The extracellular RNAs (exRNAs) from human biofluid have recently been systematically characterized. However, the correlations of biofluid exRNA levels and human diseases remain largely untested. Here, considering the unmet need for presymptomatic biomarkers of sporadic Alzheimer's disease (AD), we leveraged the recently developed SILVER-seq (small-input liquid volume extracellular RNA sequencing) technology to generate exRNA profiles from a longitudinal collection of human plasma samples. These 164 plasma samples were collected from research subjects 70 years or older with up to 15 years of clinical follow-up prior to death and whose clinical diagnoses were confirmed by pathological analysis of their post mortem brains. The exRNAs of AD-activated genes and transposons in the brain exhibited a concordant trend of increase in AD plasma in comparison with age-matched control plasma. However, when we required statistical significance with multiple testing adjustments, phosphoglycerate dehydrogenase (PHGDH) was the only gene that exhibited consistent upregulation in AD brain transcriptomes from 3 independent cohorts and an increase in AD plasma as compared to controls. We validated PHGDH's serum exRNA and brain protein expression increases in AD by using 5 additional published cohorts. Finally, we compared the time-course exRNA trajectories between "converters" and controls. Plasma PHGDH exRNA exhibited presymptomatic increases in each of the 11 converters during their transitions from normal to cognitive impairment but remained stable over the entire follow-up period in 8 out of the 9 control elderly subjects. These data suggest the potential utilities of plasma exRNA levels for screening and longitudinal exRNA changes as a presymptomatic indication of sporadic AD.

中文翻译：

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血浆中细胞外 RNA 的症状前增加与阿尔茨海默病的发展有关。

最近系统地表征了来自人类生物体液的细胞外 RNA (exRNA)。然而，生物流体 exRNA 水平与人类疾病的相关性在很大程度上仍未得到检验。在这里，考虑到对散发性阿尔茨海默病 (AD) 症状前生物标志物的未满足需求，我们利用最近开发的 SILVER-seq（小输入液体体积细胞外 RNA 测序）技术从纵向收集的人血浆样本中生成 exRNA 谱。这 164 份血浆样本是从 70 岁或以上的研究对象中收集的，这些研究对象在死亡前进行了长达 15 年的临床随访，并且其临床诊断通过其死后大脑的病理分析得到证实。与年龄匹配的对照血浆相比，大脑中 AD 激活基因和转座子的 exRNA 表现出 AD 血浆增加的一致趋势。然而，当我们需要多次测试调整的统计显着性时，磷酸甘油酸脱氢酶 (PHGDH) 是唯一一个在 3 个独立队列的 AD 脑转录组中表现出一致上调的基因，与对照组相比，AD 血浆增加。我们通过使用另外 5 个已发表的队列验证了 PHGDH 的血清 exRNA 和脑蛋白表达在 AD 中的增加。最后，我们比较了“转化者”和对照之间的时间进程 exRNA 轨迹。血浆 PHGDH exRNA 在 11 名转化者从正常到认知障碍的过渡期间表现出症状前增加，但在 9 名对照老年受试者中的 8 名在整个随访期间保持稳定。这些数据表明血浆 exRNA 水平在筛选和纵向 exRNA 变化方面的潜在效用，作为散发性 AD 的症状前指示。