SECmeres outperform extracellular vesicles as potential blood RNA biomarkers for Alzheimer's disease.

Cells release heterogeneous extracellular vesicles and particles (EVPs) into circulation, carrying RNA and proteins that reflect their origin. Recently, brain-derived EVs have gained significant attention as non-invasive biomarkers for Alzheimer's disease (AD). Here, we identified sub-50nm extracellular nanoparticles in human brain and blood that lack the hallmarks of small EVs, exosomes, exomeres, and supermeres but are enriched for brain-specific markers, hereafter termed small EPs or 'SECmeres'. We discovered that RNAs associated with SECmeres discriminated AD cases from controls with higher significance than small EVs, large EVs showed no differences. Discriminating RNAs were enriched in small EVs (Synaptotagmin, Alpha-synuclein, MAPT) or SECmeres (L1CAM, Syntaxin, Neurogranin), indicating distinct brain-derived signatures. Single-cell RNAseq deconvolution shows small EVs contain RNAs from diverse brain cells, whereas SECmeres enrich brain endothelial transcripts, lining cerebral blood vessels and forming the blood-brain barrier (BBB). These findings challenge the prevailing view that small EVs are the primary carriers of biomarkers. Collectively, our study shows that blood EVPs carry brain-specific information for liquid biopsy, pending validation in larger blinded clinical trials.