Shigemizu Daichi, Akiyama Shintaro, Mitsumori Risa, Niida Shumpei, Ozaki Kouichi
Medical Genome Center, Research Institute, National Center for Geriatrics and Gerontology, Aichi, 474-8511, Japan.
RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, Japan.
NPJ Aging. 2022 Nov 4;8(1):15. doi: 10.1038/s41514-022-00096-9.
Mild cognitive impairment (MCI) is a clinical precursor of Alzheimer's disease (AD). Recent genetic studies have reported on associations between AD risk genes and immunity. Here, we obtained samples and data from 317 AD, 432 MCI, and 107 cognitively normal (CN) subjects and investigated immune-cell type composition and immune clonal diversity of T-cell receptor (TRA, TRB, TRG, and TRD) and B-cell receptor (IGH, IGK, and IGL) repertoires through bulk RNA sequencing. We found the proportions of plasma cells, γδ T cells, neutrophils, and B cells were significantly different and the diversities of IGH, IGK, and TRA were significantly small with AD progression. We then identified a differentially expressed gene, WDR37, in terms of risk of MCI-to-AD conversion. Our prognosis prediction model using the potential blood-based biomarkers for early AD diagnosis, which combined two immune repertoires (IGK and TRA), WDR37, and clinical information, successfully classified MCI patients into two groups, low and high, in terms of risk of MCI-to-AD conversion (log-rank test P = 2.57e-3). It achieved a concordance index of 0.694 in a discovery cohort and of 0.643 in an independent validation cohort. We believe that further investigation, using larger sample sizes, will lead to practical clinical use in the near future.
轻度认知障碍（MCI）是阿尔茨海默病（AD）的临床前驱症状。最近的基因研究报道了AD风险基因与免疫之间的关联。在此，我们获取了317例AD患者、432例MCI患者和107例认知正常（CN）受试者的样本及数据，并通过批量RNA测序研究了T细胞受体（TRA、TRB、TRG和TRD）和B细胞受体（IGH、IGK和IGL）库的免疫细胞类型组成及免疫克隆多样性。我们发现，随着AD病情进展，浆细胞、γδ T细胞、中性粒细胞和B细胞的比例存在显著差异，IGH、IGK和TRA的多样性显著降低。然后，我们根据MCI向AD转化的风险鉴定出一个差异表达基因WDR37。我们利用潜在的基于血液的生物标志物构建了早期AD诊断的预后预测模型，该模型结合了两个免疫库（IGK和TRA）、WDR37和临床信息，成功地将MCI患者根据MCI向AD转化的风险分为低风险和高风险两组（对数秩检验P = 2.57e - 3）。在发现队列中，其一致性指数为０.694，在独立验证队列中为０.643。我们相信，在不久的将来，通过更大样本量的进一步研究将实现其在临床中的实际应用。
