Proteomic signatures of APOE ε4 and APOE ε2 genetic variants and Alzheimer's dis
The APOE gene is the strongest genetic factor for Alzheimer's disease, with the ε4 variant increasing risk and ε2 decreasing it, but the molecular mechanisms behind these opposing effects are not fully understood. A multicohort proteomic analysis across plasma and cerebrospinal fluid revealed distinct molecular pathways associated with each variant, detectable before amyloid pathology and stable across disease stages. APOE2 is linked to cellular maintenance and anti-inflammatory processes, while APOE4 is associated with cell-cycle dysregulation, vascular dysfunction, and downstream pathological changes.
- ▪APOE ε4 increases Alzheimer's disease risk in a dose-dependent manner, while APOE ε2 reduces it.
- ▪Proteomic changes linked to APOE variants are detectable before amyloid pathology and remain stable across aging and disease progression.
- ▪APOE2-associated proteins are enriched in cellular maintenance and anti-inflammatory pathways, whereas APOE4 is linked to cell-cycle dysregulation and downstream vascular, immune, and proteostatic dysfunction.
- ▪The study analyzed data from multiple cohorts including GNPC, BioFINDER-2, ADNI, UK Biobank, and PPMI, enhancing generalizability.
- ▪Distinct molecular architectures underlying APOE2 and APOE4 suggest potential targets for allele-specific interventions in Alzheimer's disease.
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| Original publisher | Nature |
| Canonical URL | https://www.nature.com/articles/s43587-026-01123-0 |
| Publication time | Sat, 16 May 2026 15:27:47 +0000 |
| Retrieval time | 2026-05-16T15:40:18.968Z |
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Download PDF Article Open access Published: 15 May 2026 Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer’s disease Lina Lu ORCID: orcid.org/0000-0001-9395-242X1, Alexa Pichet Binette1,2,3, Ines Hristovska1, Shorena Janelidze ORCID: orcid.org/0000-0003-2869-83781, Bart Smets4, Irene Cumplido-Mayoral1, Aparna Vasanthakumar5, Britney Milkovich5, The Global Neurodegeneration Proteomics Consortium (GNPC), Lijun An ORCID: orcid.org/0000-0003-1030-46256, Rik Ossenkoppele1,7,8, Varsha Krish9, Farhad Imam ORCID: orcid.org/0000-0003-2854-25689, Sebastian Palmqvist ORCID: orcid.org/0000-0002-9267-19301,10, Jacob W.
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