启动子是基因表达的“开关”，启动子区变异将会引起下游编码区基因转录活性改变，造成一些关键病理蛋白的表达异常，从而影响疾病病理的发生和进展。当前，国内外AD遗传机制研究主要集中在编码区，启动子区变异研究开展较少。
贾建平教授率领团队发现53个AD相关启动子变异，占世界23%，从基因层面上解释了AD的重要遗传规律，发表相关SCI文章48篇，引用率高达529，为世界AD启动子区变异研究提供了宝贵数据。
这些基因启动子区单核苷酸多态性(SNPs)通过改变基因表达、剪接和RNA稳定性，调控了AD的多个病理蛋白的生物学过程，影响AD关键病理过程。团队研究发现APP启动子区变异上调APP表达水平，增加AD易感。一些与Aβ代谢有关的剪切酶启动子区变异，也会促进AD发生，如ADAM基因启动子区变异可提高ADAM转录活性，促进APP裂解阻止Aβ生成，降低AD发病风险；而BACE1启动子区变异会增加BACE1表达，促进AD发生。此外，MAPT基因启动子变异增加了tau蛋白生成和神经丝轻链的沉积，促进了神经变性进程。APH-1A基因启动子多态性可导致APH-1A和γ-分泌酶活性的升高，而IDE启动子区变异降低IDE表达，这些促进了Aβ的生成，增加了AD的易感性。
启动子区变异为AD的遗传模式以及致病机制提供了关键的基础证据，更为早期基因检测和干预提供了候选靶点，提高重大疾病AD的源头防控能力，奠基实现“全民脑健康”。
作者：聂淑雅 庞亚娜
编辑：宁玉烨?梁玉梅
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