Li He, Wei Meiqi, Ye Tianyuan, Liu Yiduan, Qi Dongmei, Cheng Xiaorui
Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China.
Institute of Chinese Medical Literature and Culture, Shandong University of Traditional Chinese Medicine, Jinan, China.
Front Neurol. 2022 Sep 20;13:901179. doi: 10.3389/fneur.2022.901179. eCollection 2022.
Alzheimer's disease (AD) is a heterogeneous pathological disease with genetic background accompanied by aging. This inconsistency is present among molecular subtypes, which has led to diagnostic ambiguity and failure in drug development. We precisely distinguished patients of AD at the transcriptome level.
We collected 1,240 AD brain tissue samples collected from the GEO dataset. Consensus clustering was used to identify molecular subtypes, and the clinical characteristics were focused on. To reveal transcriptome differences among subgroups, we certificated specific upregulated genes and annotated the biological function. According to RANK METRIC SCORE in GSEA, TOP10 was defined as the hub gene. In addition, the systematic correlation between the hub gene and "A/T/N" was analyzed. Finally, we used external data sets to verify the diagnostic value of hub genes.
We identified three molecular subtypes of AD from 743 AD samples, among which subtypes I and III had high-risk factors, and subtype II had protective factors. All three subgroups had higher neuritis plaque density, and subgroups I and III had higher clinical dementia scores and neurofibrillary tangles than subgroup II. Our results confirmed a positive association between neurofibrillary tangles and dementia, but not neuritis plaques. Subgroup I genes clustered in viral infection, hypoxia injury, and angiogenesis. Subgroup II showed heterogeneity in synaptic pathology, and we found several essential beneficial synaptic proteins. Due to presenilin one amplification, Subgroup III was a risk subgroup suspected of familial AD, involving abnormal neurogenic signals, glial cell differentiation, and proliferation. Among the three subgroups, the highest combined diagnostic value of the hub genes were 0.95, 0.92, and 0.83, respectively, indicating that the hub genes had sound typing and diagnostic ability.
The transcriptome classification of AD cases played out the pathological heterogeneity of different subgroups. It throws daylight on the personalized diagnosis and treatment of AD.
阿尔茨海默病（AD）是一种具有遗传背景且伴随衰老的异质性病理疾病。这种不一致性存在于分子亚型之间，导致了诊断的模糊性以及药物研发的失败。我们在转录组水平精确区分了AD患者。
我们从GEO数据集中收集了1240份AD脑组织样本。采用一致性聚类来识别分子亚型，并关注临床特征。为了揭示亚组间的转录组差异，我们鉴定了特异性上调基因并注释了生物学功能。根据GSEA中的RANK METRIC SCORE，将排名前10的基因定义为核心基因。此外，分析了核心基因与“A/T/N”之间的系统相关性。最后，我们使用外部数据集验证核心基因的诊断价值。
我们从743份AD样本中鉴定出AD的三种分子亚型，其中亚型I和III具有高危因素，亚型II具有保护因素。所有三个亚组的神经炎斑块密度都较高，亚型I和III的临床痴呆评分和神经原纤维缠结比亚型II更高。我们的结果证实了神经原纤维缠结与痴呆之间存在正相关，但与神经炎斑块无关。亚型I的基因聚集在病毒感染、缺氧损伤和血管生成方面。亚型II在突触病理学上表现出异质性，我们发现了几种重要的有益突触蛋白。由于早老素1扩增，亚型III是一个疑似家族性AD的风险亚组，涉及异常的神经发生信号、胶质细胞分化和增殖。在这三个亚组中，核心基因的最高联合诊断价值分别为0.95、0.92和0.83，表明核心基因具有良好的分型和诊断能力。
AD病例的转录组分类揭示了不同亚组的病理异质性。它为AD的个性化诊断和治疗提供了线索。
