流行病学研究发现，VA缺乏与胰岛素抵抗及认知功能下降密切相关，并可能是老年人MCI及AD发生的重要风险因素。课题组前期研究发现，T2DM患者血清VA水平明显低于对照组；T2DM-MCI个体较T2DM-非MCI个体血清VA水平更低，提示VA缺乏及胰岛素抵抗与MCI发生的相关关系。研究表明，VA可依赖RBP4调控STRA6及其下游信号通路影响外周组织胰岛素代谢。然而，VA是否通过RBP4/STRA6信号通路调控中枢胰岛素代谢，进而影响老年人认知功能及MCI发生目前尚不清楚。本研究以RBP4/STRA6信号通路为切入点，通过开展人群现况调查、病例对照及随访研究，探讨VA营养状况及胰岛素抵抗对老年人认知功能的影响；通过开展动物饮食干预及海马神经元体外干预实验，探讨RBP4/STRA6信号通路在VA缺乏、胰岛素抵抗促老年人MCI发生过程中的作用及机制，为揭示AD的病因及制定早期干预措施提供科学依据。

Epidemiological studies indicated that VA deficiency is closely related to insulin resistance and cognitive function decline; and might be an important risk factor for the occurrence of MCI and AD in the elderly. Our previous study found that serum VA level of patients with type 2 diabetes mellitus (T2DM) was significantly lower than that of the control subjects. Also serum VA level of T2DM-MCI individuals was lower than that of T2DM-non-MCI subjects, which suggesting the correlation between VA deficiency, insulin resistance and MCI. It is reported that VA could RBP4-dependently affect peripheral tissue insulin metabolism by regulating STRA6 and its downstream target gene expression. However, whether VA affects brain insulin metabolism through regulating the RBP4/STRA6 signaling pathway, and therefore affects cognition and involves in the development of MCI in elderly remains unclear. In this study, we take RBP4/STRA6 signaling pathway as pointcut to investigate the influences of circulating VA status and insulin resistance on cognitive function in the elderly through cross-sectional study, case control and follow-up study. Experimental animal dietary intervention and in vitro hippocampal neuron interventional experiment are also applied to explore the role of RBP4/STRA6 signaling pathway in VA deficiency and insulin resistance promoted cognitive impairment. Our work will provide scientific basis and references for revealing the etiology of AD and formulating early AD intervening measure.