Lina Lu, Alexa Pichet Binette, Inès Hristovska, Shorena Janelidze, B. 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
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.