Liu Cuicui, Cong Lin, Zhu Min, Wang Yongxiang, Tang Shi, Han Xiaojuan, Zhang Qinghua, Tian Na, Liu Keke, Liang Xiaoyan, Fa Wenxin, Wang Nan, Hou Tingting, Du Yifeng
Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Curr Alzheimer Res. 2022;19(10):724-733. doi: 10.2174/1567205020666221028112915.
Early-onset Alzheimer's disease (EOAD) is highly influenced by genetic factors. Numerous mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) have been identified for EOAD, but they can only account for a small proportion of EOAD cases.
This study aimed to screen genetic mutations and variants associated with EOAD among Han Chinese adults.
This study included 34 patients with EOAD and 26 controls from a population-based study and neurological ward. We first sequenced mutations in APP/PSENs and then performed whole-exome sequencing in the remaining patients with negative mutations in APP/PSENs to screen for additional potential genetic variants. Among patients who were negative in genetic screening tests, we further evaluated the risk burden of genes related to the Aβ metabolism-centered network to search for other probable causes of EOAD.
We identified 7 functional variants in APP/PSENs in 8 patients, including 1 APP mutation (p. Val715Met), 3 PSEN1 mutations (p. Phe177Ser; p. Arg377Met; p. Ile416Thr), and 3 PSEN2 mutations (p. Glu24Lys; p. Gly34Ser; p. Met239Thr). Of the remaining 26 EOAD cases without mutations in APP/PSENs, the proportion of carrying rare variants of genes involved in Aβ and APP metabolism was significantly higher than that of controls (84.6% vs. 73.1%, P=0.042). Thirty-one risk genes with 47 variants were identified in 22 patients. However, in 26 normal subjects, only 20 risk genes with 29 variants were identified in 19 subjects.
Our findings demonstrate the role of APP/PSENs mutations in EOAD, identifying a new PSEN2 missense mutation, and further offer valuable insights into the potential genetic mechanisms of EOAD without APP/PSENs mutations among Han Chinese.
早发型阿尔茨海默病（EOAD）受遗传因素影响很大。已确定淀粉样前体蛋白（APP）、早老素1和2（PSEN1和PSEN2）存在大量突变与EOAD相关，但它们仅占EOAD病例的一小部分。
本研究旨在筛查中国汉族成年人中与EOAD相关的基因突变和变异。
本研究纳入了来自一项基于人群的研究和神经科病房的34例EOAD患者及26例对照。我们首先对APP/PSENs中的突变进行测序，然后对APP/PSENs突变阴性的其余患者进行全外显子组测序，以筛查其他潜在的遗传变异。在基因筛查试验阴性的患者中，我们进一步评估以Aβ代谢为中心的网络相关基因的风险负担，以寻找EOAD的其他可能病因。
我们在8例患者的APP/PSENs中鉴定出7个功能性变异，包括1个APP突变（p.Val715Met）、3个PSEN1突变（p.Phe177Ser；p.Arg377Met；p.Ile416Thr）和3个PSEN2突变（p.Glu24Lys；p.Gly34Ser；p.Met239Thr）。在其余26例APP/PSENs无突变的EOAD病例中，携带Aβ和APP代谢相关基因罕见变异的比例显著高于对照组（84.6%对73.1%，P=0.042）。在22例患者中鉴定出31个风险基因，共47个变异。然而，在26例正常受试者中，仅在19例受试者中鉴定出20个风险基因，共29个变异。
我们的研究结果证明了APP/PSENs突变在EOAD中的作用，鉴定出一个新的PSEN2错义突变，并进一步为中国汉族人群中无APP/PSENs突变的EOAD潜在遗传机制提供了有价值的见解。
