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Plasma Exosomal miRNAs in Persons with and without Alzheimer Disease: Altered Expression and Prospects for Biomarkers
Giovanni Lugli1, Aaron M Cohen2, David A Bennett3
1Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
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.
Insights
Exosomal microRNAs in plasma show promise as Alzheimer disease (AD) biomarkers. A panel of seven miRNAs accurately predicted AD status, with miR-342-3p being a key indicator.
Area of Science:
- Neuroscience
- Biomarker Discovery
- Genomics
Background:
- Alzheimer disease (AD) diagnosis relies on clinical assessment and costly biomarkers.
- Exosomal microRNAs (miRNAs) are emerging as potential non-invasive biomarkers.
- Identifying reliable AD biomarkers is crucial for early diagnosis and treatment.
Purpose of the Study:
- To evaluate the diagnostic value of exosomal miRNAs in plasma for Alzheimer disease.
- To identify a specific panel of miRNAs that can accurately predict AD status.
Main Methods:
- Exosomes were isolated from plasma using differential centrifugation.
- MicroRNA expression was analyzed using Illumina deep sequencing in 35 AD patients and 35 controls.
- Machine learning models were employed to predict AD status based on miRNA profiles.
Main Results:
- Deep sequencing provided reliable miRNA expression data even from low RNA quantities.
- Twenty miRNAs showed significant expression differences between AD patients and controls.
- A panel of seven miRNAs achieved 83-89% accuracy in predicting AD status, validated on separate test sets.
- miR-342-3p was significantly down-regulated in AD and correlated with other altered miRNAs.
Conclusions:
- Exosomal miRNAs in plasma represent a promising, non-invasive biomarker for Alzheimer disease.
- The identified miRNA panel demonstrates high accuracy in AD prediction.
- Further validation in larger, well-characterized cohorts is warranted to confirm these findings.
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