The new scheme of Chinese experts' consensus on Alzheimer's disease diagnosis and treatment has been released!

01 diagnostic methods of ad induced MCI
The diagnosis and differential diagnosis of ad derived MCI can be divided into five links: history collection, physical examination, neuropsychological evaluation, humoral examination and imaging examination. Among them, history collection, physical examination and neuropsychological evaluation belong to disease screening, while humoral examination and imaging examination have more clinical significance.
Body fluid examination is usually divided into blood examination and cerebrospinal fluid examination. At present, cerebrospinal fluid examination is widely used in clinical practice. However, due to sampling and other problems, this method is often applicable to patients whose diseases have been identified. Therefore, in order to achieve the purpose of early detection, diagnosis and Prevention of AD, blood examination should be promoted to the clinical stage as soon as possible.
In the fourth part of consensus 2021 on blood examination, blood examination is proposed for the first time. In addition to general examination of blood, the detection of biological markers related to ad has also become a hot topic.
With the development of new disease modification therapy for AD, non-invasive, low-cost, hematology based biomarker detection has become a hot research direction. Detection based on single ⁃ molecular array (also known as simoa Technology) β⁃ Amyloid 42 (amyloid β⁃ protein 42，A β 42)、 β⁃ Amyloid 40 (amyloid β⁃ protein 40，A β 40). Phosphorylated tau (P ⁃ tau) 181 and neurofilament light chain (NFL) were proved to have significant correlation with cerebrospinal fluid and PET results, which may replace cerebrospinal fluid and imaging examination. At present, these indicators have been incorporated into the framework of AD research standard ATN.
A β It is a characteristic marker in the pathological process of AD. a β 42/A β 40 ratio compared to a β 42 or a β 40, more valuable in predicting the conversion of normal people to MCI or ad (AUC = 0.77).
Hyperphosphorylation of tau protein is another typical pathological manifestation of AD. According to the recent longitudinal data of a large prospective elderly cohort in the Alzheimer's disease neuroimaging program (ADNI), plasma P ⁃ tau181 was found in cerebrospinal fluid and pet, respectively β The abnormal level of plasma P ⁃ tau181 was reached 6.5 and 5.7 years before the abnormality, suggesting that plasma P ⁃ tau181 can be used as a new diagnostic and screening tool for the pre dementia stage of AD. Plasma P ⁃ tau181 is also a marker that can be used to monitor neurodegeneration and cognitive decline, and has specificity for AD. at present, the plasma p-tau 181 index has been recognized by the U.S. FDA in October 2021 as a breakthrough auxiliary method to diagnose the progress and prognosis of AD.
NFL is a marker of axonal injury. Plasma NFL had changed 10 years before clinical symptoms such as cognitive impairment appeared. The rapid increase of plasma NFL level in MCI patients is related to faster hippocampal atrophy, lower glucose metabolic rate and faster overall cognitive deterioration.
Recommendation:
(1) Plasma a β 42/A β 40. P ⁃ tau217, P ⁃ tau181 and NFL can be used for early diagnosis of ad derived MCI and evaluation of disease progression (class IIa recommendation, class a evidence).
(2) Cerebrospinal fluid a β 42、A β 42/A β 40. P ⁃ tau181, P ⁃ tau217, t ⁃ tau and NFL can be used for the early diagnosis of ad derived MCI and the evaluation of disease progression (level I recommendation, level a evidence).
In terms of imaging examination, MRI structural images can show different lesions such as cerebral infarction, white matter lesions, brain tumors, hydrocephalus, and brain atrophy, which help to diagnose the cause of MCI and monitor the progress of MCI.
The most common local changes in AD - induced MCI are atrophy of hippocampus and entorhinal cortex. 18F ⁃ FDG ⁃ pet and SPECT in patients with AD induced MCI mainly showed decreased glucose metabolism and perfusion in hippocampus, temporoparietal lobe and posterior cingulate gyrus. 18F ⁃ FDG ⁃ pet is useful for early diagnosis and can be used as an effective imaging marker for the progress of ad derived MCI.
So far, the European drug administration and the US Food and drug administration have approved three fluorinated a β⁃ PET tracers (18F ⁃ flubendabi, 18F ⁃ flubendabine and 18F ⁃ flubendamol) were used in clinic.
Pathological mechanism and main clinical manifestations of ad derived MCI
The etiological hypothesis of ad derived MCI mainly includes a β Amyloid hypothesis, tau protein hyperphosphorylation hypothesis, prion like transmission hypothesis, a β Interaction with cerebrovascular abnormalities and neuroinflammatory hypothesis.
Ad is a continuous disease spectrum, including preclinical AD, ad derived MCI, mild AD, moderate AD and severe AD. The long preclinical stage of ad occurs 10-20 years before clinical symptoms, when a β It began to deposit gradually in the precuneus and cerebral cortex, followed by low metabolism, tau pathology and hippocampal volume reduction in these areas, and finally showed cognitive impairment. Paying attention to the etiology and pathological mechanism of ad derived MCI, finding and managing ad derived MCI as soon as possible will help to maintain the existing cognitive function of patients for a longer time and delay the deterioration of the disease.
The main clinical manifestations of ad induced MCI are divided into three parts, namely, cognitive impairment, mild impairment of complex instrumental daily ability, and non cognitive neuropsychiatric symptoms.
The prevalence of non cognitive neuropsychiatricsymptoms (NPS) is between 35% and 85%, which can occur in the early stage of MCI patients, even earlier than cognitive impairment. However, some symptoms are not obvious, which are easy to be ignored by the patients themselves, their families and doctors.
Among the common NPs in MCI patients, the prevalence of apathy, depression and anxiety is relatively high. The occurrence of NPs is an important indicator to predict the conversion of MCI to AD. the more the number and severity of NPs symptoms, the greater the risk of conversion to AD and the faster the speed of conversion. However, the risks of conversion from NPs to AD are different.
03 non drug and drug treatment of ad derived MCI
Non drug treatment mainly includes the following aspects:
1. lifestyle intervention:
The results of relevant clinical trials showed that lifestyle interventions such as diet (such as Mediterranean diet, control of tobacco and alcohol intake) and improvement of sleep quality were beneficial to MCI patients;
2. cognitive intervention and multimodal intervention:
The results of meta-analysis showed that cognitive training 5~6 times a week for 1 hour was helpful to improve the overall cognitive function of MCI patients;
3. sports training:
Meta analysis found that aerobic exercise could improve the overall cognitive function of MCI patients;
4. other therapies:
Repetitive transcranial magnetic stimulation (rTMS) provides a series of pulses in the form of rhythm and repetition to regulate neural activity and cortical excitability. In addition, music can also improve the cognitive function of MCI patients.
The main points of drug treatment are as follows:
At present, there is no drug approved for the treatment of ad derived MCI. Try to use AD treatment drugs and take a β Antibody based immunotherapy and secretase inhibitors were used to intervene ad derived MCI.
DMT of ad focuses on the clearance of pathological proteins, mainly including a β And tau protein. For a β The whole human IgG1 monoclonal antibody aducanumab (biib037) can target with a β Aggregate binding promotes microglia phagocytosis and clearance of a β， The two phase III clinical studies included 2661 patients with AD derived MCI. The results showed that:
The primary end point of the emergency trial was reached after 78 weeks. The deterioration of the clinical dementia rating scale ⁃ sum of boxes in the high-dose group was slower than that in the placebo group, and the cognitive ability, mental behavior and instrumental daily ability of the patients were improved; A β⁃ The results of pet and tau protein in cerebrospinal fluid confirmed that the level of biomarkers decreased in a dose-dependent manner in the high-dose group.
Another targeted soluble a β The humanized IgG1 antibody lecanemab (ban2401) of fibrils showed good safety and tolerability in the phase 2B clinical trial. The 18 month analysis results for the ad derived MCI population showed that a β Significantly reduced, cognitive decline improved. Others for a β Phase III studies such as gantenerumab are also in progress.
    
New drugs under development for tau protein are divided into small molecule inhibitors, monoclonal antibodies against tau protein, vaccines, etc. Lmtm (trx0237) is a small molecule tau protein aggregation inhibitor, which can prevent tau protein aggregation. The results of two clinical studies on all-cause dementia and AD were negative.
Other tau protein drugs entering phase II clinical stage include monoclonal antibodies semolinemab and zagotenemab (ly3303560). Tau protein vaccine aadvac1 effectively reduced the production of P ⁃ tau in patients with mild AD in the phase II clinical study.
Drug treatment recommendations:
(1) Cholinesterase inhibitor donepezil can delay the progression of ad derived MCI to ad in the early stage, but its long-term effect still needs more large-scale clinical trials (class IIa recommendation, class B evidence).
(2) For a β DMT with monoclonal antibodies (such as aducanumab) may be an effective treatment for ad derived mCi (class IIa recommendation, class B evidence).
(3) Drugs that reshape the balance of intestinal flora (such as mannate sodium) can reduce the metabolites of peripheral related amino acids, reduce cerebral neuroinflammation, improve cognitive function, and may improve ad derived mCi (level IIb recommendation, level B evidence).
(4) Ginkgo biloba extract EGb761 improves the cognitive function of AD, but its effect on ad derived MCI still needs to be studied in large sample clinical trials (IIB recommendation, B evidence).
(5) Patients with AD induced MCI need to pay attention to emotional disorders (anxiety, depression, etc.) and deal with them in time, which may benefit from reducing the risk of MCI to AD. Donepezil can delay the progression of ad derived MCI to ad with depression (level IIA recommendation, level B evidence).
(6) For ad MCI patients with abnormal gait and risk of falling, donepezil may benefit (level IIA recommendation, level B evidence).
(7) When antipsychotics are used to treat NPs of ad derived MCI, the risk of cognitive decline must be weighed (expert consensus).
04 prevention of ad induced MCI
The prevention of ad induced MCI is divided into primary prevention and secondary prevention. Primary prevention is to determine the controllable risk factors of ad derived MCI and reduce the risk to prevent the occurrence of MCI or the pathophysiological progress of ad derived MCI; Secondary prevention is to prevent the conversion from MCI to ad through early detection of pathological markers and intervention in the preclinical stage of AD.
Primary prevention aims to reduce the controllable risk of ad induced MCI. The strategies include lifestyle intervention, comorbidity treatment, dietary supplement and multi field intervention. The results of systematic review and meta-analysis of existing studies show that maintaining a healthy weight, more physical exercise and mental activities, quitting smoking, ensuring good sleep, controlling hypertension, preventing and treating comorbidities (diabetes, cerebrovascular diseases, atrial fibrillation, etc.) are all effective measures for primary prevention. Studies have shown that the risk of ad induced MCI can also be reduced by strengthening adult continuing education and learning and improving intellectual level.
Secondary prevention is to initiate mechanism based intervention to block potential pathophysiological changes and prevent the occurrence and development of cognitive impairment symptoms. Secondary prevention through the use of pre clinical biomarkers (i.e., a β And tau protein deposition). These individuals are ideal candidates to participate in the secondary prevention trial.
For secondary prevention, experts recommend:
(1) Reasonable diet, regular physical and mental exercise, good sleep, control of blood pressure, prevention and treatment of diabetes, cerebrovascular diseases, atrial fibrillation, etc. are helpful for the prevention of ad induced mCi (level I recommendation, level B evidence).
(2) At present, there is no effective secondary prevention measure for ad induced mCi (class IIa recommendation, class B evidence).