Cao Jixin, Zhang Cheng, Lo Chun-Yi Zac, Guo Qihao, Ding Jing, Luo Xiaohui, Zhang Zi-Chao, Chen Feng, Cheng Tian-Lin, Chen Jingqi, Zhao Xing-Ming
Department of Neurology, Zhongshan Hospital and Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.
Institute for Translational Brain Research, Fudan University, Shanghai, China.
Alzheimers Dement. 2025 Feb;21(2):e14444. doi: 10.1002/alz.14444. Epub 2024 Dec 23.
Increasing evidence has highlighted rare variants in Alzheimer's disease (AD). However, insufficient sample sizes, especially in underrepresented ethnic groups, hinder their investigation. Additionally, their impact on endophenotypes remains largely unexplored.
We prioritized rare likely-deleterious variants based on whole-genome sequencing data from a Chinese AD cohort (n = 988). Gene-based optimal sequence kernel association tests were conducted between AD cases and normal controls to identify AD-related genes. Network clustering, endophenotype association, and cellular experiments were conducted to evaluate their functional consequences.
We identified 11 novel AD candidate genes, which captured AD-related pathways and enhanced AD risk prediction performance. Key genes (RABEP1, VIPR1, RPL3L, and CABIN1) were linked to cognitive decline and brain atrophy. Experiments showed RABEP1 p.R845W inducing endocytosis dysregulation and exacerbating toxic amyloid β accumulation, underscoring its therapeutic potential.
Our findings highlighted the contributions of rare variants to AD and provided novel insights into AD therapeutics.
Identified 11 novel AD candidate genes in a Chinese AD cohort. Correlated candidate genes with AD-related cognitive and brain imaging traits. Indicated RABEP1 p.R845W as a critical AD contributor in the endocytic pathway.
越来越多的证据凸显了阿尔茨海默病（AD）中的罕见变异。然而，样本量不足，尤其是在代表性不足的种族群体中，阻碍了对它们的研究。此外，它们对中间表型的影响在很大程度上仍未得到探索。
我们基于一个中国AD队列（n = 988）的全基因组测序数据，对罕见的可能有害变异进行了优先级排序。在AD病例和正常对照之间进行基于基因的最优序列核关联检验，以确定与AD相关的基因。进行了网络聚类、中间表型关联和细胞实验，以评估它们的功能后果。
我们鉴定出11个新的AD候选基因，这些基因涵盖了与AD相关的通路，并提高了AD风险预测性能。关键基因（RABEP1、VIPR1、RPL3L和CABIN1）与认知衰退和脑萎缩有关。实验表明，RABEP1 p.R845W诱导内吞失调并加剧有毒淀粉样β的积累，突出了其治疗潜力。
我们的发现突出了罕见变异对AD的贡献，并为AD治疗提供了新的见解。
在中国AD队列中鉴定出11个新的AD候选基因。将候选基因与AD相关的认知和脑成像特征相关联。表明RABEP1 p.R845W是内吞途径中AD的关键促成因素。
