Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China.
Evidence-Based Medicine Center, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China.
Alzheimers Res Ther. 2022 Feb 14;14(1):35. doi: 10.1186/s13195-022-00977-x.
Plasma amyloid-β (Aβ) may facilitate identification of individuals with brain amyloidosis. Gut microbial dysbiosis in Alzheimer's disease (AD) is increasingly being recognized. However, knowledge about alterations of gut microbiota in preclinical AD, as well as whether the combination of plasma Aβ and gut microbiota could identify preclinical AD, remains largely unknown.
This study recruited 34 Aβ-negative cognitively normal (CN-) participants, 32 Aβ-positive cognitively normal (CN+) participants, and 22 patients with cognitive impairment (CI), including 11 patients with mild cognitive impairment (MCI) and 11 AD dementia patients. All participants underwent neuropsychological assessments and fecal microbiota analysis through 16S ribosomal RNA (rRNA) Illumina Miseq sequencing technique. Meso Scale Discovery (MSD) kits were used to quantify the plasma Aβ, Aβ, and Aβ/Aβ in CN- and CN+ participants. Using Spearman's correlation analysis, the associations of global standard uptake value rate (SUVR) with altered gut microbiota and plasma Aβ markers were separately evaluated. Furthermore, the discriminative power of the combination of gut microbiota and plasma Aβ markers for identifying CN+ individuals was investigated.
Compared with the CN- group, the CN+ group showed significantly reduced plasma Aβ (p = 0.011) and Aβ/Aβ (p = 0.003). The relative abundance of phylum Bacteroidetes was significantly enriched, whereas phylum Firmicutes and class Deltaproteobacteria were significantly decreased in CN+ individuals in comparison with that in CN- individuals. Particularly, the relative abundance of phylum Firmicutes and its corresponding SCFA-producing bacteria exhibited a progressive decline tendency from CN- to CN+ and CI. Besides, the global brain Aβ burden was negatively associated with the plasma Aβ/Aβ (r = -0.298, p = 0.015), family Desulfovibrionaceae (r = -0.331, p = 0.007), genus Bilophila (r = -0.247, p = 0.046), and genus Faecalibacterium (r = -0.291, p = 0.018) for all CN participants. Finally, the combination of plasma Aβ markers, altered gut microbiota, and cognitive performance reached a relatively good discriminative power in identifying individuals with CN+ from CN- (AUC = 0.869, 95% CI 0.782 ~ 0.955).
This study provided the evidence that the gut microbial composition was altered in preclinical AD. The combination of plasma Aβ and gut microbiota may serve as a non-invasive, cost-effective diagnostic tool for early AD screening. Targeting the gut microbiota may be a novel therapeutic strategy for AD.
This study has been registered in ClinicalTrials.gov (NCT03370744, https://www.clinicaltrials.gov ) in November 15, 2017.
血浆淀粉样蛋白-β（Aβ）可能有助于识别有脑淀粉样蛋白沉积的个体。越来越多的研究表明，阿尔茨海默病（AD）患者的肠道微生物群失调。然而，关于在临床前 AD 中肠道微生物群的改变，以及血浆 Aβ和肠道微生物群的组合是否可以识别临床前 AD，我们知之甚少。
本研究纳入了 34 名 Aβ阴性认知正常（CN-）参与者、32 名 Aβ阳性认知正常（CN+）参与者和 22 名认知障碍（CI）患者，包括 11 名轻度认知障碍（MCI）患者和 11 名 AD 痴呆患者。所有参与者均接受神经心理学评估和粪便微生物组分析，采用 16S rRNA（rRNA）Illumina Miseq 测序技术。Meso Scale Discovery（MSD）试剂盒用于定量测定 CN-和 CN+参与者的血浆 Aβ、Aβ和 Aβ/Aβ。采用 Spearman 相关分析，分别评估全球标准摄取值率（SUVR）与改变的肠道微生物群和血浆 Aβ标志物的相关性。此外，还研究了肠道微生物群和血浆 Aβ标志物的组合对识别 CN+个体的判别能力。
与 CN-组相比，CN+组的血浆 Aβ（p=0.011）和 Aβ/Aβ（p=0.003）显著降低。与 CN-个体相比，CN+个体的厚壁菌门丰度显著增加，而拟杆菌门和δ变形菌纲的丰度显著降低。特别是，从 CN-到 CN+和 CI，厚壁菌门及其相应的产生 SCFA 的细菌的相对丰度呈逐渐下降趋势。此外，大脑整体 Aβ负担与血浆 Aβ/Aβ（r=-0.298，p=0.015）、脱硫弧菌科（r=-0.331，p=0.007）、拟杆菌属（r=-0.247，p=0.046）和粪杆菌属（r=-0.291，p=0.018）呈负相关。最后，血浆 Aβ标志物、改变的肠道微生物群和认知表现的组合在识别 CN+个体与 CN-个体方面具有较好的判别能力（AUC=0.869，95%CI 0.782~0.955）。
本研究提供的证据表明，在临床前 AD 中肠道微生物组成发生了改变。血浆 Aβ和肠道微生物群的组合可能成为 AD 早期筛查的一种非侵入性、经济有效的诊断工具。靶向肠道微生物群可能是 AD 的一种新的治疗策略。
本研究于 2017 年 11 月 15 日在 ClinicalTrials.gov（NCT03370744，https://www.clinicaltrials.gov）注册。
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