PICALM、CLU及CR1基因多态性对人脑记忆环路调控机制的多模态MRI研究

Late-onset Alzheimer' disease (LOAD) severely impaired memory function of the human brain. APOE, PICALM, CLU and CR1 are the main risk genes for LOAD. Although the effects of APOE gene polymorphism on the memory circuit of the human brain have been extensively investigated, the modulation mechanisms of PICALM, CLU and CR1 on the memory circuit remain largely unknown. Based on our previous findings of the modulation effects of the PICALM and CLU on the functional connectivity of the hippocampus in healthy young adults, we aimed to use multi-modality MRI techniques to systematically investigate the modulation mechanisms of the PICALM, CLU and CR1 on the structure and function of the memory circuit in young adults, elder subjects and patients with AD. We also want to investigate the relationships between imaging genetic findings and memory impairments in different groups. We focus on both the main effects and interactions of these genes on human memory circuit in different groups and we also hope to clarify the relationship between structural and functional impairments in the AD risk gene carriers. The study may help to determine the neural mechanisms of the main risk genes of LOAD resulting in memory impairments and facilitating the development of AD. It also help to establish imaging genetic markers that could identify risk population of LOAD at an early stage. Finally, the study may pave the way to the early diagnosis of LOAD, early treatment, and the development of related drugs.

迟发型阿尔茨海默病（LOAD）严重损害人脑记忆功能，APOE、PICALM、CLU、CR1是主要LOAD风险基因。以往，对APOE基因多态性影响人脑记忆神经环路的研究较多，而PICALM、CLU及CR1基因多态性对人脑记忆神经环路调控机制尚不清楚。本项目在前期发现PICALM和CLU影响健康青年人海马功能连接的基础上，利用多模态MRI技术系统研究PICALM、CLU及CR1基因多态性对青年人、老年人及AD患者记忆神经环路结构和功能的调控机制及其与记忆功能损害的关系。重点阐述上述基因多态性调控不同人群脑记忆神经环路的主效应及其交互效应，阐明AD风险基因携带者结构损害与功能变化的关系。该研究将有助于明确LOAD主要遗传风险因素造成记忆功能损害乃至进展为LOAD的神经机制，有助建立早期识别LOAD风险人群的影像遗传学指标，进而为LOAD患者的早期诊断、早期治疗以及相关药物的研发奠定理论基础。

迟发型阿尔茨海默病（LOAD）严重损害人脑记忆功能，APOE、PICALM、CLU等单核苷酸多态性是主要的LOAD风险基因。以往，对APOE基因多态性影响人脑记忆神经环路的研究较多，其它风险基因如PICALM、CLU、CR1、KIBRA和SOLR1等对人脑记忆神经环路调控机制尚不清楚。本项目在前期研究基础上，利用多模态MRI技术系统研究APOE、PICALM、CLU、CR1、KIBRA以及SOLR1等基因多态性对青年人、老年人及AD患者记忆神经环路结构和功能的调控机制及其与记忆功能损害的关系。重点阐述上述基因多态性调控不同人群脑记忆神经环路的主效应及其交互效应，阐明AD风险基因携带者结构损害与功能变化的关系。研究发现:（1)PICALM风险基因携带者的海马负功能连接减弱；而CLU风险基因携带者海马正负功能连接均增强；PICALM和CLU对海马负功能连接的影响存在交互效应，表现为CLU风险基因携带者海马负功能连接随PICALM风险等位基因数量的增加而逐渐减弱，而CLU保护基因携带者海马负功能连接随PICALM风险等位基因的数量增加而逐渐增强。（2) ApoE与KIBRA基因存在加性效应和上位效应两种交互作用：随着ApoE-KIBRA风险等位基因的增加，左海马旁回和右颞中回的全脑FCD减低，双侧枕中回的全脑FCD增加；在KIBRA TT基因型下，双侧背外侧前额叶的全脑FCD减低，效应具有ApoE等位基因风险依赖性；在KIBRA CT/CC基因型下，双侧背外侧前额叶的全脑FCD增加，效应亦具有ApoE等位基因风险依赖性。（3）SORL1风险等位基因携带者右侧颞下回的全局FCD小于TT保护基因携带者，并呈等位基因线性依赖效应）；SORL1的效应与APOE基因多态性无关；右侧颞下回FCD与记忆商数关系不显著。本该研究将有助于明确LOAD主要遗传风险因素造成记忆功能损害乃至进展为LOAD的神经机制，有助建立早期识别LOAD风险人群的影像遗传学指标，进而为LOAD患者的早期诊断、早期治疗以及相关药物的研发奠定理论基础。