SnoRNAs in plasma extracellular vesicles of AD patients are differentially associated with APOE genotype

Abstract

AbstractBackgroundStandardized disease specific PET patterns correctly classify 95% of AD MCI patients. The cost of PET, however, is still prohibitive as a widespread AD diagnostic test. Diagnostic tests using CSF have also been established to measure the levels of Aβ and hyperphosphorylated tau for early diagnosis of AD or to monitor the effects of therapeutics and progression of the disease. CSF biomarkers show a good agreement with amyloid imaging and a combination of CSF Aβ42/Aβ40 increases the agreement between markers of amyloid pathology. Plasma extracellular vesicles (EVs) and their cargo present an opportunity to isolate and profile molecules associated with human pathological conditions. We have recently found small nucleolar non‐coding RNAs (snoRNAs) of box C/D (SNORDs), transcribed from imprinted chromosomal domains SNURF‐SNRPN at human chromosomal region 15q11q13 and DLK1‐DIO3 at region 14q32, highly enriched in plasma EVs of AD patients compared to non‐demented individuals.MethodDuring the discovery phase of the study, using RNA‐seq we profiled four major classes of ncRNAs in EVs isolated from early stage AD patients and control non‐demented individuals: miRNAs, snoRNAs, tRNAs and piRNAs. We verified the results by Digital Droplet PCR in plasma samples of independent group of AD and control plasma samples.ResultWe report a significant enrichment of SNORDs in AD samples compared to controls. Through verification assays we confirmed these results and identified SNORD115s & SNORD116s with the highest discriminatory power to differentiate AD samples against Controls.ConclusionThe results of our study present evidence that AD is associated with changes in enrichment of SNORDs, transcribed from imprinted genomic loci, in plasma EVs and provide a rationale to further explore validity of snoRNAs as plasma biomarkers for AD.