ABSTRACT
Introduction: Circulating cell-free RNA (cfRNA) is a potential hallmark for early diagnosis of Alzheimer's Disease (AD) as it construes the genetic expression level, giving insights into the pathological progress from the outset. Profiles of cfRNA in Caucasian AD patients have been investigated thoroughly, yet there was no report exploring cfRNAs in the ASEAN groups. This study examined the gap, expecting to support the development of point-of-care AD diagnosis. Methods: cfRNA profiles were characterized from 20 Vietnamese plasma samples (10 probable AD and 10 age-matched controls). RNA reads were subjected to differential expression (DE) analysis. Weighted gene correlation network analysis (WGCNA) was performed to identify gene modules that were significantly co-expressed. These modules' expression profiles were then correlated with AD status to identify relevant modules. Genes with the highest intramodular connectivity (module membership) were selected as hub genes. Transcript counts of differentially expressed genes were correlated with key AD measures-MMSE and MTA scores-to identify potential biomarkers. Results: 136 genes were identified as significant AD hallmarks (p < 0.05), with 52 downregulated and 84 upregulated in the AD cohort. 45.6% of these genes are highly expressed in the hippocampus, cerebellum, and cerebral cortex. Notably, all markers related to chronic inflammation were upregulated, and there was a significant shift in all apoptotic markers. Three co-expressed modules were found to be significantly correlated with Alzheimer's status (p < 0.05; R2> 0.5). Functional enrichment analysis on these modules reveals an association with focal adhesion, nucleocytoplasmic transport, and metal ion response leading to apoptosis, suggesting the potential participation of these pathways in AD pathology. 47 significant hub genes were found to be differentially expressed genes with the highest connectivity. Six significant hub genes (CREB1, YTHDC1, IL1RL1, PHACTR2, ANKRD36B, RNF213) were found to be significantly correlated with MTA and MMSE scores. Other significant transcripts (XRN1, UBB, CHP1, THBS1, S100A9) were found to be involved in inflammation and neuronal death. Overall, we have identified candidate transcripts in plasma cf-RNA that are differentially expressed and are implicated in inflammation and apoptosis, which can jumpstart further investigations into applying cf-RNA as an AD biomarker in Vietnam and ASEAN countries.
ABSTRACT
Purpose of the study: Alzheimer's disease (AD) is the most common type of dementia and its prevalence is rapidly increasing worldwide. Early-onset Alzheimer's disease (EOAD) constitutes of patients with age of onset earlier than 65 year-old and is known to be associated with genetic mutations. In this study, we reported the first genetic analysis of Vietnamese patients with EOAD.Materials and methods: We analyzed targeted sequencing data obtained from a cohort of 51 Vietnamese EOAD patients to identify pathogenic variants in twenty nine well-characterized neurodengerative genes.Results: We identified four missense mutations in APP/PSEN1 genes from six individuals, which accounts for 11.8% of all tested cases. Three of these mutations were previously reported as pathogenic and one mutation in the APP gene was newly identified and might be specific for Vietnamese patients. Our study also found eight individuals carrying homozygous APOE ε4 allele, the main risk factor gene for late-onset AD.Conclusions: Our findings showed that mutation rate in APP/PSEN genes in Vietnamese EOAD patients is consistent with that in other ethnic groups. Although further functional studies are required to validate the pathogenesis of the new mutations, our study demonstrated the necessity of genetic screening for EOAD patients as well as additional genetic data collection in Vietnamese population.
Subject(s)
Alzheimer Disease , Humans , Aged , Alzheimer Disease/epidemiology , Alzheimer Disease/genetics , Presenilin-1/genetics , Amyloid beta-Protein Precursor/genetics , Genetic Testing , Mutation/genetics , Asian People/genetics , Age of OnsetABSTRACT
[This corrects the article DOI: 10.1016/j.radcr.2021.04.049.].
