Plasma extracellular vesicles from APOE3 Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease.

INTRODUCTION: The PSEN1(E280A) mutation causes autosomal dominant Alzheimer's disease (ADAD) with predictable onset, enabling presymptomatic studies. Extracellular vesicles (EVs) are emerging biomarkers of cognitive decline, but their role in early ADAD is unclear. The rare apolipoprotein E (APOE3) Christchurch (APOE3(Ch)) variant delays disease onset, yet its effect on EVs is unknown. METHODS: We analyzed plasma EVs from mild cognitive impairment (MCI) and non-MCI PSEN1(E280A)-APOE3 carriers and non-MCI PSEN1(E280A)-APOE3(Ch) carriers using flow cytometry, proteomics, and co-culture assays. RESULTS: APOE3(Ch)-EVs showed reduced vascular activation and inflammatory cargo linked to β-catenin signaling, higher apoE levels, and enrichment in lipid-loaded EVs. They mimicked the protective effect of recombinant ApoE3Ch on endothelial integrity by restoring β-catenin nuclear localization. In contrast, EVs from non-MCI PSEN1(E280A)-APOE3 carriers displayed vascular and inflammatory signatures associated with poorer cognition and detrimental astrocyte-endothelium effects. These findings highlight APOE3(Ch)-EVs as modulators of vascular and inflammatory pathways with biomarker and therapeutic potential in ADAD.