Yaqub Amber, Mustafa Rima, Ikram M Arfan, Ghanbari Mohsen
Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 40, Rotterdam, 3015 GD, the Netherlands.
Nuffield Department of Population Health, University of Oxford, Old Road Campus, Oxford, OX3 7LF, UK.
Alzheimers Res Ther. 2025 Jul 30;17(1):179. doi: 10.1186/s13195-025-01831-6.
MicroRNAs (miRNAs) are small non-coding RNAs with a vast array of biological functions, including the regulation of gene expression. It remains to be determined whether circulatory miRNAs are associated with markers of neurodegeneration in plasma (neurofilament light chain (NfL), total tau (t-tau) and amyloid beta (Aβ)), before the clinical onset of dementia.
We included 1959 dementia-free participants of the population-based Rotterdam Study (mean age 70.5 years, 56.8% women), who visited the research center for blood sampling between 2002 and 2005. Plasma levels of 591 well-expressed circulatory miRNAs were measured by the HTG EdgeSeq Whole Transcriptome Assay, while t-tau, NfL, Aβ-40 and Aβ-42 were analysed using the Simoa NF-light and N3PA assays. We used linear regression models to determine associations between circulatory miRNAs and markers of neurodegeneration, while adjusting for potential confounders. To account for the high-dimensional structure of miRNAs, we repeated the analysis using elastic net regularization models. Finally, we performed a post-hoc in-silico analysis to study the common miRNAs between all four biomarkers, their potential target genes and their link to dementia.
We found 58 miRNAs significantly associated with t-tau, 96 miRNAs with NfL, 158 miRNAs with Aβ-40, and 83 miRNAs with Aβ-42 (all with false discovery rate (FDR)-adjusted p-value ≤ 0.05). Notably, twelve miRNAs (miR-3141, miR-7107-5p, miR-146a-5p, miR-6887-5p, miR-221-3p, miR-4681, miR-6810-3p, miR-6821-5p, miR-654-5p, miR-4486, miR-4478, miR-326) were shared among all four neurodegeneration biomarkers. Subsequent in-silico analysis showed that many of these miRNAs are expressed across various brain regions, where they have important putative target genes (e.g., SORT1, TSPAN14, ADAM17, KLF16, WDR12). A pathway analysis highlighted the Notch signalling cascade, with possible implications for the amyloid precursor protein (APP).
This population-based study revealed many circulatory miRNAs associated with biomarkers of neurodegeneration, including 12 miRNAs that were common to all, potentially offering valuable insights into regulatory pathways underlying dementia. These miRNAs could be valuable for monitoring dementia and developing effective diagnostic or therapeutic strategies.
微小RNA（miRNA）是一类具有多种生物学功能的小非编码RNA，包括基因表达调控。在痴呆临床发病前，循环miRNA是否与血浆中的神经退行性变标志物（神经丝轻链（NfL）、总tau蛋白（t-tau）和淀粉样β蛋白（Aβ））相关仍有待确定。
我们纳入了基于人群的鹿特丹研究中的1959名无痴呆参与者（平均年龄70.5岁，女性占56.8%），他们于2002年至2005年期间到研究中心进行血液采样。通过HTG EdgeSeq全转录组分析检测591种表达良好的循环miRNA的血浆水平，同时使用Simoa NF-light和N3PA分析检测t-tau、NfL、Aβ-40和Aβ-42。我们使用线性回归模型确定循环miRNA与神经退行性变标志物之间的关联，同时对潜在混杂因素进行调整。为了考虑miRNA的高维结构，我们使用弹性网络正则化模型重复分析。最后，我们进行了一项事后的计算机模拟分析，以研究所有四种生物标志物之间的共同miRNA、它们的潜在靶基因以及它们与痴呆的联系。
我们发现58种miRNA与t-tau显著相关，96种miRNA与NfL显著相关，158种miRNA与Aβ-40显著相关，83种miRNA与Aβ-42显著相关（所有均为错误发现率（FDR）调整后的p值≤0.05）。值得注意的是，12种miRNA（miR-3141、miR-7107-5p、miR-146a-5p、miR-6887-5p、miR-221-3p、miR-4681、miR-6810-3p、miR-6821-5p、miR-654-5p, miR-4486、miR-4478、miR-326）在所有四种神经退行性变生物标志物中都有共享。随后的计算机模拟分析表明，这些miRNA中的许多在不同脑区表达，在这些脑区它们有重要的假定靶基因（例如，SORT1、TSPAN14、ADAM17、KLF16, WDR12）。通路分析突出了Notch信号级联反应，这可能对淀粉样前体蛋白（APP）有影响。
这项基于人群的研究揭示了许多与神经退行性变生物标志物相关的循环miRNA，包括12种共同的miRNA，这可能为痴呆潜在的调控通路提供有价值的见解。这些miRNA对于监测痴呆以及制定有效的诊断或治疗策略可能具有重要价值。
