This project belongs to the field of vascular cognitive dysfunction in neurology. In our early case-control study involving more than 1,200 patients, we confirmed that hyperhomocysteinemia, hyperglycemia, and hypoxemia are important risk factors for cognitive dysfunction. At the same time, we conducted in-depth research on the mechanisms linking these risk factors to cognitive dysfunction and applied and promoted them in the clinical prevention and treatment of cognitive impairment, achieving the following innovative results: 1. For the first time at home and abroad, we confirmed that homocysteine can reduce the expression of anti-apoptotic factor 14-3-3 protein and increase the activity of calcineurin, leading to apoptosis of hippocampal neurons; overexpression of 14-3-3 protein or inhibition of calcineurin activity can reduce neuronal apoptosis. We confirmed that Homocysteine-induced neuronal apoptosis is accompanied by a decrease in the expression of intracellular protein kinase Camk2b, which can reverse neuronal apoptosis by increasing the transcriptional activity of hypoxia-inducible factor HIF. Hyperhomocysteinemia tends to lead to intracranial small vessel disease, and microhemorrhages associated with small vessel disease are the main cause of cognitive dysfunction. Based on the above research results, we propose to monitor homocysteine levels in patients with cognitive dysfunction and supplement folic acid therapy for those with high homocysteine levels. 2. For the first time at home and abroad, it has been proposed that frequent and multiple hypoxic exposures can reduce extracellular adenosine levels in neuronal cells by about 50%, leading to cognitive dysfunction. However, in this case, there is no significant change in the transcriptional activity of hypoxia-inducible factors. In studies on key proteins involved in the metabolism and transport of extracellular adenosine, We have confirmed that the mechanism behind the decrease in extracellular adenosine levels is due to frequent and multiple episodes of hypoxia, which increase the expression of the neuronal cell surface adenosine transporter ENT1. Based on the aforementioned research findings, we propose that tissue hypoxia should be actively corrected in patients with cognitive dysfunction accompanied by obstructive sleep apnea. 3. For the first time at home and abroad, we have confirmed that hyperglycemia can lead to excessive neuronal autophagy, increase extracellular Aβ deposition, and cause neuronal damage; the combination of hyperglycemia and hypoxia can significantly reduce the expression of synaptic protein Synaptophysin (Syp) and damage synaptic transmission function, leading to cognitive dysfunction, while neither hyperglycemia alone nor hypoxia alone can cause a decrease in Syp expression. Through the detection of the expression of the Syp-specific ubiquitin ligase Siah-1 and molecular biological intervention, we have confirmed that The above phenomenon is caused by the increased expression of Siah-1 due to hyperglycemia combined with hypoxia. In a clinical case-control study, we found that about 70% of diabetic patients have concomitant obstructive sleep apnea syndrome, and these patients show significant cognitive decline. Based on the aforementioned research results, we propose that for diabetic patients with cognitive dysfunction, it is necessary to reasonably control blood sugar levels and actively correct tissue hypoxia. Under the intervention of various measures mentioned above, we have reduced the dementia conversion rate in patients with mild cognitive impairment to 8%, which is significantly lower than the 12-14% reported by the American Aging, Demographics, and Memory Study (ADAMS). The aforementioned achievements have been widely applied and achieved significant effects in several top-tier hospitals in China. This project has published over 100 papers, including more than 60 SCI articles, received funding from 5 National Natural Science Foundation projects, More than 10 projects from the Shanghai Municipal Science and Technology Commission. Held training classes for 6 times, with a total of more than 3,000 trainees. Currently, the cognitive team has 2 doctoral supervisors and 3 master's supervisors, and has trained over 30 graduate students.