title: Plasma Exosomal miRNAs in Persons with and without Alzheimer Disease: Altered Expression and Prospects for Biomarkers.
abstract: To assess the value of exosomal miRNAs as biomarkers for Alzheimer disease (AD), the expression of microRNAs was measured in a plasma fraction enriched in exosomes by differential centrifugation, using Illumina deep sequencing. Samples from 35 persons with a clinical diagnosis of AD dementia were compared to 35 age and sex matched controls. Although these samples contained less than 0.1 microgram of total RNA, deep sequencing gave reliable and informative results. Twenty miRNAs showed significant differences in the AD group in initial screening (miR-23b-3p, miR-24-3p, miR-29b-3p, miR-125b-5p, miR-138-5p, miR-139-5p, miR-141-3p, miR-150-5p, miR-152-3p, miR-185-5p, miR-338-3p, miR-342-3p, miR-342-5p, miR-548at-5p, miR-659-5p, miR-3065-5p, miR-3613-3p, miR-3916, miR-4772-3p, miR-5001-3p), many of which satisfied additional biological and statistical criteria, and among which a panel of seven miRNAs were highly informative in a machine learning model for predicting AD status of individual samples with 83-89% accuracy. This performance is not due to over-fitting, because a) we used separate samples for training and testing, and b) similar performance was achieved when tested on technical replicate data. Perhaps the most interesting single miRNA was miR-342-3p, which was a) expressed in the AD group at about 60% of control levels, b) highly correlated with several of the other miRNAs that were significantly down-regulated in AD, and c) was also reported to be down-regulated in AD in two previous studies. The findings warrant replication and follow-up with a larger cohort of patients and controls who have been carefully characterized in terms of cognitive and imaging data, other biomarkers (e.g., CSF amyloid and tau levels) and risk factors (e.g., apoE4 status), and who are sampled repeatedly over time. Integrating miRNA expression data with other data is likely to provide informative and robust biomarkers in Alzheimer disease.
authors.affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lugli
authors.affiliation: Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Cohen
authors.affiliation: Rush Alzheimer's Disease Center, Rush University, Chicago, Illinois, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Rush Alzheimer's Disease Center, Rush University, Chicago, Illinois, United States of America.
authors.forename: Raj C
authors.initials: RC
authors.lastname: Shah
authors.affiliation: HPCBio, University of Illinois, Urbana, Illinois, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fields
authors.affiliation: Roy J. Carver Biotechnology Center, Urbana, Illinois, United States of America.
authors.forename: Alvaro G
authors.initials: AG
authors.lastname: Hernandez
authors.affiliation: Department of Psychiatry and Psychiatric Institute, University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Smalheiser
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016022:Case-Control Studies; D055354:Exosomes / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010949:Plasma / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs