer Disease
- Apolipoprotein E2
- Apolipoprotein E4
- Biomarkers
- Female
- Genetic Predisposition to Disease
- Genetic Variation
- Humans
- Male
- Middle Aged
- Proteomics
17 Authors
- Lina Lu
- Alexa Pichet Binette
- Ines Hristovska
- Shorena Janelidze
- Bart Smets
- Irene Cumplido-Mayoral
- Aparna Vasanthakumar
- Britney Milkovich
- Lijun An
- Rik Ossenkoppele
- Varsha Krish
- Farhad Imam
- Sebastian Palmqvist
- Jacob W. Vogel
- Erik Stomrud
- Oskar Hansson
- Niklas Mattsson-Carlgren
1 Application
| Application ID | Title |
|---|---|
| 105777 | Building a multi-disease prognostic panel toward individualized preventive medicine |
Enabling scientific discoveries that improve human health