The Efficacy and Safety of Metformin Intervention in Elderly Overweight or Obesity With Mild Cognitive Impairment

1. The prevalence of cognitive impairment among elderly obese patients is high, and early intervention for them is of great significance. Cognitive impairment refers to the impairment of one or more aspects such as learning and memory, language, executive function, perceptual-motor function, complex attention, and social cognition, often accompanied by mental, behavioral, and personality abnormalities, including mild cognitive impairment (MCI) and dementia. Epidemiological studies have shown that the prevalence of MCI among people aged 60 and above in China is 15.5%, and the affected population reaches 38 million. Numerous studies have confirmed the clear association between obesity and cognitive impairment. The daily life of MCI patients is less interfered by cognitive deficits, but the proportion of their annual progression to dementia can reach 5-10%, which is much higher than the 1-2% incidence rate of the general population. 50% of MCI patients can develop dementia within 5 years and 20-30% of MCI patients can recover normal cognition. Therefore, early detection of MCI in elderly obese patients and timely intervention have important clinical significance and value.
2. Central nervous system insulin resistance plays a role in the pathogenesis of cognitive dysfunction. Functional magnetic resonance imaging(fMRI) can assess cognitive dysfunction by observing central insulin resistance. Currently, the mechanisms of cognitive dysfunction in elderly obese patients include the pathological physiological effects of microvascular mechanisms and fat-derived factors. Insulin not only regulates peripheral metabolism but also acts on the central nervous system to regulate cognitive function. All cell types in the brain have an insulin signaling pathway, and studies have shown that brain insulin resistance can damage the plasticity of hippocampal synapses and memory function, thereby leading to cognitive decline. The evaluation of cognitive function is usually conducted using the Montreal Cognitive Assessment Scale(Moca), which includes multiple dimensions such as memory, attention, executive function, and language function, with a maximum score of 30. The score considered for diagnosing MCI is 20-26 (education> 10 years) or 20-25 (education≤ 10 years). However, in practical work, the collection of the scale is affected by many factors. fMRI can show changes in local blood flow and metabolic activities in the brain before brain structure changes, and can deeply understand brain functional changes, which is an important means for early diagnosis of cognitive dysfunction, efficacy monitoring, and mechanism research. By combining fMRI with nasal insulin inhalation, the response of different brain regions to insulin can be observed to assess the degree of central insulin resistance. If there is no neuroimaging or neurophysiological response after nasal insulin inhalation, it indicates the presence of central nervous system insulin resistance. Previous studies have shown that improving the state of central insulin resistance can delay or reverse cognitive decline. Therefore, the central insulin resistance state observed by fMRI can be used as an objective basis for evaluating cognitive function.
3. Metformin may improve cognitive dysfunction by improving the central insulin resistance of elderly obese patients.

Metformin, as the first-line medication for type 2 diabetes, has been widely used. Basic research shows that metformin has the potential to activate the 5'AMP-activated protein kinase (AMPK) pathway, which plays a crucial role in the pathogenesis of dementia. Metformin can improve insulin resistance, reduce neuronal apoptosis, and reduce oxidative stress and inflammatory responses in the brain. Recent studies have shown that the use of metformin is associated with a significant reduction in the risk of dementia in elderly patients with type 2 diabetes. However, these studies were conducted on diabetes patients in large-scale databases, and drawing conclusions by comparing whether metformin was used or not would be affected by many interfering factors. Some earlier studies have shown that long-term use of metformin may even increase the risk of dementia. This may be related to vitamin B12 deficiency, the duration of metformin use, and the course of diabetes. Some small-sample short-term controlled studies have shown that in non-diabetic MCI patients, metformin can penetrate the blood-brain barrier and improve learning, memory, and attention. In conclusion, as a widely used traditional hypoglycemic drug, basic research suggests that metformin can improve central insulin resistance. Clinical studies in diabetes patients suggest a relatively definite possibility of improving cognitive impairment. However, there are currently few studies on the use of metformin to improve cognitive function in elderly overweight or obese patients with MCI.

Therefore, the investigators plan to conduct an intervention using an adequate dose of metformin in elderly overweight or obese patients with MCI, while using patients with simple lifestyle intervention as the control group. The investigators will use fMRI to evaluate the state of central insulin resistance as an objective basis for cognitive function assessment, reducing the limitations of cognitive scales and achieving early detection and intervention of cognitive impairment.