After the first national prescription of the new drug lencanazumab for the treatment of Alzheimer's disease, recently, the first national prescription of donenumab injection was issued at Xuanwu Hospital of Capital Medical University, which has attracted widespread attention. The emergence of these two drugs has brought new hope to Alzheimer's disease patients. What are the mechanisms of the two treatments for Alzheimer's disease? What are the challenges facing drug therapy for Alzheimer's disease? The reporter from Science and Technology Daily interviewed experts in neurology regarding this matter. Implement a precise 'garbage recycling system' for treating the brain. This system can regularly clean up the waste generated by cellular metabolism. But when the system malfunctions, toxic waste such as beta amyloid cannot be cleared in a timely manner, and over time, they will eventually block the entire "memory channel". Xing Yan, Vice Chairman and Secretary General of the Neurodegenerative Disease Professional Committee of the Chinese Microcirculation Society and Director of the Neurology Department of the Aviation General Hospital, said that these "garbage" accumulated in the brain not only damage neurons, but also trigger inflammatory reactions, leading to deteriorating brain memory and triggering Alzheimer's disease. Alzheimer's disease is currently incurable, and in the past few decades, doctors have mainly used traditional drugs such as cholinesterase inhibitors or NMDA receptor antagonists to improve patients' symptoms. Sun Yong'an, chief physician of the neurology department at Peking University First Hospital, introduced that these traditional medicines mainly improve symptoms by regulating neurotransmitters. They can alleviate some discomfort caused by "garbage accumulation", but cannot slow down the speed of "garbage" accumulation, nor can they fundamentally treat the cause. The emergence of two targeted drugs, lencamab and donenumab, has opened up a new era in the treatment of Alzheimer's disease. They can accurately identify and eliminate beta amyloid proteins in the brain, equivalent to a special cleaning team handling garbage. However, lencanavir monoclonal antibody mainly acts on β - amyloid monomers and β - amyloid oligomers (soluble β - amyloid protein), while donentinib monoclonal antibody mainly targets senile plaques (β - amyloid plaques, which are insoluble β - amyloid protein) deposited in the brain parenchyma. The stages of action of the two are different. If lencanazumab is used for upstream treatment, then donenumab is used for downstream treatment, "Sun Yong'an told reporters. One major advantage of donenumab injection is that it only requires one injection per month. This is mainly due to its larger globulin antibody molecular structure. This molecular structure has a longer half-life after entering the bloodstream and can maintain a relatively stable blood concentration in the veins, continuously clearing beta amyloid plaques in the brain parenchyma. ”Sun Yong'an said. Both lencanazumab and donenumab directly act on the pathological factors of the disease, which is expected to delay the progression of Alzheimer's disease. Their launch has breakthrough significance, which means that Alzheimer's disease has entered a new stage of disease modification therapy. ”Xing Yan stated. Clinical application is limited, however, these two drugs are not perfect either. For example, in clinical trials, donenumab has been exposed to some side effects. Sun Yong'an introduced: "The side effects of donenumab mainly include cerebral edema and microbleeds. Public research data shows that about 24% of Alzheimer's disease patients using this drug will experience cerebral edema, 31.4% of patients will experience microbleeds, while the placebo group will experience 6.1% and 13.6% respectively. However, these side effects are mainly manifested at the imaging level." The occurrence of side effects is closely related to the patient's genotype, and patients carrying specific genotypes (such as APOE4) are at higher risk. Therefore, before administering medication, doctors usually conduct genotype testing on patients, and for high-risk patients, they will strengthen brain imaging monitoring to detect and handle problems in a timely manner, "said Sun Yong'an. Although donenumab and lencamab have certain advantages in therapeutic efficacy, they face some difficulties in clinical application. Sun Yong'an explained, "On the one hand, patients can only use lencanazumab and lencanazumab if they have a clear diagnosis of Alzheimer's disease. However, to achieve a clear diagnosis, either the price is expensive or the operation is complex. On the other hand, monoclonal antibody drugs are expensive and many families cannot afford them." "Moreover, lencanazumab and lencanazumab are suitable for early-stage mild Alzheimer's disease patients, but have poor efficacy for moderate to severe patients. ”Xing Yan said. Due to multiple factors, traditional medication is still the main treatment for Alzheimer's disease. However, traditional drug therapy and targeted drug therapy are not contradictory. Targeted drugs and traditional drugs can usually be used in combination because they treat Alzheimer's disease from different mechanisms, "Xing Yan emphasized. The etiology of Alzheimer's disease is complex, involving factors such as β - amyloid deposition, abnormal phosphorylation of tau protein, neuroinflammation, and vascular factors. So, for Alzheimer's disease, only multi-target comprehensive treatment can achieve better results, "said Sun Yong'an. Prevention and treatment require a multi pronged approach. Although the launch of two new drugs, lencamab and donenumab, has brought new hope to patients, if we want to further overcome the treatment difficulties of Alzheimer's disease, we still need to make breakthroughs in the treatment of tau protein lesions. The degree of tau protein pathology is related to the severity of Alzheimer's disease - the more severe the tau protein pathology in the brain, the more severe the patient's symptoms. If drugs targeting tau protein lesions can be successfully developed, the improvement in symptoms may be more significant than clearing beta amyloid protein. ”Sun Yong'an said. However, the development of drugs targeting tau protein is difficult. On the one hand, tau protein is an intracellular structure, and related drugs need to first cross the blood-brain barrier to enter the brain parenchyma, and then pass through the cell membrane to reach the lesion site inside the cell. On the other hand, in the process of clearing abnormal tau proteins, drugs also need to retain normal tau proteins, which is a complex process. So far, drugs developed for tau protein lesions have not been successful. ”Sun Yong'an said. However, in the long run, there is still hope for breakthroughs in the treatment of Alzheimer's disease. In terms of disease understanding, many researchers are conducting related scientific research. In addition to studying the toxicity and severity of pathological proteins, they are also studying the impact of other factors on the progression of the disease. Once the influencing factors are identified, intervention targets can be found. In terms of treatment strategies, some traditional Chinese medicines are also used to treat Alzheimer's disease. In addition, the medical community has also accumulated some clinical experience in surgical treatment of Alzheimer's disease. Some cases have shown that surgery has short-term improvements in behavioral abnormalities, emotions, and language in Alzheimer's disease patients, but the long-term efficacy is still unclear. Currently, a nationwide multicenter double-blind controlled study has been initiated to clarify the indications and efficacy of surgery, "Xing Yan said. Researchers have made some progress in the early identification and diagnosis of Alzheimer's disease. For example, research has found that plasma tau 217 levels are highly consistent with A β - PET or cerebrospinal fluid tau protein levels during lumbar puncture, and can be used for early screening to improve early diagnostic accuracy. In addition, various auxiliary diagnostic technologies are constantly developing, such as intelligent cognitive assessment tools, imaging analysis algorithms, etc. Xing Yan suggested that plasma biomarkers related to brain health be included in physical examination items, "especially for high-risk populations over 65 years old or with specific genes or family medical histories, early screening should be done to achieve early screening, diagnosis, and treatment of Alzheimer's disease." Xing Yan also called for increasing investment in drug research and development for Alzheimer's disease and raising public awareness of Alzheimer's disease. Regular exercise, healthy diet, and staying away from smoking and alcohol are beneficial for preventing the occurrence of Alzheimer's disease, "she said. (New Society)