Application of pTau181 in plasma and combination of pTau181 in diagnosis of Alzheimer disease

Abstract

The invention discloses application of pTau181 in plasma and a combination of the pTau181 in diagnosis of Alzheimer's disease. The plasma biomarker provided by the invention is pTau181, pTau217 / pTau181, pTau181 / A beta 1-42 or pTau181 / A beta 1-40, and the detection of the plasma biomarker not only belongs to a reliable, simple and convenient non-invasive means, but also can efficiently evaluate the disease risk of the Alzheimer's disease. The invention is easy to widely apply clinically and has important application value.

Description

Technical Field

[0001] The present invention belongs to the field of medical care informatics, and specifically relates to the application of pTau181 and a combination thereof in plasma in diagnosing Alzheimer's disease. Background Art

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disease with an insidious onset. It is the most common form of dementia, with a continuously increasing incidence and an increasing socioeconomic burden. It is a major medical and social problem that threatens the health of urban and rural residents in my country. In my country, about 10% of people over 60 years old suffer from AD, and the prevalence of AD in people over 90 years old can be as high as 20%. With the aggravation of aging, the number of AD patients has a trend of continuous growth (Ren Rujing, Yin Peng, Wang Zhihui, et al. China Alzheimer's Disease Report 2021 [J]. Diagnostics Theory and Practice, 2021, 20 (4): 317-337.). The clinical manifestations of AD mainly include memory impairment, aphasia, apraxia, agnosia, and visual-spatial ability impairment. It is the only incurable disease among the top ten causes of death worldwide. Therefore, early identification and early intervention of AD are very important.

[0003] In 2018, the National Institute of Aging (NIA) and the Alzheimer's Association (AA) proposed the ATN biomarker research diagnostic criteria for Alzheimer's disease (abbreviated as the ATN standard). The introduction of this standard has greatly promoted the diagnosis and treatment of early Alzheimer's disease and brought important breakthroughs to research in related fields. The standard comprehensively considers multiple biomarkers such as β-amyloid protein (Aβ), phosphorylated tau protein (Ptau) and neuron-specific enolase (NFL), providing an important basis for the diagnosis of early Alzheimer's disease.

[0004] Although cerebrospinal fluid biomarkers and positron emission tomography (PET) technology can detect early pathological changes in Alzheimer's disease, their invasiveness, high cost, and radioactive safety issues limit their widespread application. New specific plasma biomarkers for Alzheimer's disease can easily and quickly achieve early detection of Alzheimer's disease biomarkers, and because of their advantages of being non-invasive, economical, and highly accurate, they have been included in the new version of the expert consensus. At present, relevant research on the detection of new plasma biomarkers for AD diagnosis has been carried out in various parts of the world, but there are great differences in the cut-off values ​​reported between different analysis platforms and laboratories. Therefore, the development of plasma biomarkers for the diagnosis of Alzheimer's disease has important application value. Summary of the invention

[0005] The purpose of the present invention is to assess the risk of Alzheimer's disease or evaluate the possibility of pathological changes of Alzheimer's disease occurring in the brain.

[0006] The present invention first protects plasma biomarkers, which include pTau181.

[0007] The plasma biomarker may specifically be pTau181.

[0008] Any of the above-mentioned plasma biomarkers may also include pTau217. The plasma biomarkers may specifically consist of pTau181 and pTau217.

[0009] Preferably, the plasma biomarker may be pTau217 / pTau181; and pTau217 / pTau181 is the concentration ratio of pTau217 and pTau181.

[0010] Any of the above-mentioned plasma biomarkers may also include Aβ1-42. The plasma biomarkers may specifically consist of pTau181 and Aβ1-42.

[0011] Preferably, the plasma biomarker may be pTau181 / Aβ1-42; and pTau181 / Aβ1-42 is the concentration ratio of pTau181 and Aβ1-42.

[0012] Any of the above-mentioned plasma biomarkers may also include Aβ1-40. The plasma biomarkers may specifically consist of pTau181 and Aβ-40.

[0013] Preferably, the plasma biomarker may be pTau181 / Aβ1-40; and pTau181 / Aβ1-40 is the concentration ratio of pTau181 and Aβ1-40.

[0014] The detection object of any of the above-mentioned plasma biomarkers can be plasma.

[0015] The use of any of the above-mentioned plasma biomarkers in the preparation of a product for assessing the risk of Alzheimer's disease or a product for evaluating the possibility of Alzheimer's disease pathological changes in the brain also falls within the scope of protection of the present invention.

[0016] The present invention also protects the use of substance A, substance B, substance C or substance D in the preparation of a product for assessing the risk of Alzheimer's disease or a product for evaluating the possibility of pathological changes of Alzheimer's disease occurring in the brain.

[0017] The substance A may be a substance for detecting the concentration of pTau181 in plasma.

[0018] The substance B may be a substance for detecting the concentration of pTau217 and pTau181 in plasma.

[0019] The substance C may be a substance for detecting the concentration of pTau181 and Aβ1-42 in plasma.

[0020] The substance D may be a substance for detecting the concentration of pTau181 and Aβ1-40 in plasma.

[0021] The present invention also protects a data processing device for evaluating the risk of a subject suffering from Alzheimer's disease or evaluating the possibility of pathological changes of Alzheimer's disease occurring in the brain of the subject, which may be data processing device 1, data processing device 2, data processing device 3 or data processing device 4.

[0022] The data processing device 1 may include the following modules:

[0023] (1) a data receiving module; the data receiving module is configured to receive the content of pTau181 in the plasma of the subject;

[0024] (2) a data processing module; the data processing module is configured to receive the content of pTau181 in the plasma of the subject from the data receiving module;

[0025] (3) a data storage module; the data storage module is configured to store the judgment threshold;

[0026] (4) a data comparison module; the data comparison module is configured to receive pTau181 sent by the data processing module, and call the judgment threshold from the data storage module for comparison with pTau181;

[0027] (5) a judgment module; the judgment module is configured to receive the comparison result sent by the data comparison module, judge the comparison result according to a predetermined judgment condition, and output the judgment result;

[0028] The predetermined judgment condition is: if the pTau181 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain.

[0029] In the data processing device 1, the judgment threshold stored in the data storage module may specifically be 3.135 pg / ml.

[0030] The data processing device 1 may specifically be composed of any of the above-mentioned data receiving modules, any of the above-mentioned data processing modules, any of the above-mentioned data storage modules, any of the above-mentioned data comparison modules and any of the above-mentioned judgment modules.

[0031] The data processing device 1 may further include a control module or a controller; the control module or the controller is used to control each module.

[0032] The data processing device 1 may specifically be composed of any of the above-mentioned data receiving modules, any of the above-mentioned data processing modules, any of the above-mentioned data storage modules, any of the above-mentioned data comparison modules, any of the above-mentioned judgment modules and a control module (or controller).

[0033] In the data processing device 1, the content of pTau181 in the plasma of the subject to be tested received by the data receiving module can be obtained according to a method comprising the following steps: collecting peripheral blood of the subject to be tested, separating the plasma, and then detecting the content of pTau181 in the plasma.

[0034] The data processing device 2 may include the following modules:

[0035] (1) a data receiving module; the data receiving module is configured to receive the content of pTau217 and the content of pTau181 in the plasma of the subject;

[0036] (2) a data processing module; the data processing module is configured to receive the content of pTau217 and the content of pTau181 in the plasma of the subject from the data receiving module, and calculate the ratio of the content of pTau217 to the content of pTau181, which is recorded as pTau217 / pTau181;

[0037] (3) a data storage module; the data storage module is configured to store the judgment threshold;

[0038] (4) a data comparison module; the data comparison module is configured to receive pTau217 / pTau181 sent by the data processing module, and call the judgment threshold from the data storage module for comparison with pTau217 / pTau181;

[0039] (5) a judgment module; the judgment module is configured to receive the comparison result sent by the data comparison module, judge the comparison result according to a predetermined judgment condition, and output the judgment result;

[0040] The predetermined judgment condition is: if the pTau217 / pTau181 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of pathological changes of Alzheimer's disease in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of pathological changes of Alzheimer's disease in the brain.

[0041] In the data processing device 2, the judgment threshold stored in the data storage module may specifically be 0.101.

[0042] The data processing device 2 can be specifically composed of any of the above-mentioned data receiving modules, any of the above-mentioned data processing modules, any of the above-mentioned data storage modules, any of the above-mentioned data comparison modules and any of the above-mentioned judgment modules.

[0043] The data processing device 2 may further include a control module or a controller; the control module or the controller is used to control each module.

[0044] The data processing device 2 can be specifically composed of any of the above-mentioned data receiving modules, any of the above-mentioned data processing modules, any of the above-mentioned data storage modules, any of the above-mentioned data comparison modules, any of the above-mentioned judgment modules and a control module (or controller).

[0045] In the data processing device 2, the content of pTau217 and the content of pTau181 in the plasma of the subject to be tested received by the data receiving module can be obtained according to a method including the following steps: collecting peripheral blood of the subject to be tested, separating the plasma, and then detecting the content of pTau217 and the content of pTau181 in the plasma.

[0046] The data processing device 3 may include the following modules:

[0047] (1) a data receiving module; the data receiving module is configured to receive the content of pTau181 and the content of Aβ1-42 in the plasma of the subject;

[0048] (2) a data processing module; the data processing module is configured to receive the pTau181 content and the Aβ1-42 content in the plasma of the subject from the data receiving module, and calculate the ratio of the pTau181 content to the Aβ1-42 content, which is recorded as pTau181 / Aβ1-42;

[0049] (3) a data storage module; the data storage module is configured to store the judgment threshold;

[0050] (4) a data comparison module; the data comparison module is configured to receive pTau181 / Aβ1-42 sent by the data processing module, and call the judgment threshold from the data storage module for comparison with pTau181 / Aβ1-42;

[0051] (5) a judgment module; the judgment module is configured to receive the comparison result sent by the data comparison module, judge the comparison result according to a predetermined judgment condition, and output the judgment result;

[0052] The predetermined judgment condition is: if the pTau181 / Aβ1-42 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of pathological changes of Alzheimer's disease in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of pathological changes of Alzheimer's disease in the brain.

[0053] In the data processing device 3, the judgment threshold stored in the data storage module may specifically be 0.132.

[0054] The data processing device 3 may specifically be composed of any of the above-mentioned data receiving modules, any of the above-mentioned data processing modules, any of the above-mentioned data storage modules, any of the above-mentioned data comparison modules and any of the above-mentioned judgment modules.

[0055] The data processing device 3 may further include a control module or a controller; the control module or the controller is used to control each module.

[0056] The data processing device 3 can be specifically composed of any of the above-mentioned data receiving modules, any of the above-mentioned data processing modules, any of the above-mentioned data storage modules, any of the above-mentioned data comparison modules, any of the above-mentioned judgment modules and a control module (or controller).

[0057] In the data processing device 3, the content of pTau181 and the content of Aβ1-42 in the plasma of the subject received by the data receiving module can be obtained according to a method including the following steps: collecting peripheral blood of the subject, separating the plasma, and then detecting the content of pTau181 and the content of Aβ1-42 in the plasma.

[0058] The data processing device 4 may include the following modules:

[0059] (1) a data receiving module; the data receiving module is configured to receive the content of pTau181 and the content of Aβ1-40 in the plasma of the subject;

[0060] (2) a data processing module; the data processing module is configured to receive the pTau181 content and the Aβ1-40 content in the plasma of the subject from the data receiving module, and calculate the ratio of the pTau181 content to the Aβ1-40 content, which is recorded as pTau181 / Aβ1-40;

[0061] (3) a data storage module; the data storage module is configured to store the judgment threshold;

[0062] (4) a data comparison module; the data comparison module is configured to receive the pTau181 / Aβ1-40 sent by the data processing module, and call the judgment threshold from the data storage module for comparison with the pTau181 / Aβ1-40;

[0063] (5) a judgment module; the judgment module is configured to receive the comparison result sent by the data comparison module, judge the comparison result according to a predetermined judgment condition, and output the judgment result;

[0064] The predetermined judgment condition is: if the pTau181 / Aβ1-40 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain.

[0065] In the data processing device 4, the judgment threshold stored in the data storage module may specifically be 0.010.

[0066] The data processing device 4 may specifically be composed of any of the above-mentioned data receiving modules, any of the above-mentioned data processing modules, any of the above-mentioned data storage modules, any of the above-mentioned data comparison modules and any of the above-mentioned judgment modules.

[0067] The data processing device 4 may further include a control module or a controller; the control module or the controller is used to control each module.

[0068] The data processing device 4 can be specifically composed of any of the above-mentioned data receiving modules, any of the above-mentioned data processing modules, any of the above-mentioned data storage modules, any of the above-mentioned data comparison modules, any of the above-mentioned judgment modules and a control module (or controller).

[0069] In the data processing device 4, the pTau181 content and Aβ1-40 content in the plasma of the subject received by the data receiving module can be obtained according to a method including the following steps: collecting peripheral blood of the subject, separating the plasma, and then detecting the pTau181 content and Aβ1-40 content in the plasma.

[0070] The present invention also protects a system for evaluating the risk of Alzheimer's disease or the possibility of Alzheimer's disease pathological changes in the brain, which may include control device 1, control device 2, control device 3 or control device 4.

[0071] The control device 1 is configured or programmed to perform the following steps:

[0072] Receiving the content of pTau181 in the plasma of the subject to be tested;

[0073] Comparing the pTau181 content in the plasma of the subject to be tested with the judgment threshold value to obtain a comparison result;

[0074] Determine the comparison result according to a predetermined determination condition and output the determination result;

[0075] The predetermined judgment condition is: if the pTau181 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain.

[0076] Furthermore, the system including the control device 1 also includes an input device and an output device; the input device is configured to input the content of pTau181 in the plasma of the subject to be tested; and the output device is configured to output the determination result.

[0077] The control device 2 is configured or programmed to perform the following steps:

[0078] Receiving the content of pTau217 and the content of pTau181 in the plasma of the subject to be tested;

[0079] According to the content of pTau217 and the content of pTau181 in the plasma of the test subject, the ratio of the content of pTau217 to the content of pTau181 is calculated, and recorded as pTau217 / pTau181;

[0080] Comparing the pTau217 / pTau181 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result;

[0081] Determine the comparison result according to a predetermined determination condition and output the determination result;

[0082] The predetermined judgment condition is: if the pTau217 / pTau181 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of pathological changes of Alzheimer's disease in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of pathological changes of Alzheimer's disease in the brain.

[0083] Furthermore, the system including the control device 2 also includes an input device and an output device; the input device is configured to input the content of pTau217 and the content of pTau181 in the plasma of the subject to be tested; and the output device is configured to output the determination result.

[0084] The control device 3 is configured or programmed to perform the following steps:

[0085] Receiving the content of pTau181 and Aβ1-42 in the plasma of the test subject;

[0086] According to the content of pTau181 and the content of Aβ1-42 in the plasma of the test subject, the ratio of the content of pTau181 to the content of Aβ1-42 is calculated, and recorded as pTau181 / Aβ1-42;

[0087] Comparing the pTau181 / Aβ1-42 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result;

[0088] Determine the comparison result according to a predetermined determination condition and output the determination result;

[0089] The predetermined judgment condition is: if the pTau181 / Aβ1-42 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of pathological changes of Alzheimer's disease in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of pathological changes of Alzheimer's disease in the brain.

[0090] Furthermore, the system including the control device 3 also includes an input device and an output device; the input device is configured to input the content of pTau181 and the content of Aβ1-42 in the plasma of the subject; and the output device is configured to output the determination result.

[0091] The control device 4 is configured or programmed to perform the following steps:

[0092] Receiving the content of pTau181 and Aβ1-40 in the plasma of the test subject;

[0093] According to the content of pTau181 and the content of Aβ1-40 in the plasma of the test subject, the ratio of the content of pTau181 to the content of Aβ1-40 is calculated, and recorded as pTau181 / Aβ1-40;

[0094] Comparing the pTau181 / Aβ1-40 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result;

[0095] Determine the comparison result according to a predetermined determination condition and output the determination result;

[0096] The predetermined judgment condition is: if the pTau181 / Aβ1-40 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain.

[0097] Furthermore, the system including the control device 4 also includes an input device and an output device; the input device is configured to input the content of pTau181 and the content of Aβ1-40 in the plasma of the subject to be tested; and the output device is configured to output the determination result.

[0098] The present invention also protects a computer-readable storage medium, wherein the computer-readable storage medium stores a computer program for executing the following steps:

[0099] The step may be step 1, step 2, step 3 or step 4.

[0100] The step 1 may be:

[0101] Receiving the content of pTau181 in the plasma of the subject to be tested;

[0102] Comparing the pTau181 content in the plasma of the subject to be tested with the judgment threshold value to obtain a comparison result;

[0103] Determine the comparison result according to a predetermined determination condition and output the determination result;

[0104] The predetermined judgment condition is: if the pTau181 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain.

[0105] The step 2 may be:

[0106] Receiving the content of pTau217 and the content of pTau181 in the plasma of the subject to be tested;

[0107] According to the content of pTau217 and the content of pTau181 in the plasma of the test subject, the ratio of the content of pTau217 to the content of pTau181 is calculated, and recorded as pTau217 / pTau181;

[0108] Comparing the pTau217 / pTau181 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result;

[0109] Determine the comparison result according to a predetermined determination condition and output the determination result;

[0110] The predetermined judgment condition is: if the pTau217 / pTau181 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of pathological changes of Alzheimer's disease in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of pathological changes of Alzheimer's disease in the brain.

[0111] The step 3 may be:

[0112] Receiving the content of pTau181 and Aβ1-42 in the plasma of the test subject;

[0113] According to the content of pTau181 and the content of Aβ1-42 in the plasma of the test subject, the ratio of the content of pTau181 to the content of Aβ1-42 is calculated, and recorded as pTau181 / Aβ1-42;

[0114] Comparing the pTau181 / Aβ1-42 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result;

[0115] Determine the comparison result according to a predetermined determination condition and output the determination result;

[0116] The predetermined judgment condition is: if the pTau181 / Aβ1-42 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of pathological changes of Alzheimer's disease in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of pathological changes of Alzheimer's disease in the brain.

[0117] The step 4 may be:

[0118] Receiving the content of pTau181 and Aβ1-40 in the plasma of the test subject;

[0119] According to the content of pTau181 and the content of Aβ1-40 in the plasma of the test subject, the ratio of the content of pTau181 to the content of Aβ1-40 is calculated, and recorded as pTau181 / Aβ1-40;

[0120] Comparing the pTau181 / Aβ1-40 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result;

[0121] Determine the comparison result according to a predetermined determination condition and output the determination result;

[0122] The predetermined judgment condition is: if the pTau181 / Aβ1-40 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain.

[0123] The plasma biomarkers provided by the present invention, pTau181, pTau217 / pTau181, pTau181 / Aβ1-42 or pTau181 / Aβ1-40, can effectively assess the risk of Alzheimer's disease, have high sensitivity and specificity, and low false positive and false negative rates, and are reliable, simple and non-invasive detection methods. The present invention has important application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0124] Figure 1 This is the cut-off value discrimination diagram of pTau181 in plasma of the SCABI cohort.

[0125] Figure 2 This is the ROC curve of the cut-off value of pTau181 in plasma of the SCABI cohort.

[0126] Figure 3 This is the cut-off value discrimination diagram of pTau217 / pTau181 in plasma of the SCABI cohort.

[0127] Figure 4 This is the ROC curve of the cut-off value of pTau217 / pTau181 in plasma of the SCABI cohort.

[0128] Figure 5 This is the cut-off value discrimination diagram of pTau181 / Aβ1-42 in plasma of the SCABI cohort.

[0129] Figure 6 This is the ROC curve of the cut-off value of pTau181 / Aβ1-42 in plasma of the SCABI cohort.

[0130] Figure 7 This is the cut-off value discrimination diagram of pTau181 / Aβ1-40 in plasma of the SCABI cohort.

[0131] Figure 8This is the ROC curve of the cut-off value of pTau181 / Aβ1-40 in plasma of the SCABI cohort. DETAILED DESCRIPTION

[0132] The present invention is further described in detail below in conjunction with specific embodiments, and the examples provided are only for illustrating the present invention, rather than for limiting the scope of the present invention. The examples provided below can be used as a guide for further improvements by those of ordinary skill in the art, and do not constitute a limitation of the present invention in any way.

[0133] The experimental methods in the following examples, unless otherwise specified, are all conventional methods, and are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial channels.

[0134] The quantitative tests in the following examples were all repeated three times, and the results were averaged.

[0135] Cut-off value refers to the critical value in medical testing, which is used to determine whether the test result is higher or lower than the clinical or analytical decision point. If the positive and negative values ​​are determined when a marker is tested, the critical value with the highest sensitivity and specificity is usually used as the decision value, and this value is called the Cut-off value. The Cut-off value is mainly a critical point set based on statistical analysis.

[0136] The following examples were approved by the Ethics Committee of the Affiliated Brain Hospital of Guangzhou Medical University (ID: AF / SC-08 / 02.3) and complied with the 1964 Declaration of Helsinki and its subsequent amendments or similar ethical standards.

[0137] Example 1. Application of the ratio of pTau181, pTau217 and pTau181 in plasma (hereinafter referred to as pTau217 / pTau181), the ratio of pTau181 to Aβ1-42 (hereinafter referred to as pTau181 / Aβ1-42), and the ratio of pTau181 to Aβ1-40 (hereinafter referred to as pTau181 / Aβ1-40) in the diagnosis of Alzheimer's disease

[0138] This example aims to explore the feasibility of diagnosing Alzheimer's disease using pTau181, pTau217 / pTau181, pTau181 / Aβ1-42 and pTau181 / Aβ1-40 in plasma and analyze its clinical value.

[0139] 1. Experimental Design

[0140] The purpose of this example is to determine the optimal cut-off values ​​of pTau181, pTau217 / pTau181, pTau181 / Aβ1-42 and pTau181 / Aβ1-40 in plasma for diagnosing Alzheimer's disease using the automatic immunoassay analyzer Lumipulse G1200, and to evaluate the consistency of pTau181, pTau217 / pTau181, pTau181 / Aβ1-42 and pTau181 / Aβ1-40 in plasma with the amyloid protein PET results.

[0141] 2. Experimental Methods

[0142] 1. Source of subjects and their inclusion and exclusion criteria

[0143] All subjects were from the Southern China Aging Brain Cohort (SCABI cohort). From March 2021 to June 2024, 182 SCABI cohort subjects underwent blood sample and amyloid PET image collection. Among them, the inclusion and exclusion criteria are as follows:

[0144] (1) Inclusion criteria

[0145] ①Age ≥50 years old;

[0146] ② Normal cognition, or MCI (according to Peterson criteria: Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 2004; 256: 183–94. https: / / doi.org / 10.1111 / j.1365-2796.2004.01388.x), or dementia (according to DSM-IV criteria for any dementia: Association AP. Diagnostic and Statistical Manual of Mental Disorders. Text

[0147] Revision 2000.).

[0148] ③Dividing amyloid-negative and amyloid-positive groups according to visual interpretation of PET amyloid: Image interpretation was completed by imaging experts who were unaware of the subject's diagnosis and biomarker levels, and all PET scan images were visually evaluated according to FDA recommendations: When one or more areas showed increased cortical gray matter signals, resulting in reduced or absent contrast between gray matter and white matter, it was classified as "positive". When the contrast between gray matter and white matter was clear, it was classified as "negative" (Approval for Amyvid (Florbetapir F 18 Injection) 2012. https: / / www.accessdata.fda.gov / drugsatfda_docs / nda / 2012 / 202008Orig1s000Approv.pdf (accessed October 18, 2024).)

[0149] ④The subjects and their families agreed to participate in this study and signed the informed consent form.

[0150] (2) Exclusion criteria

[0151] ① Malignant tumors and severe cerebrovascular diseases (accompanied by neurological deficits, cerebral infarction and cerebral hemorrhage)

[0152] ②Severe neurological diseases (such as metabolic encephalopathy, encephalitis, multiple sclerosis, epilepsy, traumatic brain injury, normal pressure hydrocephalus, etc.)

[0153] ③Severe mental illness (schizophrenia, bipolar disorder, schizoaffective disorder, paranoid psychosis, intellectual disability, etc.)

[0154] ④ Other physical diseases that cause cognitive impairment (liver dysfunction, renal insufficiency, thyroid dysfunction, severe anemia, folic acid or vitamin B12 deficiency, syphilis, HIV infection, alcohol and drug abuse, etc.)

[0155] 2. Data Collection

[0156] (1) Clinical data collection

[0157] The age, gender, height, weight, waist circumference, medical history (including hypertension, diabetes, hypercholesterolemia, coronary heart disease, etc.), personal history (such as smoking, drinking, etc.), family history, medication history, education level, overall cognitive function scale score (MMSE), dementia grade scale score, etc. of each subject were recorded.

[0158] (2) Obtaining and testing plasma samples

[0159] ① Use 5 ml polypropylene tubes to collect blood samples. The blood samples should be collected within three months after the amyloid protein PET image is collected.

[0160] ② Take the collected blood sample, centrifuge it at 4°C and 2000rpm for 10min, collect 0.5ml of supernatant and store it at -80°C; the supernatant is the plasma sample (the plasma sample must be separated within 4h after the blood sample is collected, for specific reference: Giulia, Musso, Chiara, Cosma, Martina, Zaninotto et al. Pre-analytical variability of the Lumipulse immunoassay for plasma biomarkers of Alzheimer's disease. [J]. Clin Chem Lab Med, 2022, 61: 0.).

[0161] ③ The automatic immunoassay analyzer Lumipulse G1200 (Fujirebio) was used to detect the levels of biomarkers in 182 plasma samples, including pTau181, Aβ1-42, Aβ1-40 and pTau217.

[0162] The measurement process uses special kits, including Lumipulse Gβ-Amyloid 1-40Plasma, Lumipulse G pTau181, Lumipulse G pTau217 and Lumipulse Gβ-Amyloid 1-42Plasma kits (Francisco, Martínez-Dubarbie, Armando, Guerra-Ruiz, Sara, López-García et al. Accuracy of plasma Aβ40, Aβ42, and pTau181 to detect CSF Alzheimer'spathological changes in cognitively unimpaired subjects using the Lumipulseautomated platform. [J]. Alzheimers Res Ther, 2023, 15: 0.).

[0163] (3) Amyloid PET Image Acquisition

[0164] 18F-AV45 was prepared by the PET Center of Guangdong Provincial Hospital of Traditional Chinese Medicine, University Town Hospital. The preparation method was referred to the following literature: Wei, Yin, Xue, Zhou, Jinping, Qiao et al. Study the pharmacokinetics of AV-45 in rat plasma and metabolism in liver microsomes by ultra-performance liquid chromatography with mass spectrometry. [J]. Biomed Chromatogr, 2011, 26: 0.

[0165] A total of 182 subjects underwent amyloid positron emission tomography (PET) imaging using 18F-AV45. PET data were captured 50 minutes after intravenous injection of 18F-AV45 10 ± 1 mCi using a SIGNA PET magnetic resonance (MR) device or a Siemens PET computed tomography (CT / MR) device.

[0166] PET subjects were given 10±1mCi of AV45 intravenously and the scan was started after 50 minutes of rest. The acquisition time was 15min. The ordered subset expectation maximization (OSEM) reconstruction algorithm was used, combined with the joint time of flight (TOF) and point spread function (PSF) algorithm to reconstruct the PET images, using 28 subsets and 6 iterations. The zero echo time (ZTE) sequence was used to correct the attenuation of the PET images. The PET image matrix size was 256×256; the DFOV (display field of view) was 46.2cm×30cm; the layer thickness was 2.78mm; and the pixel size was: 2.8mm×2.8mm.

[0167] The PET CT / MR scans were acquired in 15 min using a 3D iterative algorithm (4 iterations and 21 subsets) with a matrix size of 336 × 336, a zoom factor of 2.0 mm, a slice thickness of 2.0 mm, and an all-pass filter. PET image reconstruction used a time-of-flight and point spread function algorithm involving 5 iterations and 16 subsets. The matrix size was 336 × 336, the zoom factor was 2.0, the slice thickness was 2.0 mm, and a Gaussian filter with a full width at half maximum of 5.0 was used.

[0168] PET amyloid visual interpretation: The images were interpreted by 2 professionally trained nuclear medicine physicians. When the 2 physicians disagreed, a senior physician interpreted the image. The image results were divided into positive (mild, moderate or severe) and negative. According to the recommendations of the U.S. Food and Drug Administration (FDA), the scan was classified as "positive" when one or more areas showed increased cortical gray matter signal, resulting in reduced or absent contrast between gray and white matter. When the contrast between gray and white matter was clear, the scan was classified as "negative."

[0169] 3. Statistical analysis

[0170] In order to determine the ability of markers and their ratios in plasma to distinguish between positive and negative states of amyloid, receiver operating characteristic (ROC) curve analysis was performed on pTau181, pTau217 / pTau181, pTau181 / Aβ1-42 and pTau181 / Aβ1-40 in plasma, and the area under the curve (AUCs) and 95% confidence intervals of pTau181, pTau217 / pTau181, pTau181 / Aβ1-42 and pTau181 / Aβ1-40 were calculated; the sensitivity, specificity, false negative rate and false positive rate were further determined. The optimal threshold (Cut-off value) was determined based on the corresponding maximum Youden J index of the marker. All statistical analyses were performed in R software version 4.3.2. Statistical significance was defined as α = 0.05, and all tests were two-sided tests.

[0171] 3. Experimental Results

[0172] 1. Demographic data statistics:

[0173] The SCABI cohort eventually included 182 subjects, including 36 normal elderly people, 120 patients with mild cognitive impairment, and 26 patients with dementia. See Table 1 for specific clinical data collection.

[0174] Table 1. SCABI cohort demographic data (mean ± standard deviation)

[0175]

[0176] 2. Single indicator analysis

[0177] The cut-off value discrimination diagram of plasma pTau181 in the SCABI cohort is shown in Figure 1 .

[0178] The ROC curve of the cut-off value of plasma pTau181 in the SCABI cohort is shown in Figure 2 .

[0179] The cut-off value discrimination diagram of plasma pTau217 / pTau181 in the SCABI cohort is shown in Figure 3 .

[0180] The ROC curve of the cut-off value of plasma pTau217 / pTau181 in the SCABI cohort is shown in Figure 4 .

[0181] The cut-off value discrimination diagram of plasma pTau181 / Aβ1-42 in the SCABI cohort is shown in Figure 5 .

[0182] The ROC curve of the cut-off value of plasma pTau181 / Aβ1-42 in the SCABI cohort is shown in Figure 6 .

[0183] The cut-off value discrimination diagram of plasma pTau181 / Aβ1-40 in the SCABI cohort is shown in Figure 7 .

[0184] The ROC curve of the cut-off value of plasma pTau181 / Aβ1-40 in the SCABI cohort is shown in Figure 8 .

[0185] The results of single-indicator analysis of pTau181, pTau217 / pTau181, pTau181 / Aβ1-42, and pTau181 / Aβ1-40 in the SCABI cohort are shown in Table 2 .

[0186] Table 2. Single index analysis results of pTau181, pTau217 / pTau181, pTau181 / Aβ1-42 and pTau181 / Aβ1-40 (mean ± standard deviation)

[0187]

[0188]

[0189] 3. Diagnostic efficacy analysis

[0190] The diagnostic performance of plasma pTau181, pTau217 / pTau181, pTau181 / Aβ1-42, and pTau181 / Aβ1-40 in the SCABI cohort is shown in Table 3 .

[0191] Table 3. Diagnostic performance of plasma pTau181, pTau217 / pTau181, pTau181 / Aβ1-42, and pTau181 / Aβ1-40 in the SCABI cohort

[0192]

[0193] The results are as follows:

[0194] ① Diagnostic efficacy of plasma pTau181 in identifying patients with Alzheimer's disease

[0195] Establishment of critical value: The area under the ROC curve (AUC) of pTau181 in plasma was 0.814, indicating that this indicator has a high efficacy in distinguishing between amyloid-positive and amyloid-negative individuals. The cut-off value of pTau181 was determined to be 3.135 pg / mL based on the maximum Youden index.

[0196] Verify the diagnostic efficacy of the cut-off value: In the cohort, pTau181 in plasma showed good performance: sensitivity was 0.711 and specificity was 0.783. That is, if the pTau181 in the subject's plasma is greater than 3.135pg / mL (Cut-off value), the subject is likely to have pathological changes of Alzheimer's disease in the brain (high risk of Alzheimer's disease); if the pTau181 in the subject's plasma is 3.135pg / mL or less, the subject is unlikely to have pathological changes of Alzheimer's disease in the brain (low risk of Alzheimer's disease).

[0197] ②The diagnostic efficacy of plasma pTau217 / pTau181 in identifying patients with Alzheimer's disease

[0198] Establishment of critical value: The area under the ROC curve (AUC) of pTau217 / pTau181 in plasma was 0.883, indicating that this indicator has a high efficacy in distinguishing between amyloid-positive and amyloid-negative individuals. The cut-off value of pTau217 / pTau181 was determined to be 0.101 based on the maximum Youden index.

[0199] Verify the diagnostic efficacy of the cut-off value: In the cohort, pTau217 / pTau181 in plasma showed good performance: sensitivity was 0.803 and specificity was 0.868. That is, if the pTau217 / pTau181 in the subject's plasma is greater than 0.101 (Cut-off value), the subject is likely to have pathological changes of Alzheimer's disease in the brain (high risk of Alzheimer's disease); if the pTau217 / pTau181 in the subject's plasma is 0.101 or less, the subject is unlikely to have pathological changes of Alzheimer's disease in the brain (low risk of Alzheimer's disease).

[0200] ③The diagnostic efficacy of plasma pTau181 / Aβ1-42 in identifying patients with Alzheimer's disease

[0201] Establishment of critical value: The area under the ROC curve (AUC) of pTau181 / Aβ1-42 in plasma was 0.872, indicating that this indicator has a high efficacy in distinguishing between amyloid-positive and amyloid-negative individuals. The cut-off value of pTau181 / Aβ1-42 was determined to be 0.132 based on the maximum Youden index.

[0202] Verify the diagnostic efficacy of the cut-off value: In the cohort, pTau181 / Aβ1-42 in plasma showed good performance: sensitivity was 0.763 and specificity was 0.811. That is, if the pTau181 / Aβ1-42 in the subject's plasma is greater than 0.132 (Cut-off value), the subject is likely to have pathological changes of Alzheimer's disease in the brain (high risk of Alzheimer's disease); if the pTau181 / Aβ1-42 in the subject's plasma is 0.132 or less, the subject is unlikely to have pathological changes of Alzheimer's disease in the brain (low risk of Alzheimer's disease).

[0203] ④ The diagnostic efficacy of plasma pTau181 / Aβ1-40 in identifying patients with Alzheimer's disease

[0204] Establishment of critical value: The area under the ROC curve (AUC) of pTau181 / Aβ1-40 in plasma was 0.815, indicating that this indicator has a high efficacy in distinguishing between amyloid-positive and amyloid-negative individuals. The cut-off value of pTau181 / Aβ1-40 was determined to be 0.010 based on the maximum Youden index.

[0205] Verify the diagnostic efficacy of the cut-off value: In the cohort, pTau181 / Aβ1-40 in plasma showed good performance: sensitivity was 0.803 and specificity was 0.726. That is, if the pTau181 / Aβ1-40 in the subject's plasma is greater than 0.010 (Cut-off value), the subject is likely to have pathological changes of Alzheimer's disease in the brain (high risk of Alzheimer's disease); if the pTau181 / Aβ1-40 in the subject's plasma is 0.010 or less, the subject is unlikely to have pathological changes of Alzheimer's disease in the brain (low risk of Alzheimer's disease).

[0206] The present invention has been described in detail above. For those skilled in the art, without departing from the purpose and scope of the present invention, and without the need to carry out unnecessary experimental conditions, the present invention can be implemented in a wide range under equivalent parameters, concentrations and conditions. Although the present invention provides specific embodiments, it should be understood that the present invention can be further improved. In a word, according to the principles of the present invention, the application is intended to include any changes, uses or improvements to the present invention, including departure from the disclosed scope in the application, and changes made with conventional techniques known in the art.

Claims

1. Plasma biomarkers, including pTau181; The detection object of the plasma biomarker is plasma.

2. The plasma biomarker according to claim 1, characterized in that: The plasma biomarkers also include pTau217; Preferably, the plasma biomarker is pTau217 / pTau181; The pTau217 / pTau181 is the concentration ratio of pTau217 and pTau181.

3. The plasma biomarker according to claim 1, characterized in that: The plasma biomarkers also include Aβ1-42; Preferably, the plasma biomarker is pTau181 / Aβ1-42; The pTau181 / Aβ1-42 is the concentration ratio of pTau181 and Aβ1-42.

4. The plasma biomarker according to claim 1, characterized in that: The plasma biomarkers also include Aβ1-40; Preferably, the plasma biomarker is pTau181 / Aβ1-40; The pTau181 / Aβ1-40 is the concentration ratio of pTau181 and Aβ1-40.

5. Use of the plasma biomarker according to any one of claims 1 to 4 in the preparation of a product for assessing the risk of Alzheimer's disease or a product for evaluating the possibility of pathological changes of Alzheimer's disease occurring in the brain.

6. Use of Substance A, Substance B, Substance C or Substance D in the preparation of a product for assessing the risk of developing Alzheimer's disease or a product for assessing the likelihood of developing Alzheimer's pathological changes in the brain; The substance A is a substance used to detect the concentration of pTau181 in plasma; The substance B is a substance used to detect the concentration of pTau217 and pTau181 in plasma; The substance C is a substance used to detect the concentration of pTau181 and Aβ1-42 in plasma; The substance D is a substance used to detect the concentrations of pTau181 and Aβ1-40 in plasma.

7. A data processing device for evaluating the risk of a subject suffering from Alzheimer's disease or evaluating the possibility of pathological changes of Alzheimer's disease in the brain of the subject, which is data processing device 1, data processing device 2, data processing device 3 or data processing device 4; The data processing device 1 comprises the following modules: (1) a data receiving module; the data receiving module is configured to receive the content of pTau181 in the plasma of the subject; (2) a data processing module; the data processing module is configured to receive the content of pTau181 in the plasma of the subject from the data receiving module; (3) a data storage module; the data storage module is configured to store the judgment threshold; (4) a data comparison module; the data comparison module is configured to receive pTau181 sent by the data processing module, and call the judgment threshold from the data storage module for comparison with pTau181; (5) a judgment module; the judgment module is configured to receive the comparison result sent by the data comparison module, judge the comparison result according to a predetermined judgment condition, and output the judgment result; The predetermined judgment condition is: if the pTau181 value is greater than the judgment threshold, the subject has a high risk of suffering from Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of suffering from Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain; The data processing device 2 includes the following modules: (1) a data receiving module; the data receiving module is configured to receive the content of pTau217 and the content of pTau181 in the plasma of the subject; (2) a data processing module; the data processing module is configured to receive the content of pTau217 and the content of pTau181 in the plasma of the subject from the data receiving module, and calculate the ratio of the content of pTau217 to the content of pTau181, which is recorded as pTau217 / pTau181; (3) a data storage module; the data storage module is configured to store the judgment threshold; (4) a data comparison module; the data comparison module is configured to receive pTau217 / pTau181 sent by the data processing module, and call the judgment threshold from the data storage module for comparison with pTau217 / pTau181; (5) a judgment module; the judgment module is configured to receive the comparison result sent by the data comparison module, judge the comparison result according to a predetermined judgment condition, and output the judgment result; The predetermined judgment condition is: if the pTau217 / pTau181 value is greater than the judgment threshold, the subject has a high risk of suffering from Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of suffering from Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain; The data processing device 3 includes the following modules: (1) a data receiving module; the data receiving module is configured to receive the content of pTau181 and the content of Aβ1-42 in the plasma of the subject; (2) a data processing module; the data processing module is configured to receive the pTau181 content and the Aβ1-42 content in the plasma of the subject from the data receiving module, and calculate the ratio of the pTau181 content to the Aβ1-42 content, which is recorded as pTau181 / Aβ1-42; (3) a data storage module; the data storage module is configured to store the judgment threshold; (4) a data comparison module; the data comparison module is configured to receive pTau181 / Aβ1-42 sent by the data processing module, and call the judgment threshold from the data storage module for comparison with pTau181 / Aβ1-42; (5) a judgment module; the judgment module is configured to receive the comparison result sent by the data comparison module, judge the comparison result according to a predetermined judgment condition, and output the judgment result; The predetermined judgment condition is: if the pTau181 / Aβ1-42 value is greater than the judgment threshold, the subject has a high risk of suffering from Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of suffering from Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain; The data processing device 4 includes the following modules: (1) a data receiving module; the data receiving module is configured to receive the content of pTau181 and the content of Aβ1-40 in the plasma of the subject; (2) a data processing module; the data processing module is configured to receive the pTau181 content and the Aβ1-40 content in the plasma of the subject from the data receiving module, and calculate the ratio of the pTau181 content to the Aβ1-40 content, which is recorded as pTau181 / Aβ1-40; (3) a data storage module; the data storage module is configured to store the judgment threshold; (4) a data comparison module; the data comparison module is configured to receive the pTau181 / Aβ1-40 sent by the data processing module, and call the judgment threshold from the data storage module for comparison with the pTau181 / Aβ1-40; (5) a judgment module; the judgment module is configured to receive the comparison result sent by the data comparison module, judge the comparison result according to a predetermined judgment condition, and output the judgment result; The predetermined judgment condition is: if the pTau181 / Aβ1-40 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain.

8. The data processing device according to claim 7, characterized in that: In the data processing device 1, the content of pTau181 in the plasma of the subject to be tested received by the data receiving module is obtained according to a method comprising the following steps: collecting peripheral blood of the subject to be tested, separating the plasma, and then detecting the content of pTau181 in the plasma; In the data processing device 2, the content of pTau217 and the content of pTau181 in the plasma of the subject to be tested received by the data receiving module are obtained according to a method comprising the following steps: collecting peripheral blood of the subject to be tested, separating the plasma, and then detecting the content of pTau217 and the content of pTau181 in the plasma; In the data processing device 3, the content of pTau181 and the content of Aβ1-42 in the plasma of the subject to be tested received by the data receiving module are obtained according to a method comprising the following steps: collecting peripheral blood of the subject to be tested, separating the plasma, and then detecting the content of pTau181 and the content of Aβ1-42 in the plasma; In the data processing device 4, the content of pTau181 and the content of Aβ1-40 in the plasma of the subject to be tested received by the data receiving module are obtained according to a method comprising the following steps: collecting peripheral blood of the subject to be tested, separating the plasma, and then detecting the content of pTau181 and the content of Aβ1-40 in the plasma; The data processing device further comprises a control module or a controller; the control module or the controller is used to control each module.

9. A system for assessing the risk of developing Alzheimer's disease or the possibility of pathological changes of Alzheimer's disease in the brain, comprising control device 1, control device 2, control device 3 or control device 4; The control device 1 is configured or programmed to perform the following steps: Receiving the content of pTau181 in the plasma of the subject to be tested; Comparing the pTau181 content in the plasma of the subject to be tested with the judgment threshold value to obtain a comparison result; Determine the comparison result according to a predetermined determination condition and output the determination result; The predetermined judgment condition is: if the pTau181 value is greater than the judgment threshold, the subject has a high risk of suffering from Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of suffering from Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain; The system including the control device 1 further includes an input device and an output device; the input device is configured to input the content of pTau181 in the plasma of the subject to be tested; the output device is configured to output the determination result; The control device 2 is configured or programmed to perform the following steps: Receiving the content of pTau217 and the content of pTau181 in the plasma of the subject to be tested; According to the content of pTau217 and the content of pTau181 in the plasma of the test subject, the ratio of the content of pTau217 to the content of pTau181 is calculated, and recorded as pTau217 / pTau181; Comparing the pTau217 / pTau181 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result; Determine the comparison result according to a predetermined determination condition and output the determination result; The predetermined judgment condition is: if the pTau217 / pTau181 value is greater than the judgment threshold, the subject has a high risk of suffering from Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of suffering from Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain; The system including the control device 2 further includes an input device and an output device; the input device is configured to input the content of pTau217 and the content of pTau181 in the plasma of the subject to be tested; the output device is configured to output the determination result; The control device 3 is configured or programmed to perform the following steps: Receiving the content of pTau181 and Aβ1-42 in the plasma of the test subject; According to the content of pTau181 and the content of Aβ1-42 in the plasma of the test subject, the ratio of the content of pTau181 to the content of Aβ1-42 is calculated, and recorded as pTau181 / Aβ1-42; Comparing the pTau181 / Aβ1-42 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result; Determine the comparison result according to a predetermined determination condition and output the determination result; The predetermined judgment condition is: if the pTau181 / Aβ1-42 value is greater than the judgment threshold, the subject has a high risk of suffering from Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of suffering from Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain; The system including the control device 3 further includes an input device and an output device; the input device is configured to input the content of pTau181 and the content of Aβ1-42 in the plasma of the subject to be tested; the output device is configured to output the determination result; The control device 4 is configured or programmed to perform the following steps: Receiving the content of pTau181 and Aβ1-40 in the plasma of the test subject; According to the content of pTau181 and the content of Aβ1-40 in the plasma of the test subject, the ratio of the content of pTau181 to the content of Aβ1-40 is calculated, and recorded as pTau181 / Aβ1-40; Comparing the pTau181 / Aβ1-40 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result; Determine the comparison result according to a predetermined determination condition and output the determination result; The predetermined judgment condition is: if the pTau181 / Aβ1-40 value is greater than the judgment threshold, the subject has a high risk of suffering from Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of suffering from Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain; The system including the control device 4 also includes an input device and an output device; the input device is configured to input the content of pTau181 and the content of Aβ1-40 in the plasma of the subject to be tested; and the output device is configured to output the determination result.

10. A computer-readable storage medium storing a computer program for executing the following steps: The steps are step 1, step 2, step 3 or step 4: The step 1 is: Receiving the content of pTau181 in the plasma of the subject to be tested; Comparing the pTau181 content in the plasma of the subject to be tested with the judgment threshold value to obtain a comparison result; Determine the comparison result according to a predetermined determination condition and output the determination result; The predetermined judgment condition is: if the pTau181 value is greater than the judgment threshold, the subject has a high risk of suffering from Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of suffering from Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain; The step 2 is: Receiving the content of pTau217 and the content of pTau181 in the plasma of the subject to be tested; According to the content of pTau217 and the content of pTau181 in the plasma of the test subject, the ratio of the content of pTau217 to the content of pTau181 is calculated, and recorded as pTau217 / pTau181; Comparing the pTau217 / pTau181 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result; Determine the comparison result according to a predetermined determination condition and output the determination result; The predetermined judgment condition is: if the pTau217 / pTau181 value is greater than the judgment threshold, the subject has a high risk of suffering from Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of suffering from Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain; The step 3 is: Receiving the content of pTau181 and Aβ1-42 in the plasma of the test subject; According to the content of pTau181 and the content of Aβ1-42 in the plasma of the test subject, the ratio of the content of pTau181 to the content of Aβ1-42 is calculated, and recorded as pTau181 / Aβ1-42; Comparing the pTau181 / Aβ1-42 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result; Determine the comparison result according to a predetermined determination condition and output the determination result; The predetermined judgment condition is: if the pTau181 / Aβ1-42 value is greater than the judgment threshold, the subject has a high risk of suffering from Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of suffering from Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain; The step 4 is: Receiving the content of pTau181 and Aβ1-40 in the plasma of the test subject; According to the content of pTau181 and the content of Aβ1-40 in the plasma of the test subject, the ratio of the content of pTau181 to the content of Aβ1-40 is calculated, and recorded as pTau181 / Aβ1-40; Comparing the pTau181 / Aβ1-40 in the plasma of the subject to be tested with the judgment threshold to obtain a comparison result; Determine the comparison result according to a predetermined determination condition and output the determination result; The predetermined judgment condition is: if the pTau181 / Aβ1-40 value is greater than the judgment threshold, the subject has a high risk of Alzheimer's disease or a high possibility of Alzheimer's disease pathological changes in the brain; otherwise, the subject has a low risk of Alzheimer's disease or a low possibility of Alzheimer's disease pathological changes in the brain.

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