SORL1基因是阿尔茨海默病（AD）重要的风险基因，然而目前关于该基因对认知与脑老化的遗传机制研究还存在两个主要问题：1.SORL1基因与认知老化的关系有争议，性别在其中的调节作用不明确；2.SORL1基因作用的脑网络机制尚不清楚，尤其对默认网络的影响缺乏直接的研究证据。本项目拟以非痴呆老年人为突破口，将神经心理学测验和静息态脑功能网络技术相结合，采用纵向追踪设计，揭示SORL1基因rs2070045位点多态性与认知老化的关系，分析性别在其中的调节作用，深入考察SORL1基因对默认网络的影响及其对认知老化的预测作用。该项目的完成将有助于从理论层面揭示脑老化过程中SORL1如何引起脑功能网络的改变，阐述遗传因素对认知老化和AD的作用机制；从临床应用层面甄别认知老化的风险基因，确定AD风险基因遗传效应的影像学标记物。申请人以第一作者发表SCI论文3篇，具有相关研究基础，能保证本项目顺利完成。

The SORL1 gene has been identified to be associated with Alzheimer’s disease (AD) risk. However, two main issues need to be resolved in researching its genetic mechanism of cognitive and brain aging. First, there is controversial relationship between SORL1 gene and cognitive aging. Sex modulation of SORL1 effects on cognitive aging remains unclear. Second, the neural network mechanism of the SORL1 gene effects is not clear. There is no direct evidence that the SORL1 gene polymorphisms have impact on default mode network (DMN). In the current longitudinal study, a battery of neuropsychological scales and resting-state fMRI scans will be collected in a cohort of non-demented elderly Chinese Han population to reveal the relationship between SORL1 and cognitive aging as well as sex modulation of the gene effects. This study also aims to explore the impacts of SORL1 gene on DMN, and its prediction of cognitive aging. For theory development, this research will be helpful in revealing how the SORL1 gene polymorphisms lead to alteration of brain functional network, and in explaining the genetic mechanism of cognitive and brain aging. For clinical practice, this research has important implication in identifying the risk allele for cognitive aging, and in determining the potential imaging-based biomarkers of genetic susceptibility to AD. The investigator of this study has research experience on cognitive psychology, brain imaging, and molecular genetic studies, and has 3 SCI research paper published as the first author (totally 15 SCI papers), which will ensure the accomplishment of the current research project.