髓鞘是脑白质的主要组成部分，也是脑内信息快速传递的结构基础。髓鞘脱失导致的脑白质病变是老年人出现认知损害的重要危险因素。胆固醇是髓鞘的主要成分，胆固醇稳态对髓鞘的完整和功能至关重要。脑内胆固醇的清除及合成的反馈调节需依赖胆固醇24S-羟化酶（CYP46A1）将胆固醇转变为24S-羟基胆固醇（24S-OHC）而直接透过血脑屏障排出。外周血90%的24S-OHC来源于中枢神经系统，可直接反映脑内胆固醇代谢情况。本项目组前期工作已证明CYP46A1可调节认知通路关键蛋白，但CYP46A1是否可通过影响脑白质结构来作用于认知功能尚缺乏研究。本项目将探讨CYP46A1基因多态性及血浆24S-OHC水平对老年人认知功能的影响，并应用弥散张量成像技术研究脑白质微结构以明确其作用机制。本项目将对通过调节CYP46A1的功能来减缓脑白质损害、改善认知功能奠定理论基础。

White matter abnormalities caused by myelin breakdown is an important risk factor for cognitive impairment. Therefore, it is highly meaningful to investigate the mechanisms of white matter lesions. Myelin encasing axons and allowing more efficient signal transduction is a major component of the white matter, while cholesterol is an important component of myelin. Thus, brain cholesterol metabolism is essential for the integrity and normal function of myelin. Cholesterol homeostasis is dependent upon the metabolism of cholesterol to 24S-hydroxycholesterol (24S-OHC) by cholesterol 24S-hydroxylase (CYP46A1). Its ability to diffuse directly into the blood makes 24S-OHC a less invasive and direct marker of cerebral cholesterol metabolism. In our previous studies, it was suggested that CYP46A1 regulated the expression of key proteins on cognitive pathways, including NMDAR, PSD95, synapthophysin and synapsin-1. However, whether CYP46A1 could influence cognitive functions through its effects on white matter integrity is still unknown. This project will apply diffusion tensor imaging (DTI) to investigate the effects of CYP46A1 gene polymorphisms and plasma 24S-OHC levels on the white matter microstructure and cognitive impairments. This study will reveal the underlying mechanisms between CYP46A1, white matter integrity and cognitive performances. Furthermore, we aim to provide a theoretical basis for regulating the function of CYP46A1 to alleviate white matter damage and improve cognitive functions.