Blood exosomes, which are extracellular vesicles secreted by living cells into the circulating blood, are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states. An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer's disease. Therefore, we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease. We performed a literature search in PubMed, Web of Science, Embase, and Cochrane Library from their inception to August 15, 2020. The research subjects mainly included Alzheimer's disease, mild cognitive impairment, and preclinical Alzheimer's disease. We identified 34 observational studies, of which 15 were included in the quantitative analysis (Newcastle-Ottawa Scale score 5.87 points) and 19 were used in the qualitative analysis. The meta-analysis results showed that core biomarkers including Aβ1-42, P-T181-tau, P-S396-tau, and T-tau were increased in blood neuron-derived exosomes of preclinical Alzheimer's disease, mild cognitive impairment, and Alzheimer's disease patients. Molecules related to additional risk factors that are involved in neuroinflammation (C1q), metabolism disorder (P-S312-IRS-1), neurotrophic deficiency (HGF), vascular injury (VEGF-D), and autophagy-lysosomal system dysfunction (cathepsin D) were also increased. At the gene level, the differential expression of transcription-related factors (REST) and microRNAs (miR-132) also affects RNA splicing, transport, and translation. These pathological changes contribute to neural loss and synaptic dysfunction. The data confirm that the above-mentioned core molecules and additional risk-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer's disease. These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer's disease. This meta-analysis was registered at the International Prospective Register of Systematic Reviews (Registration No. CRD4200173498, 28/04/2020).

中文翻译：

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临床前和临床阿尔茨海默病的新兴基于血液外泌体的生物标志物：荟萃分析和系统评价。

血液外泌体是活细胞分泌到循环血液中的细胞外囊泡，被认为是一种用于监测大脑生理和疾病状态的相对无创的新型工具。越来越多的载血外泌体正在成为临床前和临床阿尔茨海默病的潜在生物标志物。因此，我们对源自血液外泌体的分子生物标志物进行了荟萃分析和系统评价，以全面分析其在临床前阿尔茨海默病、轻度认知障碍和阿尔茨海默病中的诊断性能。我们在 PubMed、Web of Science、Embase 和 Cochrane 图书馆从它们成立到 2020 年 8 月 15 日进行了文献检索。研究对象主要包括阿尔茨海默病、轻度认知障碍、和临床前阿尔茨海默病。我们确定了 34 项观察性研究，其中 15 项纳入定量分析（Newcastle-Ottawa 量表得分 5.87 分），19 项用于定性分析。荟萃分析结果显示，包括 Aβ1-42、P-T181-tau、P-S396-tau 和 T-tau 在内的核心生物标志物在临床前阿尔茨海默病、轻度认知障碍和阿尔茨海默病的血液神经元衍生外泌体中增加患者。与神经炎症 (C1q)、代谢紊乱 (P-S312-IRS-1)、神经营养缺乏 (HGF)、血管损伤 (VEGF-D) 和自噬-溶酶体系统功能障碍（组织蛋白酶 D ) 也增加了。在基因水平上，转录相关因子 (REST) 和 microRNA (miR-132) 的差异表达也会影响 RNA 剪接、转运和翻译。这些病理变化导致神经损失和突触功能障碍。数据证实，血液外泌体中的上述核心分子和其他风险相关因素可以作为临床前和临床阿尔茨海默病的候选生物标志物。这些发现支持进一步开发用于阿尔茨海默病临床血液检测的外泌体生物标志物。该荟萃分析已在国际系统评价前瞻性登记册（注册号 CRD4200173498，2020 年 4 月 28 日）注册。数据证实，血液外泌体中的上述核心分子和其他风险相关因素可以作为临床前和临床阿尔茨海默病的候选生物标志物。这些发现支持进一步开发用于阿尔茨海默病临床血液检测的外泌体生物标志物。该荟萃分析已在国际系统评价前瞻性登记册（注册号 CRD4200173498，2020 年 4 月 28 日）注册。数据证实，血液外泌体中的上述核心分子和其他风险相关因素可以作为临床前和临床阿尔茨海默病的候选生物标志物。这些发现支持进一步开发用于阿尔茨海默病临床血液检测的外泌体生物标志物。该荟萃分析已在国际系统评价前瞻性登记册（注册号 CRD4200173498，2020 年 4 月 28 日）注册。