Application of Yangxue Oral Solution in the Preparation of Drugs for Improving Memory and / or Cognitive Function in Preclinical Alzheimer's Disease Patients

Abstract

This invention relates to the field of biopharmaceutical technology, specifically to the application of Yangxue Oral Liquid in the preparation of a drug for improving memory and / or cognitive function in preclinical Alzheimer's disease patients. This application, through a randomized, double-blind, placebo-controlled clinical trial, demonstrates that the marketed traditional Chinese medicine Yangxue Oral Liquid can target and enhance the gyral complexity (gyriization index, GI) of the entorhinal cortex and posterior cingulate cortex in preclinical Alzheimer's disease patients, suggesting that it can promote positive changes in cortical structure and ultimately improve memory and cognitive function in preclinical Alzheimer's disease patients, providing a new strategy for early intervention in preclinical Alzheimer's disease.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical technology, specifically to the use of Yangxue Oral Liquid in the preparation of a drug for improving memory and / or cognitive function in preclinical Alzheimer's disease patients. Background Technology

[0002] Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly worldwide. The preclinical stage—when Aβ pathology is positive but cognition has not yet declined significantly—is considered the golden window for intervention. Early AD pathology preferentially damages the core brain regions of the default mode network (DMN), namely the entorhinal cortex and posterior cingulate cortex. This pathology is mainly manifested by the degeneration of gyral folds and a decrease in gyral complexity (gyriization index GI), accompanied by cortical atrophy, neuroinflammation, positive Aβ (β-amyloid) pathology, elevated p-tau protein, decreased brain oxygenation, and gut microbiota imbalance, eventually progressing to the dementia stage.

[0003] Currently, the main clinically approved drugs for the treatment of Alzheimer's disease (AD) are cholinesterase inhibitors (such as donepezil and rivastigmine) and NMDA receptor antagonists (such as memantine). The former compensates for the function of cholinergic neurons by increasing the level of acetylcholine in the synaptic cleft, while the latter protects the remaining neurons by blocking the excitotoxicity of glutamate. Both types of drugs can only improve cognitive symptoms or delay functional decline to a certain extent. Their targets are limited to the neurotransmitter level, and they still have limitations in Aβ deposition, tau pathology, neuroinflammation, gyral degeneration, and brain structural remodeling, and cannot stop the pathological progression of AD.

[0004] Gyral complexity (gyralization index, GI) is a sensitive, quantitative, and visual imaging biomarker for early brain structural damage in Alzheimer's disease (AD). Its changes precede gray matter volume, objectively reflecting the effectiveness of cortical structural remodeling. Traditional Chinese medicine (TCM), with its synergistic effects across multiple components, targets, and pathways, demonstrates unique potential in intervening in the complex pathological network of Alzheimer's disease. However, among currently marketed TCM preparations, no clinical studies have proven their ability to specifically target and increase the gyral complexity (GI) of the entorhinal cortex and posterior cingulate cortex in preclinical Alzheimer's patients. Furthermore, data on early structural remodeling interventions based on multimodal brain imaging evidence are lacking. Research on TCM interventions targeting the critical intervention window of preclinical Alzheimer's disease, with gyral complexity as the core imaging outcome indicator, remains incomplete.

[0005] The main functions of Yangxue Oral Liquid (active ingredients: ferrous sulfate, sea buckthorn, hawthorn, jujube) are to nourish blood and qi, strengthen the spleen and stomach. However, there are currently no reports on the efficacy of Yangxue Oral Liquid in improving memory and / or cognitive function in preclinical Alzheimer's disease patients. Summary of the Invention

[0006] The purpose of this invention is to provide an application of Yangxue Oral Liquid in the preparation of a drug for improving memory and / or cognitive function in preclinical Alzheimer's disease patients. It confirms that the marketed traditional Chinese medicine Yangxue Oral Liquid can target and increase the gyral complexity (gyriization index, GI) of the entorhinal cortex and posterior cingulate cortex in preclinical Alzheimer's disease patients, suggesting that it may promote positive changes in the structure of the cerebral cortex and ultimately improve the memory and cognitive function of preclinical Alzheimer's disease patients, providing a new strategy for early intervention in preclinical Alzheimer's disease.

[0007] This application provides the use of a blood-nourishing oral liquid in the preparation of a medicament for improving memory and / or cognitive function in preclinical Alzheimer's disease patients.

[0008] Yangxue Oral Liquid can significantly improve episodic memory, working memory and overall cognitive function in preclinical AD patients, providing direct clinical evidence for expanding the indications of preclinical AD early intervention for existing Chinese patent medicines.

[0009] Preferably, the preclinical Alzheimer's disease patient is Aβ-PET positive and has normal cognitive function or only subjective cognitive decline.

[0010] This application precisely targets the preclinical AD population who are Aβ-PET positive but whose cognition has not yet significantly declined—the "golden window" for AD intervention. The intervention effect of Yangxue Oral Liquid was verified in this population, filling a gap in the field of preclinical AD early intervention research for marketed traditional Chinese medicines.

[0011] Preferably, the improvement in memory and / or cognitive function includes at least one of episodic memory, working memory, and overall cognitive function.

[0012] The oral liquid for nourishing blood showed statistically significant improvement effects on multiple cognitive dimensions, including episodic memory (AVLT-H), working memory (n-back task), and overall cognitive function (MoCA, MMSE), indicating that the drug has a comprehensive effect on improving memory and / or cognitive function in preclinical AD patients.

[0013] Preferably, the improvement in memory and / or cognitive function includes improvement in assessment results of at least one of the following scales: AVLT-H delayed recall, n-back task, MoCA, MMSE.

[0014] This application validated the effects of Yangxue Oral Liquid on improving memory and / or cognitive function from different dimensions using four internationally recognized standardized neuropsychological scales (AVLT-H, n-back, MoCA, and MMSE). The evaluation system is complete, objective, and reproducible, enhancing the credibility of the clinical data.

[0015] Preferably, the drug increases the gyriization index (GI) and / or gyri complexity of the entorhinal cortex and / or posterior cingulate cortex in the patient's brain.

[0016] Early pathological changes in Alzheimer's disease (AD) preferentially affect brain regions such as the entorhinal cortex, temporal pole, and insula. These regions are not only the earliest targets of AD pathological damage but also the "windows" through which drug intervention is most effective. Traditional AD imaging studies mainly focus on changes in cortical thickness. Through multimodal brain imaging data analysis of preclinical AD patients, the applicant discovered that the effect of Yangxue oral liquid is not only to delay cortical atrophy (i.e., "protective thickness" in the traditional sense) but also to significantly improve the microstructural complexity of the gyri—that is, to increase the gyrification index (GI). Specifically, Yangxue oral liquid can significantly increase the gyrification index (GI) of the entorhinal cortex and / or posterior cingulate cortex in preclinical Alzheimer's disease patients (P < 0.05), increase the number and depth of gyral folds, improve gyral flattening and cortical atrophy, and achieve positive changes in the structure of the cerebral cortex. This discovery transcends the traditional cognitive framework of AD research, elevating the evaluation of efficacy from "delaying atrophy" to the level of "structural remodeling," and providing a completely new imaging evaluation dimension for early intervention in AD.

[0017] Preferably, the drug increases the level of oxyhemoglobin (HbO) in the patient's frontal lobe and / or posterior cingulate cortex.

[0018] The oral solution for nourishing blood increases the level of oxyhemoglobin (HbO) in the prefrontal cortex and posterior cingulate cortex, enhances the activation of the n-back task brain region, significantly enhances the functional connectivity of the default mode network (DMN), and improves the neural activity and functional synergy of the entorhinal cortex-hippocampus-posterior cingulate cortex circuit.

[0019] Preferably, the drug reduces the level of at least one of the following Alzheimer's disease-related biomarkers in the patient's plasma: p-tau217, neurofilament light chain protein (NfL), and glial fibrillary acidic protein (GFAP).

[0020] The blood-nourishing oral liquid can significantly reduce the levels of p-tau217, NfL and GFAP, the core pathological markers of AD, in the plasma of preclinical AD patients, and promote the improvement of Aβ to normal levels, thus supporting its role in intervening in the pathological process of AD from a hematological perspective.

[0021] Preferably, the drug downregulates the levels of TNF-α and / or IL-6 in the patient's serum.

[0022] The blood-nourishing oral liquid can downregulate serum TNF-α and IL-6 levels, inhibit neuroinflammatory responses, and protect the structural and functional integrity of neurons and synapses.

[0023] Preferably, the drug improves the diversity of gut microbiota α and / or the composition of gut microbiota in patients.

[0024] Yangxue oral liquid can improve the diversity and composition of gut microbiota in preclinical AD patients, increase the abundance of beneficial bacteria and reduce the abundance of pathogenic bacteria. Correlation analysis showed that the improvement of microbiota was significantly positively correlated with positive changes in brain structure (GI enhancement) and cognitive function improvement, and positively regulated brain structure and brain function through the brain-gut axis mechanism.

[0025] In summary, this application proposes the following complete mechanism of action of Yangxue Oral Liquid in improving memory and / or cognitive function in preclinical Alzheimer's disease patients: "Targeting key brain regions → remodeling cortical structure → improving brain oxygenation and function → inhibiting neuroinflammation → regulating gut microbiota → improving core AD pathology → ultimately improving memory and cognitive function." Through the synergistic effects of the above multiple targets and pathways, Yangxue Oral Liquid ultimately achieves a comprehensive improvement in episodic memory, working memory, and overall cognitive function, suggesting that Yangxue Oral Liquid may delay the progression of preclinical AD to the dementia stage.

[0026] Preferably, the drug comprises a pharmaceutically acceptable carrier and / or excipient.

[0027] Yangxue Oral Liquid is a marketed traditional Chinese medicine with a well-established safety profile, and therefore does not require long-term toxicological evaluation.

[0028] Preferably, the dosage form of the drug includes an oral formulation.

[0029] The blood-nourishing oral liquid described in this application can be prepared into oral dosage forms such as oral liquid, powder, tablet, capsule, granule, and ointment using conventional pharmaceutical processes.

[0030] Oral formulations are convenient for long-term use by patients, have high compliance, and can directly expand new indications for early intervention in AD in the preclinical stage. They also have a short conversion cycle and high feasibility for clinical promotion.

[0031] In summary, this application has the following beneficial effects: (1) This application demonstrates through a randomized, double-blind, placebo-controlled clinical trial that the marketed traditional Chinese medicine Yangxue Oral Liquid can target and enhance the gyriine complexity (gyriation index, GI) of the entorhinal cortex and posterior cingulate cortex in preclinical Alzheimer's disease patients, achieving reversible remodeling at the brain structural level. This discovery breaks through the limitation of existing AD treatment drugs that are only for symptomatic relief, and provides a new strategy for early intervention in preclinical AD.

[0032] (2) This application is based on a randomized, double-blind, placebo-controlled parallel clinical trial of 60 preclinical AD patients. It adopts a multi-dimensional evaluation system including multimodal brain imaging (sMRI, rs-fMRI, fNIRS), blood AD biomarkers, gut microbiota and cognitive scales. The data is complete, the evidence chain is closed, and it has a high level of evidence-based medicine.

[0033] (3) This application systematically verified the positive intervention effects of Yangxue Oral Liquid in the following multiple dimensions: Brain structural imaging: The gyriization index (GI) of the entorhinal cortex and posterior cingulate cortex was significantly increased (P < 0.05). Brain functional imaging: The level of oxyhemoglobin (HbO) in the prefrontal cortex and posterior cingulate cortex was significantly elevated, and the functional connectivity of the default mode network (DMN) was enhanced (P<0.05). Inflammation: Serum TNF-α and IL-6 were significantly downregulated (P<0.05), with a decrease of 38% to 42%; The core blood markers of AD were: significantly decreased plasma p-tau217, NfL, and GFAP, and the Aβ42 / 40 ratio tended to normalize (P < 0.05). Gut microbiota: α-diversity of gut microbiota was significantly increased, the abundance of beneficial bacteria was increased, and it was significantly positively correlated with GI improvement and cognitive improvement (P < 0.05). Cognitive function: The scores of AVLT-H delayed recall, N-back working memory, MoCA, and MMSE scales were all significantly better than those of the placebo group (P<0.05). The aforementioned multidimensional markers corroborate each other, forming a complete chain of evidence: "brain structural remodeling → brain function recovery → cognitive function enhancement".

[0034] (4) Yangxue oral liquid exerts a multi-target intervention effect on preclinical AD through a complete cascade pathway of “targeting key brain regions → reshaping cortical structure → improving brain oxygenation and function → inhibiting neuroinflammation → regulating gut microbiota → improving AD core pathology → ultimately improving memory and cognitive function”, suggesting that Yangxue oral liquid may help delay the progression of preclinical AD to dementia.

[0035] (5) Yangxue Oral Solution is a marketed traditional Chinese medicine (National Drug Approval Number B20020043), with a well-established safety profile. It does not require long-term toxicological evaluation and can be directly expanded to include new indications for early intervention in preclinical Alzheimer's disease. The conversion cycle is short, and clinical promotion is highly feasible. Therefore, the application provided in this application offers a new approach for preparing drugs to improve memory and / or cognitive function in preclinical Alzheimer's patients. Detailed Implementation

[0036] The following will provide a clear and complete description of the technical solutions of this invention. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0037] Preparation Example Preparation of Blood-Nourishing Oral Solution: The sea buckthorn, hawthorn, and jujube used in this preparation example are all pharmaceutical grade processed slices with a moisture content of no more than 12%; the ferrous sulfate is pharmaceutical grade ferrous sulfate, and the vitamin C, sucrose, sulfuric acid, sodium hydroxide, and citric acid all meet the standards for pharmaceutical excipients or food grade; the conductivity of the purified water is no more than 10 μS / cm.

[0038] Sea buckthorn, hawthorn, and jujube were cleaned, crushed to a particle size of 2-5 mm, mixed, and then decocted in 4000 mL of purified water for 1.5 h. The decoction was then filtered to obtain the first decoction. The residue was then decocted in 3200 mL of purified water for 1 h and filtered to obtain the second decoction. The first and second decoctions were combined and concentrated under reduced pressure at -0.08 MPa to a concentration of 1 g of crude drug per mL. The concentrate was then cooled to 25 °C. Ethanol was added to the concentrate to bring the alcohol content to 70%. The mixture was stirred at 300 r / min for 30 min and allowed to stand at 4 °C for 12 h. The supernatant was then filtered and the supernatant was collected. The ethanol in the supernatant was recovered under reduced pressure below 55 °C until no alcohol odor remained, yielding the first decoction. Add 5.3g of ferrous sulfate to 50mL of sulfuric acid aqueous solution (mass concentration of 0.1%), stir for 20min at 25℃ and 300r / min to dissolve it, filter, add 5g of vitamin C to the filtrate and continue stirring for 10min to obtain the second solution; Take 200g of sucrose, add purified water to make a simple sugar syrup with a mass concentration of about 60%, filter it, add the first and second drug solutions, and mix well; add 0.5g of sodium hydroxide, and adjust the pH to 3.7 with citric acid, add purified water to make up to 1000mL, stir well, let stand for 30min, filter, fill, and sterilize according to routine procedures to obtain the blood-nourishing oral liquid. Example

[0039] A randomized, double-blind, placebo-controlled clinical trial of blood-nourishing oral liquid for the intervention of preclinical Alzheimer's disease. 1. Experimental subjects This clinical trial was approved by the relevant hospital's ethics committee, and all subjects or their legal representatives signed informed consent forms.

[0040] Sixty preclinical Alzheimer's disease subjects diagnosed by Aβ-PET (standardized uptake ratio SUVr ≥ 1.2) were selected. They were aged 60 to 80 years, had normal cognitive function or only subjective cognitive decline, and did not meet the diagnostic criteria for mild cognitive impairment (MCI).

[0041] The groups were randomly assigned in a 1:1 ratio using a random number table method. Experimental group: 30 cases, treated with blood-nourishing oral liquid; Placebo group: 30 patients, who received oral placebo intervention.

[0042] There were no statistically significant differences between the experimental group and the placebo group in terms of age, sex, education level, baseline cognitive score, and Aβ-PET standardized uptake ratio (SUVr) (P>0.05), making them comparable.

[0043] 2. Intervention methods Both groups of participants maintained basic lifestyle interventions and did not use other nootropic drugs, antidementia drugs, or anti-inflammatory drugs during the trial.

[0044] Experimental group: Oral administration of blood-nourishing oral liquid, 1 bottle (10mL) each time, twice a day, after breakfast and dinner, for 3 consecutive months; Placebo group: Oral placebo liquid (appearance, taste, and packaging are the same as blood-nourishing oral liquid), usage, dosage, and course of treatment are the same as the experimental group.

[0045] 3. Observation indicators and detection methods 3.1 Brain structural imaging indicators T1-weighted three-dimensional structural images of subjects before and after treatment were acquired using a 3.0T superconducting magnetic resonance imaging system. Surface-based morphometry (SBM) analysis was used to calculate the local gyrification index (LGI), cortical thickness, and gyral complexity of the entorhinal cortex and posterior cingulate cortex. The LGI is the local measurement value of the gyrification index (GI) in different brain regions as described in this application.

[0046] 3.2 Brain functional imaging indicators The changes in oxyhemoglobin (HbO) concentration in the frontal lobe and posterior cingulate cortex of subjects before and after treatment were detected using functional near-infrared spectroscopy (fNIRS).

[0047] 3.3 Default Mode Network Function Connection Analysis Resting-state functional magnetic resonance imaging (rs-fMRI) was used to acquire resting-state brain functional imaging data of subjects before and after treatment. Using the posterior cingulate cortex (PCC) as a seed point, the functional connectivity strength between the PCC and brain regions such as the entorhinal cortex and hippocampus was calculated to assess changes in the functional connectivity of the default mode network (DMN).

[0048] 3.4 Cognitive Function Assessment The following neuropsychological scales were used to assess all subjects before and after treatment: Auditory Vocabulary Learning Test (AVLT-H): assesses episodic memory function, with delayed recall score as the main analytical indicator; N-back task: Assess working memory function; Montreal Cognitive Assessment (MoCA): assesses overall cognitive function; Mini-Mental State Examination (MMSE): assesses overall cognitive function.

[0049] 3.5 Detection of inflammatory factors Fasting venous blood was collected from subjects before and after treatment. Serum was separated and serum levels were detected by enzyme-linked immunosorbent assay (ELISA).

[0050] 3.6 Alzheimer's Disease Blood Biomarker Detection The levels of phosphorylated tau protein 217 (p-tau217), neurofilament light chain protein (NfL), and glial fibrillary acidic protein (GFAP) in the plasma of subjects before and after treatment were measured using ultrasensitive single-molecule immunoassay.

[0051] 3.7 Gut microbiota analysis Fecal samples were collected from subjects before and after treatment. Genomic DNA of gut microbiota was extracted, and 16S rRNA gene high-throughput sequencing technology was used to analyze the α diversity (Shannon index, Simpson index) and composition structure of gut microbiota.

[0052] 4. Statistical Methods Data analysis was performed using SPSS 26.0 statistical software. Quantitative data were expressed as mean ± standard deviation (x ± s). Paired t-tests were used for comparisons within groups before and after treatment, and independent samples t-tests or mixed-effects models were used for comparisons between groups. A p-value < 0.05 was considered statistically significant.

[0053] 5. Experimental Results 5.1 Significantly increased complexity of brain gyri Compared with the placebo group, the intervention in the experimental group significantly increased the regional gyriization index (LGI) of the entorhinal cortex and posterior cingulate cortex (P < 0.05). Increased cortical thickness, shallower sulci, and more and deeper gyral folds suggest that Yangxue oral liquid can effectively improve gyral flattening in preclinical AD patients and promote positive improvement in cortical structure.

[0054] 5.2 Significant improvement in brain oxygenation level and brain function Compared with the placebo group, the concentrations of oxyhemoglobin (HbO) in the prefrontal cortex and posterior cingulate cortex were significantly increased in the experimental group after intervention (P < 0.05), and activation of brain regions for N-back working memory tasks was enhanced. Functional connectivity of the default mode network (DMN) was significantly enhanced, and the function of the entorhinal cortex-hippocampus-posterior cingulate cortex circuit was improved.

[0055] 5.3 Significant improvement in memory and cognitive function Compared with the placebo group, the experimental group showed significantly better performance in AVLT-H delayed recall score, N-back working memory task performance, MoCA score and MMSE score after intervention, with statistically significant differences (P < 0.05).

[0056] 5.4 Inflammatory factor levels were significantly downregulated Compared with the placebo group, the serum levels of TNF-α and IL-6 in the experimental group were significantly reduced after intervention, and the difference was statistically significant (P<0.05). The reduction of TNF-α and IL-6 was 38% to 42%, respectively, suggesting that Yangxue oral liquid can effectively inhibit neuroinflammatory response.

[0057] 5.5 Significant improvement in Alzheimer's disease blood markers and Aβ pathology. Compared with the placebo group, the levels of plasma p-tau217, NfL, and GFAP in the experimental group decreased significantly after intervention, with statistically significant differences (P < 0.05); the plasma Aβ42 / 40 ratio showed an improving trend towards normal levels. These results indicate that Yangxue Oral Solution can effectively improve the levels of core pathological markers of Alzheimer's disease (AD), supporting its role in intervening in the pathological process of AD from a hematological perspective.

[0058] 5.6 Significantly improved gut microbiota structure Compared with the placebo group, the experimental group showed a significant increase in gut microbiota α diversity (Shannon index, Simpson index) after intervention (P < 0.05), an increase in the relative abundance of beneficial bacteria, and a decrease in the relative abundance of pathogenic bacteria. Correlation analysis showed a significant positive correlation between improved gut microbiota structure and improved brain gyral complexity (GI) and cognitive function scores (P < 0.05), suggesting that Yangxue oral liquid may positively regulate brain structure and function through the "brain-gut axis" mechanism.

[0059] 5.7 Security During the trial, no abnormalities were found in the blood routine, liver and kidney function, or other safety indicators in both groups of subjects, and no significant adverse reactions related to the test drug were observed, indicating that Yangxue Oral Liquid has good safety and tolerability in the preclinical AD population.

[0060] This application is based on a randomized, double-blind, placebo-controlled parallel clinical trial involving 60 preclinical Alzheimer's disease (AD) patients. Using a multimodal brain imaging system (sMRI, rs-fMRI, fNIRS), blood AD biomarkers, gut microbiota, and cognitive scales, it demonstrates that the marketed traditional Chinese medicine Yangxue Oral Liquid can target and improve the gyral complexity (gyriization index, GI) of the entorhinal cortex and posterior cingulate cortex in preclinical Alzheimer's patients, increase the level of oxyhemoglobin (HbO) in the prefrontal cortex and posterior cingulate cortex, enhance the functional connectivity of the default mode network (DMN), downregulate serum TNF-α and IL-6 levels, and reduce plasma AD nuclei. This drug improves cardiovascular biomarkers, gut microbiota structure, and scores on AVLT-H delayed recall, N-back working memory, MoCA, and MMSE scales. It exerts a multi-target intervention effect on preclinical AD through a complete cascade pathway: targeting key brain regions → reshaping cortical structure → improving brain oxygenation and function → inhibiting neuroinflammation → regulating gut microbiota → improving core AD pathology → ultimately improving memory and cognitive function. This overcomes the limitations of existing AD treatments that only provide symptomatic relief, suggesting that Yangxue Oral Liquid may help delay the progression of preclinical AD to dementia, providing a novel strategy for early intervention in preclinical AD. Yangxue Oral Liquid is a marketed traditional Chinese medicine (National Drug Approval Number B20020043) with a well-established safety profile. It does not require long-term toxicology evaluation and can directly expand into new indications for early intervention in preclinical AD, with a short conversion cycle and high feasibility for clinical promotion.

[0061] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. The use of a blood-nourishing oral liquid in the preparation of a drug for improving memory and / or cognitive function in preclinical Alzheimer's disease patients.

2. The application according to claim 1, characterized in that, The preclinical Alzheimer's disease patients were Aβ-PET positive and had normal cognitive function or only subjective cognitive decline.

3. The application according to claim 1 or 2, characterized in that, The improvement of memory and / or cognitive function includes at least one of episodic memory, working memory, and overall cognitive function.

4. The application according to any one of claims 1 to 3, characterized in that, The improvement in memory and / or cognitive function includes improvement in assessment results of at least one of the following scales: AVLT-H delayed recall, n-back task, MoCA, MMSE.

5. The application according to any one of claims 1 to 4, characterized in that, The drug increases the gyriization index (GI) and / or gyri complexity of the entorhinal cortex and / or posterior cingulate cortex in the patient's brain.

6. The application according to any one of claims 1 to 5, characterized in that, The drug increases the level of oxyhemoglobin (HbO) in the patient's frontal lobe and / or posterior cingulate cortex.

7. The application according to any one of claims 1 to 6, characterized in that, The drug reduces the level of at least one of the following Alzheimer's disease-related biomarkers in the patient's plasma: p-tau217, neurofilament light chain protein (NfL), and glial fibrillary acidic protein (GFAP).

8. The application according to any one of claims 1 to 7, characterized in that, The drug downregulates serum TNF-α and / or IL-6 levels in patients.

9. The application according to any one of claims 1 to 8, characterized in that, The drug improves the diversity of gut microbiota α and / or the composition of gut microbiota in patients.

10. The application according to any one of claims 1 to 9, characterized in that, The drug includes a pharmaceutically acceptable carrier and / or excipient; and / or, the dosage form of the drug includes an oral formulation.