Background:Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer’s disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI). Objective:To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive toearly-stage pathology as exemplified by MCI diagnosis. Methods:We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ4 allele (APOE ɛ4) genotype and amyloid-β42 to total tau ratio (Aβ42:T-Tau). We identified predicted targets of trending miRNAs using pathway analysis. Results:Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42:T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42:T-Tau was weak. Conclusion:Selected miRNAs combined with Aβ42:T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aβ42:T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers.

中文翻译：

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经验证的 MicroRNA 生物标志物在轻度认知障碍中阿尔茨海默病的表现。

背景：阿尔茨海默病 (AD) 的脑脊液 (CSF) microRNA (miRNA) 生物标志物已被鉴定，但尚未在前驱 AD 中进行评估，包括轻度认知障碍 (MCI)。目的：评估 CSF 中一组经过验证的 AD miRNA 生物标志物是否也对以 MCI 诊断为例的早期病理学敏感。方法：我们测量了来自 AD、MCI 和认知正常对照 (NC) 的 CSF 样本中 17 种 AD miRNA 生物标志物的表达。然后我们单独和组合地检查了 miRNA 的分类性能。对于每个 miRNA，我们评估了每个诊断组的中值表达，并将三组标记物分类为线性趋势、非线性趋势或缺乏任何趋势。对于趋势 miRNA，我们单独评估了多标志物分类性能，并结合载脂蛋白 E ɛ4 等位基因 (APOE ɛ4) 基因型和淀粉样蛋白-β42 与总 tau 比率 (Aβ42:T-Tau) 进行了评估。我们使用通路分析确定了趋势 miRNA 的预测目标。结果：五种 miRNA 在整个有序诊断（从 MCI 到 AD 的对照）中显示出中值表达下降的线性趋势。趋势 miRNA 共同预测 AD（曲线下面积 (AUC) 为 0.770）和 MCI（AUC 为 0.705）。Aβ42:T-Tau 单独预测 MCI，AUC 为 0.758，添加趋势 miRNA 后，AUC 提高至 0.813 (p = 0.051)。五个趋势 miRNA 与 Aβ42:T-Tau 的多变量相关性较弱。结论：选定的 miRNA 与 Aβ42:T-Tau 相结合可提高 MCI 的分类性能（相对于单独的蛋白质生物标志物），尽管与 Aβ42:T-Tau 的相关性较弱。这些数据共同表明，即使在 MCI 阶段，这些 miRNA 也携带与 AD 相关的新信息。初步目标预测分析表明这些生物标志物具有新的作用。