DDIT4L cleavage product as diagnostic marker of dementia early

Abstract

The invention relates to a DDIT4L shear product serving as a diagnostic marker of Alzheimer's disease and application of the DDIT4L shear product in diagnosis of Alzheimer's disease. Specifically, the invention provides a method. The present application relates to the detection of a substance encoding an intron retention cleavage product DIR from a sample of a subject that encodes a DNA damage-induced transcript 4-like transcript (DDIT4L) for the preparation of a product (e.g., kit or detection system) for the diagnosis of dementia early age, the diagnosis of mild cognitive impairment and / or the assessment of the course of cognitive impairment development (e.g., grading or staging) of said subject The invention also relates to a related product and a method for screening drugs by using DIR.

Description

DDIT4L shear products, a diagnostic marker for Alzheimer's disease Technical Field This application relates to the biomedical field, specifically to the application of DIR, the intron retention shearing product of DNA damage-inducible transcript 4 (DDIT4L), as a blood biomarker for Alzheimer's disease or mild cognitive impairment, and related products and methods. Background Technology As the most prevalent neurodegenerative disease among those that harm the human brain, Alzheimer's disease (AD) causes immense suffering for patients and places a heavy burden on their families and society. According to the Alzheimer's Disease International (ADI) World Alzheimer's Report 2017, global costs for caring for dementia patients increased from $604 billion in 2010 to $1 trillion in 2017, a growth rate of 65.6%. In the United States alone, there are 5 million AD patients, requiring 18 billion hours of care annually. Globally, there were 50 million AD patients in 2017, and this number is expected to continue to rise due to the world's aging population. Given the current lack of drugs to treat, slow, or halt the progression of the disease, the number of patients is projected to double every 20 years, reaching 82 million in 2030 and 150 million in 2050. According to the "China Development Report 2020: Development Trends and Policies of Population Aging in China" released by the China Development Foundation (a national social organization initiated by the Development Research Center of the State Council), in 2020, there were approximately 180 million people aged 65 and above in China, accounting for about 13% of the total population. By 2025, when the 14th Five-Year Plan is completed, the number of people aged 65 and above will exceed 210 million, accounting for about 15% of the total population. By 2035 and 2050, the number of people aged 65 and above in China will reach 310 million and nearly 380 million, respectively, accounting for 22.3% and 27.9% of the total population. The incidence of Alzheimer's disease (AD) is age-related, ranging from 2% to 4% in the general population. The prevalence is particularly high among middle-aged and elderly individuals over 65 years of age, reaching 5%, and increasing exponentially with age. Analysis shows that the prevalence can increase to 25% in those over 85 years of age, and as high as 60% in those over 95 years of age. my country is now gradually entering an aging society, and statistics indicate that there are nearly ten million AD patients in my country, with more than 300,000 new cases added annually. The primary symptom of Alzheimer's disease (AD) is cognitive impairment. Ultimately, this cognitive impairment stems from synaptic and neuronal damage, and abnormalities in the structure and function of neural circuits. The main reason for the continuous failures in clinical trials of new AD drugs is that the mechanisms of synaptic and neuronal damage remain unclear, and there is a lack of cell / animal models that closely resemble the pathophysiological characteristics of human diseases (such as neurodegeneration). This has resulted in slow progress in research on effective prevention and treatment methods for Alzheimer's disease (AD) and early diagnostic biomarkers that can reflect disease progression. Metabolic abnormalities are likely one of the main mechanisms of Alzheimer's disease (AD). In AD patients, lipid metabolism abnormalities (represented by cholesterol, etc.) and glucose metabolism abnormalities (represented by glucose, etc.) are the most common metabolic abnormalities. Other abnormalities include energy metabolism disorders caused by insufficient blood supply to the brain, such as degenerative changes in cerebral small vessels, leading to cerebral ischemia and hypoxia. However, the mechanisms by which abnormal lipid and glucose metabolism in the brain affect the occurrence and development of AD are unclear. Mitochondria are key organelles for the metabolism of major energy substances; mitochondrial dysfunction leads to abnormal energy metabolism and also damages the function of neurons and cerebral small vessel endothelial cells. However, the relationship between mitochondrial dysfunction and lipid and glucose metabolism abnormalities in the early stages of AD development is unclear. Mild cognitive impairment (MCI) is a syndrome involving a decline in objective cognitive abilities. It is a state between mild dementia and healthy aging, characterized by prominent memory impairment, although other cognitive functions may show some degree of decline. However, daily activities remain normal, and it does not meet the diagnostic criteria for dementia. Each year, 10%–15% of MCI cases progress to Alzheimer's disease (AD), which is 10 times the rate in the normal control group. As a transitional state from normal aging to dementia, MCI is receiving increasing attention, and research on MCI is a crucial step in the early diagnosis and intervention of AD. Current diagnostic biomarkers for Alzheimer's disease (AD) mainly include cerebrospinal fluid Aβ and Tau level detection, PET, and MRI neuroimaging techniques. While these methods have high, even very high, diagnostic efficacy, they also have drawbacks such as being difficult to operate, expensive, and having weak correlations with disease progression and outcome. Therefore, there is an urgent need to develop novel, simple, cost-effective biomarkers suitable for large-scale population screening and effectively used for the early diagnosis of AD. Summary of the Invention This application provides a novel blood biomarker for Alzheimer's disease (AD) or mild cognitive impairment (MCI). On one hand, this application provides the use of an intron-retained cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L), and / or a nucleic acid encoding said DIR, in disease diagnosis and / or disease progression assessment, wherein said disease includes cognitive impairment. On one hand, this application provides the use of an intron-retaining cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L), and / or a nucleic acid encoding said DIR, in disease diagnosis and / or disease progression assessment, wherein said diseases include neurodegenerative diseases. In some embodiments, the DIR comprises the amino acid sequence shown in SEQ ID NO:1. In some embodiments, the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:8. In some embodiments, the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:93. In some embodiments, the cognitive impairment includes cognitive impairment due to normal aging, Lewis body dementia (LBD), frontotemporal dementia, and / or vascular dementia. In some implementations, the inducing diseases of the cognitive impairment include Alzheimer's disease, multiple infarct type, Parkinson's disease, AIDS, and / or Creutzfeldt-Jakob disease (CJD). In some implementations, the cognitive impairment includes early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment. In some implementations, the cognitive impairment includes amnesic MCI with multiple cognitive domain impairment (aMCI-m). In some embodiments, the neurodegenerative disease includes acute neurodegenerative diseases and chronic neurodegenerative diseases. In some embodiments, the neurodegenerative diseases include neurodegenerative diseases caused by neuronal death and glial cell homeostasis, neurodegenerative diseases caused by aging, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegenerative diseases caused by impaired cell motility. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and / or Huntington's disease (HD). In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, the neurodegenerative disease includes early-stage Alzheimer's disease, mid-stage Alzheimer's disease, and / or late-stage Alzheimer's disease. On the other hand, this application provides a substance for detecting the intron retention cleavage product DIR of DNA damage-induced transcript 4-like transcript (DDIT4L) and / or the nucleic acid encoding said DIR, in the preparation of products for disease diagnosis and / or disease progression assessment, wherein said disease includes cognitive impairment. On the other hand, this application provides a substance for detecting the intron retention cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) and / or the nucleic acid encoding said DIR, in the preparation of products for disease diagnosis and / or disease progression assessment, wherein said diseases include neurodegenerative diseases. On the other hand, this application provides a diagnostic kit comprising the intron retention cleavage product DIR of DNA damage-induced transcript 4-like transcript (DDIT4L) as described in this application, and / or a substance encoding the nucleic acid of said DIR. The diagnostic kit is used to diagnose cognitive impairment and / or assess the disease progression of cognitive impairment; and / or to diagnose neurodegenerative diseases and / or assess the disease progression of neurodegenerative diseases. In some embodiments, the diagnostic kit includes instructions describing methods for diagnosing cognitive impairment and / or assessing the disease progression of cognitive impairment using the diagnostic kit; and / or diagnosing neurodegenerative diseases and / or assessing the disease progression of neurodegenerative diseases. In some embodiments, the DIR comprises the amino acid sequence shown in SEQ ID NO:1. In some embodiments, the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:8. In some embodiments, the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:93. In some embodiments, the cognitive impairment includes cognitive impairment due to normal aging, Lewis body dementia (LBD), frontotemporal dementia, and / or vascular dementia. In some implementations, the inducing diseases of the cognitive impairment include Alzheimer's disease, multiple infarct type, Parkinson's disease, AIDS, and / or Creutzfeldt-Jakob disease (CJD). In some implementations, the cognitive impairment includes early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment. In some implementations, the cognitive impairment includes amnesic MCI with multiple cognitive domain impairment (aMCI-m). In some embodiments, the neurodegenerative disease includes acute neurodegenerative diseases and chronic neurodegenerative diseases. In some embodiments, the neurodegenerative diseases include neurodegenerative diseases caused by neuronal death and glial cell homeostasis, neurodegenerative diseases caused by aging, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegenerative diseases caused by impaired cell motility. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and / or Huntington's disease (HD). In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, the neurodegenerative disease includes early-stage Alzheimer's disease, mid-stage Alzheimer's disease, and / or late-stage Alzheimer's disease. In some embodiments, the substance includes reagents and / or devices capable of detecting the DIR and / or encoding the nucleic acid of the DIR. In some embodiments, the substance includes reagents for specifically detecting the DIR and / or encoding the nucleic acid of the DIR. In some embodiments, the substance includes an antigen-binding protein capable of specifically binding to DIR, a probe capable of specifically binding to DIR, primers capable of specifically amplifying nucleic acids encoding DIR, a gene chip capable of specifically detecting nucleic acids encoding DIR, an aptamer capable of specifically binding to nucleic acids encoding DIR, and / or a guide RNA capable of specifically binding to nucleic acids encoding DIR. In some embodiments, the antigen-binding protein comprises LCDR2, which comprises the amino acid sequence shown in SEQ ID NO:74. In some embodiments, the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:26 or 16. In some embodiments, the antigen-binding protein comprises LCDR1, wherein LCDR1 comprises SEQ ID NO:73 The amino acid sequence shown. In some embodiments, the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 25, 52, and 15. In some embodiments, the antigen-binding protein comprises LCDR3, which comprises the amino acid sequence shown in SEQ ID NO:75. In some embodiments, the LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 27, 53, 67, 17. In some embodiments, the antigen-binding protein comprises LCDR1, LCDR2, and LCDR3, wherein, a) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:25, the LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:27; b) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:52, the LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:53; c) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:52, the LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:67; or, d) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:15, the LCDR2 contains the amino acid sequence shown in SEQ ID NO:16, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:17. In some embodiments, the antigen-binding protein comprises HCDR1, which comprises the amino acid sequence shown in SEQ ID NO:70. In some embodiments, the HCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 20, 35, 56, 10. In some embodiments, the antigen-binding protein comprises HCDR2, which comprises the amino acid sequence shown in SEQ ID NO:71. In some embodiments, the HCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 21, 36, 42, 48, 11. In some embodiments, the antigen-binding protein comprises HCDR3, which comprises the amino acid sequence shown in SEQ ID NO:70. In some embodiments, the HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 22, 30, 37, 43, 49, 57, 62, 12. In some embodiments, the antigen-binding protein comprises HCDR1, HCDR2, and HCDR3, wherein, a) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, and HCDR2 contains the amino acid sequence shown in SEQ ID NO: The amino acid sequence shown in SEQ ID NO: 21, and the HCDR3 contains the amino acid sequence shown in SEQ ID NO: 22; b) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:21, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:30. c) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:37; d) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:42, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:43; e) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:48, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:49; f) HCDR1 contains the amino acid sequence shown in SEQ ID NO:56, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:57; g) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:62; h) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:42, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:37; i) HCDR1 contains the amino acid sequence shown in SEQ ID NO:56, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:57; or, j) HCDR1 contains the amino acid sequence shown in SEQ ID NO:10, HCDR2 contains the amino acid sequence shown in SEQ ID NO:11, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:12. In some embodiments, the antigen-binding protein includes a heavy chain variable region VH, the VH comprising the amino acid sequence shown in any one of SEQ ID NO: 13, 23, 31, 38, 44, 50, 58, 63, 65. In some embodiments, the antigen-binding protein includes a light chain variable region VL, the VL containing an amino acid sequence represented by any one of SEQ ID NO: 18, 28, 33, 40, 46, 54, 60, 68. In some embodiments, the antigen-binding protein comprises a heavy chain variable region VH and a light chain variable region VL, wherein: a) The VH contains the amino acid sequence shown in SEQ ID NO:23, and the VL contains the amino acid sequence shown in SEQ ID NO:28; b) The VH contains the amino acid sequence shown in SEQ ID NO:31, and the VL contains the amino acid sequence shown in SEQ ID NO:33; c) The VH contains the amino acid sequence shown in SEQ ID NO:38, and the VL contains the amino acid sequence shown in SEQ ID NO:40; d) The VH contains the amino acid sequence shown in SEQ ID NO:44, and the VL contains the amino acid sequence shown in SEQ ID NO:46; e) The VH contains the amino acid sequence shown in SEQ ID NO:50, and the VL contains the amino acid sequence shown in SEQ ID NO:54; f) The VH contains the amino acid sequence shown in SEQ ID NO:58, and the VL contains the amino acid sequence shown in SEQ ID NO:60; g) The VH contains the amino acid sequence shown in SEQ ID NO:63, and the VL contains the amino acid sequence shown in SEQ ID NO:60; h) The VH contains the amino acid sequence shown in SEQ ID NO:65, and the VL contains the amino acid sequence shown in SEQ ID NO:54; i) The VH contains the amino acid sequence shown in SEQ ID NO:58, and the VL contains the amino acid sequence shown in SEQ ID NO:68; or, j) The VH contains the amino acid sequence shown in SEQ ID NO:13, and the VL contains the amino acid sequence shown in SEQ ID NO:18. In some embodiments, the antigen-binding protein includes a heavy chain constant region, and the heavy chain constant region includes a constant region derived from IgG. In some embodiments, the heavy chain constant region comprises a constant region derived from the following histones: IgG1, IgG2, IgG3, and IgG4. In some embodiments, the antigen-binding protein includes a light chain constant region, and the light chain constant region includes a constant region derived from Igκ or a constant region derived from Igλ. In some implementations, the light chain constant region includes a constant region derived from human Igκ. In some embodiments, the antigen-binding protein includes an antibody or an antigen-binding fragment thereof. In some embodiments, the antigen-binding fragment is selected from the group consisting of: Fab, Fab', F(ab)2, Fv fragment, F(ab')2, scFv, di-scFv, VHH and / or dAb. In some embodiments, the antibody is selected from the group consisting of monoclonal antibodies, murine antibodies, and chimeric antibodies. In some embodiments, the product includes a diagnostic kit. On the other hand, this application provides a method for diagnosing cognitive impairment and / or assessing the disease progression of cognitive impairment, comprising the steps of: detecting the content of intron-retaining cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) and / or the content of nucleic acid encoding said DIR in a sample derived from a subject in need. On the other hand, this application provides a method for diagnosing neurodegenerative diseases and / or assessing the disease progression of neurodegenerative diseases. The method comprises the following steps: detecting the content of intron-retaining cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) and / or the content of nucleic acid encoding said DIR in a sample derived from a subject in need. In some embodiments, the DIR comprises the amino acid sequence shown in SEQ ID NO:1. In some embodiments, the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:8. In some embodiments, the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:93. In some embodiments, the cognitive impairment includes cognitive impairment due to normal aging, Lewis body dementia (LBD), frontotemporal dementia, and / or vascular dementia. In some implementations, the inducing diseases of the cognitive impairment include Alzheimer's disease, multiple infarct type, Parkinson's disease, AIDS, and / or Creutzfeldt-Jakob disease (CJD). In some implementations, the cognitive impairment includes early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment. In some implementations, the cognitive impairment includes amnesic MCI with multiple cognitive domain impairment (aMCI-m). In some embodiments, the neurodegenerative disease includes acute neurodegenerative diseases and chronic neurodegenerative diseases. In some embodiments, the neurodegenerative diseases include neurodegenerative diseases caused by neuronal death and glial cell homeostasis, neurodegenerative diseases caused by aging, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegenerative diseases caused by impaired cell motility. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and / or Huntington's disease (HD). In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, the neurodegenerative disease includes early-stage Alzheimer's disease, mid-stage Alzheimer's disease, and / or late-stage Alzheimer's disease. In some implementations, the subjects include mammals. In some implementations, the subjects include cancer patients. In some implementations, the subject is in an elderly stage. In some implementations, the sample includes blood samples and / or tissue or cell samples. In some embodiments, the sample includes whole blood, serum, plasma, and / or cerebrospinal fluid. In some embodiments, the method includes comparing the levels of the DIR and / or the nucleic acid encoding the DIR in a sample of the subject with normal control values, wherein the normal control values ​​include the levels of the DIR and / or the nucleic acid encoding the DIR in normal subjects. In some implementations, the normal subject does not suffer from the cognitive impairment and / or the neurodegenerative disease. In some implementations, when the subject's sample has a significantly higher DIR level and / or the level of the nucleic acid encoding DIR than the normal control value, the subject is diagnosed with the cognitive impairment and / or the neurodegenerative disease. In some embodiments, the method includes comparing the levels of the DIR and / or the nucleic acid encoding the DIR in a sample of the subject with an earlier control value, wherein the earlier control value includes the levels of the DIR and / or the nucleic acid encoding the DIR previously measured for the same subject. In some implementations, the subject has been diagnosed with the cognitive impairment and / or the neurodegenerative disease. In some implementations, when the level of DIR and / or the level of nucleic acid encoding DIR in the subject's sample is significantly higher than the earlier control value, the subject is diagnosed with an accelerated progression of the cognitive impairment and / or the neurodegenerative disease. In some embodiments, the method further includes the step of detecting the levels of biomarkers associated with cognitive impairment and / or neurodegenerative diseases in a sample derived from the subject. In some implementations, the biomarkers associated with cognitive impairment and / or neurodegenerative diseases include AD7C-NTP, pTau-181, pTau-217, and / or Aβ1-42. In some embodiments, the method further includes the step of observing brain imaging of the subject. On the other hand, this application provides a system for diagnosing cognitive impairment and / or assessing the disease progression of cognitive impairment, comprising detecting the intron retention cleavage product DIR of DNA damage-induced transcript 4-like transcript (DDIT4L), and / or a substance encoding the nucleic acid of said DIR. On the other hand, this application provides a system for diagnosing neurodegenerative diseases and / or assessing the disease progression of neurodegenerative diseases, comprising detecting the intron retention cleavage product DIR of DNA damage-induced transcript 4-like transcript (DDIT4L), and / or a substance encoding the nucleic acid of said DIR. In some embodiments, the DIR comprises the amino acid sequence shown in SEQ ID NO:1. In some embodiments, the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:8. In some embodiments, the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:93. In some embodiments, the cognitive impairment includes cognitive impairment due to normal aging, Lewis body dementia (LBD), frontotemporal dementia, and / or vascular dementia. In some implementations, the inducing diseases of the cognitive impairment include Alzheimer's disease, multiple infarct type, Parkinson's disease, AIDS, and / or Creutzfeldt-Jakob disease (CJD). In some implementations, the cognitive impairment includes early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment. In some implementations, the cognitive impairment includes amnesic MCI with multiple cognitive domain impairment (aMCI-m). In some embodiments, the neurodegenerative disease includes acute neurodegenerative diseases and chronic neurodegenerative diseases. In some embodiments, the neurodegenerative diseases include neurodegenerative diseases caused by neuronal death and glial cell homeostasis, neurodegenerative diseases caused by aging, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegenerative diseases caused by impaired cell motility. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and / or Huntington's disease (HD). In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, the neurodegenerative disease includes early-stage Alzheimer's disease, mid-stage Alzheimer's disease, and / or late-stage Alzheimer's disease. In some implementations, the system is available in the form of a kit. In some implementations, the system includes a collection module capable of collecting samples from subjects in need. In some implementations, the subjects include mammals. In some implementations, the subjects include cancer patients. In some implementations, the subject is in an elderly stage. In some implementations, the sample includes blood samples and / or tissue or cell samples. In some embodiments, the sample includes whole blood, serum, plasma, and / or cerebrospinal fluid. In some embodiments, the system includes a detection module capable of detecting the content of the DIR and / or the nucleic acid encoding the DIR. In some embodiments, the detection module detects the content of the DIR and / or the nucleic acid encoding the DIR in the sample obtained by the collection module. In some embodiments, the detection module includes a substance capable of detecting the DIR and / or the amount of nucleic acid encoding the DIR. In some embodiments, the substance includes an antigen-binding protein capable of specifically binding to DIR, a probe capable of specifically binding to DIR, primers capable of specifically amplifying nucleic acids encoding DIR, a gene chip capable of specifically detecting nucleic acids encoding DIR, an aptamer capable of specifically binding to nucleic acids encoding DIR, and / or a guide RNA capable of specifically binding to nucleic acids encoding DIR. In some embodiments, the antigen-binding protein comprises LCDR2, said LCDR2 comprising SEQ ID NO:74 The amino acid sequence shown. In some embodiments, the LCDR2 comprises the amino acid sequence shown in SEQ ID NO:26 or 16. In some embodiments, the antigen-binding protein comprises LCDR1, which contains the amino acid sequence shown in SEQ ID NO:73. In some embodiments, the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 25, 52, and 15. In some embodiments, the antigen-binding protein comprises LCDR3, which comprises the amino acid sequence shown in SEQ ID NO:75. In some embodiments, the LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 27, 53, 67, 17. In some embodiments, the antigen-binding protein comprises LCDR1, LCDR2, and LCDR3, wherein, a) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:25, the LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:27; b) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:52, the LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:53; c) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:52, the LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:67; or, d) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:15, the LCDR2 contains the amino acid sequence shown in SEQ ID NO:16, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:17. In some embodiments, the antigen-binding protein comprises HCDR1, which comprises the amino acid sequence shown in SEQ ID NO:70. In some embodiments, the HCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 20, 35, 56, 10. In some embodiments, the antigen-binding protein comprises HCDR2, which comprises the amino acid sequence shown in SEQ ID NO:71. In some embodiments, the HCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 21, 36, 42, 48, 11. In some embodiments, the antigen-binding protein comprises HCDR3, which comprises the amino acid sequence shown in SEQ ID NO:70. In some embodiments, the HCDR3 comprises SEQ ID NO: 22, 30, 37, 43, 49, 57, 62, 12. The amino acid sequence shown in any one of them. In some embodiments, the antigen-binding protein comprises HCDR1, HCDR2, and HCDR3, wherein, a) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:21, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:22; b) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:21, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:30. c) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:37; d) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:42, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:43; e) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:48, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:49; f) HCDR1 contains the amino acid sequence shown in SEQ ID NO:56, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:57; g) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:62; h) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:42, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:37; i) HCDR1 contains the amino acid sequence shown in SEQ ID NO:56, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:57; or, j) HCDR1 contains the amino acid sequence shown in SEQ ID NO:10, HCDR2 contains the amino acid sequence shown in SEQ ID NO:11, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:12. In some embodiments, the antigen-binding protein includes a heavy chain variable region VH, the VH comprising the amino acid sequence shown in any one of SEQ ID NO: 13, 23, 31, 38, 44, 50, 58, 63, 65. In some embodiments, the antigen-binding protein includes a light chain variable region VL, the VL containing an amino acid sequence represented by any one of SEQ ID NO: 18, 28, 33, 40, 46, 54, 60, 68. In some embodiments, the antigen-binding protein comprises a heavy chain variable region VH and a light chain variable region VL, wherein: a) The VH contains the amino acid sequence shown in SEQ ID NO:23, and the VL contains the amino acid sequence shown in SEQ ID NO:28; b) The VH contains the amino acid sequence shown in SEQ ID NO:31, and the VL contains the amino acid sequence shown in SEQ ID NO:33. The amino acid sequence shown; c) The VH contains the amino acid sequence shown in SEQ ID NO:38, and the VL contains the amino acid sequence shown in SEQ ID NO:40; d) The VH contains the amino acid sequence shown in SEQ ID NO:44, and the VL contains the amino acid sequence shown in SEQ ID NO:46; e) The VH contains the amino acid sequence shown in SEQ ID NO:50, and the VL contains the amino acid sequence shown in SEQ ID NO:54; f) The VH contains the amino acid sequence shown in SEQ ID NO:58, and the VL contains the amino acid sequence shown in SEQ ID NO:60; g) The VH contains the amino acid sequence shown in SEQ ID NO:63, and the VL contains the amino acid sequence shown in SEQ ID NO:60; h) The VH contains the amino acid sequence shown in SEQ ID NO:65, and the VL contains the amino acid sequence shown in SEQ ID NO:54; i) The VH contains the amino acid sequence shown in SEQ ID NO:58, and the VL contains the amino acid sequence shown in SEQ ID NO:68; or, j) The VH contains the amino acid sequence shown in SEQ ID NO:13, and the VL contains the amino acid sequence shown in SEQ ID NO:18. In some embodiments, the antigen-binding protein includes a heavy chain constant region, and the heavy chain constant region includes a constant region derived from IgG. In some embodiments, the heavy chain constant region comprises a constant region derived from the following histones: IgG1, IgG2, IgG3, and IgG4. In some embodiments, the antigen-binding protein includes a light chain constant region, and the light chain constant region includes a constant region derived from Igκ or a constant region derived from Igλ. In some implementations, the light chain constant region includes a constant region derived from human Igκ. In some embodiments, the antigen-binding protein includes an antibody or an antigen-binding fragment thereof. In some embodiments, the antigen-binding fragment is selected from the group consisting of: Fab, Fab', F(ab)2, Fv fragment, F(ab')2, scFv, di-scFv, VHH and / or dAb. In some embodiments, the antibody is selected from the group consisting of monoclonal antibodies, murine antibodies, and chimeric antibodies. In some embodiments, the detection module includes an instrument capable of detecting the intron-retained cleavage product DIR of DNA damage-induced transcript 4-like transcript (DDIT4L), and / or the amount of nucleic acid encoding the DIR. In some embodiments, the detection module includes substances and / or instruments capable of detecting the levels of biomarkers associated with cognitive impairment and / or neurodegenerative diseases. In some implementations, the biomarkers associated with cognitive impairment and / or neurodegenerative diseases include AD7C-NTP, pTau-181, pTau-217, and / or Aβ1-42. In some implementations, the detection module outputs the content value of the DIR and / or the nucleic acid encoding the DIR. In some embodiments, the system includes a judgment module capable of determining the subject's diagnosis and / or disease progression based on the content of the DIR and / or the nucleic acid encoding the DIR compared with normal control values ​​and / or early control values; wherein the normal control values ​​include the content of the DIR and / or the nucleic acid encoding the DIR in normal subjects; wherein the early control values ​​include the content of the DIR and / or the nucleic acid encoding the DIR previously measured in the same subject. In some implementations, the normal subject does not suffer from the cognitive impairment and / or the neurodegenerative disease. In some implementations, when the level of DIR and / or the level of nucleic acid encoding DIR in the subject's sample is significantly higher than the normal control value, the judgment module diagnoses the subject as having the cognitive impairment and / or the neurodegenerative disease. In some implementations, the subject has been diagnosed with the cognitive impairment and / or the neurodegenerative disease. In some implementations, when the DIR and / or the content of the nucleic acid encoding DIR in the subject's sample are significantly higher than the earlier control value, the judgment module diagnoses the subject as having an accelerated disease progression of the cognitive impairment and / or the neurodegenerative disease. In some implementations, the judgment module outputs the diagnostic result of the subject. In some embodiments, the system includes a display module, wherein the display module is capable of displaying the diagnostic results of the judgment module. In some embodiments, the system includes a storage module, wherein the storage module is capable of storing the content value output by the detection module and / or the diagnostic result output by the judgment module. On the other hand, this application provides a drug screening method, which includes the following steps: detecting changes in the content of DIR and / or nucleic acids encoding DIR in a subject after administration of a candidate drug, wherein the drug is used to prevent, treat and / or alleviate cognitive impairment and / or neurodegenerative diseases. In some embodiments, the DIR comprises the amino acid sequence shown in SEQ ID NO:1. In some embodiments, the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:8. In some embodiments, the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:93. In some embodiments, the cognitive impairment includes cognitive impairment due to normal aging, Lewis's physical dementia (LBD), etc. Frontotemporal dementia and / or vascular dementia. In some implementations, the inducing diseases of the cognitive impairment include Alzheimer's disease, multiple infarct type, Parkinson's disease, AIDS, and / or Creutzfeldt-Jakob disease (CJD). In some implementations, the cognitive impairment includes early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment. In some implementations, the cognitive impairment includes amnesic MCI with multiple cognitive domain impairment (aMCI-m). In some embodiments, the neurodegenerative disease includes acute neurodegenerative diseases and chronic neurodegenerative diseases. In some embodiments, the neurodegenerative diseases include neurodegenerative diseases caused by neuronal death and glial cell homeostasis, neurodegenerative diseases caused by aging, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegenerative diseases caused by impaired cell motility. In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and / or Huntington's disease (HD). In some embodiments, the neurodegenerative disease includes Alzheimer's disease. In some embodiments, the neurodegenerative disease includes early-stage Alzheimer's disease, mid-stage Alzheimer's disease, and / or late-stage Alzheimer's disease. In some embodiments, the candidate drug has a therapeutic effect if the levels of DIR and / or the nucleic acids encoding DIR are reduced in the subject when the candidate drug is administered. In some embodiments, the application includes injection. In some embodiments, the drug includes small molecule drugs and / or biological macromolecule drugs. In a first aspect of this application, the use of a substance for detecting the intron-retained cleavage product DIR encoding DNA damage-inducible transcript 4-like transcript (DDIT4L) from a subject sample in the preparation of a product (e.g., a kit) for the diagnosis of Alzheimer's disease, diagnosis of mild cognitive impairment, and / or assessment of the progression of Alzheimer's disease (e.g., grading or staging) in the subject is provided. In some implementations, the object is selected from: humans, non-human primates, rodents (such as rats, mice, guinea pigs), dogs, cats, horses, cattle, and sheep. In some implementations, the subject does not have cancer. In some implementations, the subject shown does not have a malignant tumor. In some embodiments, the DIR has a sequence selected from the group consisting of: a nucleotide sequence (mRNA) having SEQ ID NO:2; a nucleotide molecule encoding the DIR peptide having the nucleotide sequence shown in SEQ ID NO:3; or, A DIR peptide having the amino acid sequence shown in SEQ ID NO:4; a variant of the above sequence obtained by substitution, deletion and / or addition of one or more nucleotides and / or amino acids; a sequence having high homology with the above sequence (e.g., higher than 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% sequence homology). In some embodiments, the early-onset dementia includes an early stage (amnesia stage), a middle stage (neurological disorder stage), and a late stage (severe dementia stage). In some embodiments, the substance is selected from reagents, devices, or combinations thereof used for detecting DIR. In some embodiments, the substance is a substance for detecting the DIR at the gene level and / or protein level. For example, the substance is a substance for use in one or more detection techniques or methods selected from the group consisting of: immunohistochemistry (such as immunofluorescence assay, chemiluminescence assay, reverse enzyme-linked immunosorbent assay, immunogold assay), Western blotting, Northern blotting, PCR, microarray assay, and protein microarray assay. In some embodiments, the substance is selected from: substances specific to the DIR, such as antibodies to the DIR (e.g., monoclonal antibodies); probes specific to the cleavage product, gene chips, PCR primers, gRNA, etc. In some embodiments, the sample is selected from: blood samples, such as whole blood, serum, and plasma; tissue or cell samples; and cerebrospinal fluid. In some embodiments, the blood sample is fresh blood or frozen blood. In some implementations, an increased level of the DIR in the sample compared to a normal control indicates that the subject has Alzheimer's disease or mild cognitive impairment. In some implementations, an increased level of DIR in the sample compared to a mild cognitive impairment control or a prior control level of a subject diagnosed with Alzheimer's disease indicates that the subject's Alzheimer's disease has progressed (e.g., to a higher grade or stage). In some implementations, an increase in the level of the DIR in the sample compared to a control at a lower grade or stage indicates that the subject has progressed in Alzheimer's disease (e.g., at a higher grade or stage). On the other hand, this application provides a diagnostic kit comprising the intron retention cleavage product DIR of DNA damage-induced transcript 4-like transcript (DDIT4L) as described in this application, and / or a substance encoding the nucleic acid of said DIR. For example, this application provides a product (e.g., a kit) for the diagnosis of Alzheimer's disease, the diagnosis of mild cognitive impairment, and / or the assessment of the progression of Alzheimer's disease (e.g., grading or staging), comprising: (i) a substance used to detect DIR in a sample; and (ii)Optional, other substances for the diagnosis of Alzheimer's disease, the diagnosis of mild cognitive impairment and / or the assessment of the progression of Alzheimer's disease (e.g., grading or staging), such as detection substances for detecting existing Alzheimer's disease biomarkers. In some embodiments, the substance in (i) is selected from one or more of the following group: Reagents, equipment, or combinations thereof used to detect the DIR; Substances for detecting said DIR at the gene and / or protein level, such as substances for use in one or more detection techniques or methods selected from the group consisting of: immunohistochemistry (e.g., immunofluorescence assay, chemiluminescence assay, reverse enzyme-linked immunosorbent assay, immunogold assay), Western blotting, Northern blotting, PCR, microarray assay; or Substances specific to the DIR, such as antibodies (preferably monoclonal antibodies); probes specific to the cleavage products, gene chips, PCR primers, gRNA. In some embodiments, the other substances in (ii) are selected from: substances for detecting one or more other Alzheimer's disease markers, such as AD7C-NTP, pTau-181, pTau-217, Aβ1-42; and / or, reagents for imaging brain amyloid; and / or, reagents for imaging diagnosis of the subject's brain. In some aspects of this application, a method for screening drugs for the treatment of Alzheimer's disease is provided, the method comprising: detecting the effect of a candidate drug on the DIR level in a subject, wherein a decrease in the DIR level after use of the candidate drug indicates that the candidate drug has a therapeutic effect on Alzheimer's disease. In some embodiments, the detection is performed using a product as described in this application. In some aspects of this application, methods are provided for diagnosing Alzheimer's disease, diagnosing mild cognitive impairment, and / or assessing the progression of cognitive impairment, the methods comprising: detecting the level of DIR in a sample from the subject, and thereby assessing the subject for diagnosis of Alzheimer's disease and / or assessment of the progression of Alzheimer's disease (e.g., grading or staging). In some embodiments, the detection is performed using a product as described in this application. In some implementations, an increased level of the DIR in the sample compared to a control indicates that the subject has Alzheimer's disease; or, an increased level of the DIR in the sample compared to a low-grade or low-stage control indicates that the subject's Alzheimer's disease has progressed (e.g., to a higher grade or stage). In some aspects of this application, a system corresponding to the method of this application is also provided, which includes the following apparatus: (a) A device for acquiring and / or receiving DIR level data in a sample; (b) An apparatus for analyzing data to diagnose Alzheimer's disease, mild cognitive impairment, and / or assess the progression of Alzheimer's disease (e.g., grading or staging) in the subject, wherein an increased level of the DIR in the sample compared to a normal control indicates that the subject has Alzheimer's disease or mild cognitive impairment; or, an increased level of the DIR in the sample compared to a mild cognitive impairment control or to a prior control level in a subject already diagnosed with Alzheimer's disease indicates that the subject has progressed in Alzheimer's disease (e.g., to a higher grade or stage). In some embodiments, the system further includes (a') means for acquiring and / or receiving data on other clinical indicators or essential characteristics of Alzheimer's disease diagnosis and / or the progression of Alzheimer's disease in samples. In some embodiments, the device described in (b) is used to combine DIR level data with other clinical indicators or basic characteristic data of Alzheimer's disease diagnosis and / or Alzheimer's disease progression to perform prognostic assessment of the subject's Alzheimer's disease diagnosis and / or Alzheimer's disease progression. Alternatively, in some embodiments, the system may further include equipment for analyzing other clinical indicators or basic characteristic data of Alzheimer's disease diagnosis and / or Alzheimer's disease progression; and / or equipment for combining DIR level data with other clinical indicators or basic characteristic data of Alzheimer's disease diagnosis and / or Alzheimer's disease progression to assess the Alzheimer's disease diagnosis and / or Alzheimer's disease progression of the subject. In some embodiments, the system further includes one or more means selected from the group consisting of: means for inputting and / or outputting and / or storing data; means for outputting and / or storing analysis results, such as means for uploading and / or storing analysis results to a cloud database or a corresponding cloud database means thereof; and means for intelligently analyzing and recommending treatment plans based on prognostic assessment results. It should be understood that those skilled in the art may add other conventional devices or programs to the system as needed. Other aspects and advantages of this application will readily be apparent to those skilled in the art from the detailed description below. Only exemplary embodiments of this application are shown and described in the following detailed description. As will be appreciated by those skilled in the art, the content of this application enables them to make modifications to the disclosed specific embodiments without departing from the spirit and scope of the invention to which this application pertains. Accordingly, the descriptions in the accompanying drawings and specification of this application are merely exemplary and not restrictive. Attached Figure Description The specific features of the invention involved in this application are shown in the appended claims. The features and advantages of the invention can be better understood by referring to the exemplary embodiments and drawings described in detail below. A brief description of the drawings is as follows: Figures 1a-1b show the splicing pattern of the DDIT4L mRNA precursor and the secretion of DIR protein from transfected cells into the culture medium. Among them: Figure a: Splicing modes of DDIT4L, where the length of the mRNA obtained by removing introns through normal splicing is 582 nt (SEQ ID NO:95), and the length of the RNA encoding DIR in the mRNA obtained by abnormal intron retention splicing is 255 nt (SEQ ID NO:8); Figure b: DIR secretion from cells into the culture medium. After transfecting HEK293 cells with the pCMV-flag-DIR plasmid and culturing for 48 hours, the secreted DIR protein was detectable in the culture medium. A 12 kDa DIR protein band was visible in the DIR plasmid lanes of the lysate. Figures 2a-2b show the changes in the levels of DIR protein in the blood of patients with AD and many other diseases. Figure a: Changes in DIR levels in the blood of patients with Alzheimer's disease and various other diseases as detected by Western spectroscopy; The plasma protein in the diagram is the light chain of the immunoglobulin used as an internal control. Figure b: Changes in DIR levels in the blood of AD patients, MCI patients, and non-AD / MCI patients detected by ELISA. *** in the figure indicates P<0.001, and * indicates P<0.05. Figure 3 shows the standard curve for the ELISA detection of the standard DIR protein. Figure 4 shows the R-°C curve of ELISA detection of clinical samples. Figure 5 shows the changes in DIR levels in the blood of patients with different types of MCI. Figure 6 shows the changes in the levels of DIR and other indicators in the blood of patients with different categories of MCI and AD. Figure 7 shows the correlation between DIR expression levels in plasma and cerebrospinal fluid. Figure 8 shows the results of the binding activity assay for the DIR antibody described in this application. Detailed Implementation The following specific embodiments illustrate the implementation of the invention. Those skilled in the art can easily understand other advantages and effects of the invention from the content disclosed in this specification. Terminology Definition The term "DDIT4L" typically refers to DNA damage-inducible transcript 4-like. It can also be called REDD2 / RTP801L. Studies have found that DDIT4L can be associated with cardiac dysfunction and may also be used to treat gliomas. The human DDIT4L gene has a GenBank accession number of 115265; the human DDIT4L protein has a GenBank accession number of NP_660287.1. The term "QDLIR" typically refers to the intron-retained cleavage product of DDIT4L. In this application, the amino acid sequence of the QDLIR may be as shown in SEQ ID NO:1. In this application, QDLIR can be used interchangeably with DIR, which can be an intron-retained form generated by abnormal cleavage during human DDIT4L gene expression. In this application, the gene encoding the DIR may be called the DIR gene. The DIR may comprise the amino acid sequence encoded by the first exon (as shown in SEQ ID NO:2) and the amino acid sequence encoded by the retained intron (as shown in SEQ ID NO:3). The amino acid sequence (IR) encoded by the retained intron may be divided into two parts: IR-I (DIR-I, amino acid sequence as shown in SEQ ID NO:4) consisting of the first 27 amino acids from the N-terminus and DIR-II (DIR-II, amino acid sequence as shown in SEQ ID NO:5) consisting of the last 27 amino acids. The term "expression level" typically refers to the protein, RNA, or mRNA level of a specific related gene. It can be measured using any method known in the art. This method determines the expression level of specific related genes (e.g., the human DDIT4L gene). In this application, "expression" generally refers to the process of transforming gene-encoded information into structures present and operating within cells. Examples include reverse transcription and amplification analysis (e.g., PCR, ligation RT-PCR, or quantitative RT-PCT), hybridization analysis, Northern blotting, dot blot blotting, in situ hybridization, gel electrophoresis, capillary electrophoresis, column chromatography, Western blotting, immunohistochemistry, immunostaining, or mass spectrometry. Analysis can be performed directly on biological samples or on proteins / nucleic acids isolated from samples. The term "neurodegenerative disease" generally refers to cognitive impairments such as dementia caused by the gradual loss of neuronal structure and function, including neuronal death and glial cell homeostasis. In some cases, age (e.g., Alzheimer's disease (AD), Parkinson's disease (PD)) or gene mutations affecting CNS cell function (e.g., Huntington's disease, early-onset AD or PD, amyotrophic lateral sclerosis (ALS)) can cause these neurodegenerative diseases. These neurodegenerative diseases may have changes and / or symptoms selected from: protein misfolding and aggregation; neuroinflammation (e.g., CNS inflammation in response to toxic stimuli (such as protein aggregation), infection, traumatic injury, or autoimmune signals); alterations in cell signal transduction; acquired aging / cell death (e.g., disrupted apoptotic signal transduction, mitochondrial dysfunction, impaired autophagy, and activation of necrosomes by stress / inflammation); motor cell damage; and epigenetic changes. The term "Alzheimer's disease" usually refers to early-onset dementia or senile dementia, a slowly progressing neurodegenerative disease that worsens over time. The most common early symptom is loss of short-term memory (difficulty remembering recent events). As the disease progresses, at least one of the following symptoms may gradually appear: language impairment, disorientation (e.g., getting lost), mood instability, loss of motivation, inability to care for oneself, and behavioral problems. The exact cause of Alzheimer's disease remains unknown, but its progression may be related to the deposition of fibrillary amyloid plaques and tau protein in the brain. Currently, there are no treatments that can stop or reverse the disease's progression; only a few methods may temporarily alleviate or improve symptoms. The term "early-onset dementia" may be used interchangeably with the term "Alzheimer's disease" in this application. Early-onset dementia may include early, intermediate, and / or late-stage early-onset dementia. For example, in early-stage dementia, learning and memory impairments become increasingly apparent, and in some cases, language impairments, executive impairments, cognitive impairments (agnosia), and / or skill executive impairments (apraxia) may occur. For example, in intermediate-stage dementia, patients will lose the ability to live independently and may be unable to perform most daily activities (in some cases, they may suffer from agnosia, speech disorder, and / or loss of sensation). For example, in late-stage dementia, patients may become dependent on caregivers. For example, they may completely lose their language abilities. For example, they may be unable to feed themselves. The term "cognitive impairment" generally refers to diseases and conditions that are believed to involve or do involve progressive loss of neuronal structure and / or function (including neuronal death) or are related to the foregoing. For example, characteristics of said cognitive impairment may include impairment in cognition (e.g., memory, attention, perception, and / or thinking). These impairments may include pathogen-induced cognitive dysfunction, such as… Examples of cognitive impairment include HIV-related cognitive impairment and Lyme disease-related cognitive impairment. Examples of cognitive impairment can include Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), autism, early cognitive impairment (MCI), stroke, traumatic brain injury (TBI), and / or age-related memory impairment (AAMI). The term "early cognitive impairment (MCI)" generally refers to an intermediate clinical state between normal cognition and cognitive impairment. In some cases, MCI can include cognitive impairment that meets the criteria for dementia but exceeds the level of normal aging. MCI varies in clinical presentation, etiology, prognosis, and prevalence. In some cases, MCI can be a pathological stage of Alzheimer's disease. Certain forms of cognitive impairment can be seen as early manifestations of neurodegenerative diseases that will eventually lead to dementia. In some cases, MCI can include subtypes selected from the following groups: aMCI-s: amnestic MCI with single cognitive domain impairment; aMCI-m: amnestic MCI with multi-cognitive domain impairment; naMCI-s: non-amnestic MCI with single cognitive domain impairment; and naMCI-m: non-amnestic MCI with multi-cognitive domain impairment. The term "age-related cognitive impairment" generally refers to cognitive impairment caused by normal aging. For example, age-related cognitive impairment may manifest as memory loss, confusion about the location of familiar places, taking longer than usual to complete daily tasks, or changes in mood and personality. The term "Lewy body dementia (LBD)" usually refers to Lewy body dementia. Lewy body dementia is characterized by the abnormal accumulation of proteins in the form of lumps called Lewy bodies. Lewy body dementia leads to a gradual decline in cognitive abilities. Patients with Lewy body dementia may experience hallucinations as well as changes in alertness and attention. Other effects include muscle stiffness, slow movement, difficulty walking, and tremors. Patients with Lewy bodies in the brain may also have plaques and tangles associated with Alzheimer's disease. The term "frontotemporal dementia" usually refers to Pick's disease, a rare, progressive disorder caused by the tau protein affecting only the frontal and temporal lobes of the brain. Individuals with frontotemporal dementia experience difficulties with higher-level reasoning, verbal expression, language perception, and memory formation. The frontal and temporal lobes of the brain in individuals with frontotemporal dementia can atrophy over time. The term "vascular dementia" generally refers to problems with reasoning, judgment, and memory caused by impaired blood flow to the brain. For example, vascular dementia can include dementia caused by factors that contribute to heart disease and stroke risk, such as high blood pressure and high cholesterol. The term "multiple infarct type" generally refers to noncortical small infarcts caused by occlusion of a single perforating branch of a large cerebral artery. This multiple infarct type can be a special type of cerebral infarction, also known as ischemic stroke. Symptoms of multiple infarct type may include hemisensory disturbance, aphasia, dysarthria, slow movement, and clumsiness (especially difficulty with fine motor skills such as writing). The term "Parkinson's disease" generally refers to a progressive neurodegenerative disease. Clinical features of Parkinson's disease (PD) can include motor symptoms (such as tremor, bradykinesia, rigidity, and postural instability), as well as neuropsychiatric and other non-motor manifestations. For example, non-motor manifestations can include cognitive impairment and dementia, mood disorders (such as depression, anxiety, and apathy), and sleep disturbances. The term "Cryptocytosis (CJD)" generally refers to a contagious spongiform encephalopathy that occurs in humans. CJD is caused by prion infection. Patients with CJD may exhibit paranoid behavior, confusion, loss of appetite and weight, depression, and a few patients may have visual or auditory abnormalities; in the progressive stage, it manifests as progressive deterioration of the neurological condition (e.g., sensory abnormalities, language impairment, and aphasia). The term "multiple sclerosis (MS)" generally refers to a demyelinating neuropathy. In MS patients, the insulating material (myelin sheath) on the surface of nerve cells in the brain or spinal cord is destroyed, impairing signal transduction in the nervous system. This can lead to a range of symptoms that affect a patient's activity, mental state, and even emotional state. These symptoms may include double vision, unilateral vision loss, muscle weakness, sensory impairment, or coordination problems. The term "amyotrophic lateral sclerosis (ALS)" usually refers to Lou Gehrig's disease or motor neuron disease, a progressive and fatal neurodegenerative disease. A small percentage of ALS patients may develop frontotemporal dementia. Some ALS patients experience a decline in their sense of smell, vision, touch, smell, and taste; a very small number of ALS patients also develop dementia. The term "Huntington's disease (HD)," or Huntington's chorea, generally refers to a genetic disorder that causes brain cell death. As the disease progresses, individuals with HD experience more pronounced incoordination, a gradual decline in abilities until movement becomes difficult and speech is lost. Mental abilities typically deteriorate to dementia. The term "aging stage" generally refers to the stage of aging of a subject. For example, for humans, the aging stage can be 60 years or older, 70 years or older, or 75 years or older; for mice, the aging stage can be 10 months or older, for example, 13 months or older or 18 months or older. In some cases, subjects in the aging stage may have one or more symptoms of learning deficits, memory impairment, memory deficits, and / or brain dysfunction. The term "variant" generally refers to a polypeptide containing an amino acid sequence that differs from the amino acid sequence of a parent or reference polypeptide (e.g., a wild-type polypeptide) by at least one amino acid residue. In this application, the variant may have a high (e.g., at least 80%) homology with the parent or reference polypeptide. This homology may include sequence similarity or identity. In this application, homology can be determined using standard techniques known in the art (see, for example, Smith and Waterman, Adv. Appl. Math.); the percentage of identity shared by polynucleotide or polypeptide sequences is determined by direct comparison of sequence information between molecules, which is performed by sequence alignment and determination of identity using methods known in the art. An example of an algorithm suitable for determining sequence similarity is the BLAST algorithm (see Altschul et al., J. Mol. Biol. Journal of Molecular Biology, 215:403-410).

[1990] The software used for BLAST analysis is publicly available from the National Center for Biotechnology Information (NCBI). In this application, the term "CDR," also known as "complementarity-determining region," typically refers to a region within the variable structural domain of an antibody whose sequence can be highly variable and / or form a structurally defining loop. For example, an antibody may include six CDRs; three in the VH domain (HCDR1, HCDR2, HCDR3) and three in the VL domain (LCDR1, LCDR2, LCDR3). In some... In the implementation plan, naturally occurring camel antibodies composed solely of heavy chains can function normally and stably even in the absence of light chains. Antibody CDRs can be determined using various coding systems, such as CCG, Kabat, Chothia, IMGT, and a combination of Kabat / Chothia. These coding systems are known in the art and can be found, for example, at www.bioinf.org.uk / abs / index.html#kabatnum. For example, the amino acid sequence number of the antigen-binding protein can be in accordance with the IMGT numbering scheme (IMGT, the international ImMunoGeneTics information system @imgt.cines.fr; imgt.cines.fr; Lefranc et al., 1999, Nucleic Acids Res. 27:209-212; Ruiz et al., 2000 Nucleic Acids Res. 28:219-221; Lefranc et al., 2001, Nucleic Acids Res. 29:207-209; Lefranc et al., 2003, Nucleic Acids Res. 31:307-310; Lefranc et al., 2005, DevComp Immunol 29:185-203). For example, the CDR of the antigen-binding protein can be determined according to the Kabat numbering system (see, for example, Kabat EA & Wu TT (1971) Ann NY Acad Sci 190:382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, Department of Health and Human Services, NIH Publication No. 91-3242). In this application, the term "FR" generally refers to a more conserved portion of the antibody variable domain, which is referred to as a frame region. For example, the variable domains of the natural heavy chain and light chain may each contain four FR regions, namely four in VH (H-FR1, H-FR2, H-FR3, and H-FR4) and four in VL (L-FR1, L-FR2, L-FR3, and L-FR4). In this application, the terms "variable domain" and "variable region" are used interchangeably and generally refer to a portion of the antibody heavy chain and / or light chain. Variable domains of the heavy and light chains may be referred to as "VH" and "VL" (or simply "VH" and "VL"). These domains are typically the most variable parts of the antibody (relative to other antibodies of the same type) and may contain antigen-binding sites. In this application, the term "variable" generally refers to the possibility that certain segments of the variable domain may differ significantly in sequence between antibodies. Variable domains mediate antigen binding and determine the specificity of a particular antibody for its specific antigen. However, variability may not be uniformly distributed across the entire variable domain. It may typically be concentrated in three segments within the light and heavy chain variable domains, referred to as hypervariable regions (CDRs or HVRs). More highly conserved portions of the variable domain may be referred to as frame regions (FRs). The variable domains of the native heavy and light chains may each contain four FR regions, mostly in a β-sheet configuration, linked by three CDRs forming a ring link, and in some cases forming part of a β-sheet structure. CDRs in each chain can be held together closely by the FR region, and CDRs from the other chain together promote the formation of antigen-binding sites for antibodies. In this application, the term "antibody" generally refers to an immunoglobulin or a fragment thereof or a derivative thereof, encompassing any polypeptide including an antigen-binding site, whether produced in vitro or in vivo. This term may include, but is not limited to, polyclonal, monoclonal, single-specific, multi-specific, non-specific, humanized, single-chain, chimeric, synthetic, recombinant, hybrid, mutant, and transplanted antibodies. Unless otherwise modified by the term "intact," as in "intact antibody,"... For the purposes of this application, the term "antibody" may also include antibody fragments such as Fab, F(ab')2, Fv, scFv, Fd, VHH, dAb, and other antibody fragments that maintain antigen-binding function (e.g., specific binding to human DIR). Typically, such fragments may include antigen-binding domains. A basic 4-chain antibody unit can be a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. IgM antibodies may consist of five basic heterotetrameric units and a polypeptide called the J chain, containing 10 antigen-binding sites, while IgA antibodies may include 2-5 basic 4-chain units that can polymerize with the J chain to form a multivalent combination. For IgG, a 4-chain unit is typically about 150,000 Daltons. Each L chain can be linked to an H chain via a covalent disulfide bond, and two H chains can be linked to each other via one or more disulfide bonds depending on the type of H chain. Each H and L chain may also have regularly spaced intrachain disulfide bridges. Each H chain may have a heavy chain variable region (VH) at its N-terminus, followed by three constant domains (CH) for α and γ chains, and four CH domains for μ and ε isoforms. Each L chain may have a light chain variable region (VL) at its N-terminus and a constant domain at its other end. VL corresponds to VH, and the light chain constant region (CL) corresponds to the first constant domain (CH1) of the heavy chain. Specific amino acid residues can be considered to form an interface between the light and heavy chain variable domains. VH and VL can pair together to form a single antigen-binding site. L chains from any vertebrate species can be classified into one of two distinct types, called κ and λ, based on the amino acid sequence of their constant domains. Immunoglobulins can be classified into different classes or isoforms based on the amino acid sequence of the heavy chain constant region (CH) constant domain. There are currently five classes of immunoglobulins: IgA, IgD, IgE, IgG such as IgG1, IgG2, IgG3 and / or IgG4, and IgM, which have heavy chains named α, δ, ε, γ and μ, respectively. In this application, the term "antigen-binding fragment" generally refers to one or more fragments having the ability to specifically bind an antigen (e.g., DIR). In this application, the antigen-binding fragment may include Fab, Fab', F(ab)2, Fv fragments, F(ab')2, scFv, di-scFv, VHH, and / or dAb. In this application, the term "Fab" generally refers to the antigen-binding fragment of an antibody. As described above, an intact antibody can be digested using papain. After digestion with papain, the antibody produces two identical antigen-binding fragments, namely the "Fab" fragment, and a residual "Fc" fragment (i.e., the Fc region). The Fab fragment may consist of a complete L chain with a variable region of a heavy chain and a first constant region (CH1) of the H chain (VH). In this application, the term "F(ab)2" generally refers to the antigen-binding fragment of an antibody. For example, F(ab)2 can be composed of two Fab fragments linked together. In this application, the term "Fab'" generally refers to a monovalent antigen-binding fragment of a human monoclonal antibody, which is slightly larger than the Fab fragment. For example, the Fab' fragment may include all light chains, all heavy chain variable regions, and all or part of the first and second constant regions of the heavy chain. For example, the Fab' fragment may also include part or all of the 220-330 amino acid residues of the heavy chain. In this application, the term "F(ab')2" generally refers to an antibody fragment produced by digesting an intact antibody with pepsin. The F(ab')2 fragment contains two Fab fragments held together by disulfide bonds and a partial hinge region. The F(ab')2 fragment exhibits bivalent antigen-binding activity and is capable of cross-linking antigens. In this application, the term "Fv fragment" generally refers to a monovalent antigen-binding fragment of a human monoclonal antibody, comprising all or part of the heavy chain variable region and light chain variable region, and lacking the heavy chain constant region and light chain constant region. The heavy chain variable region and light chain variable region include, for example, CDRs. For example, an Fv fragment comprises all or part of the amino-terminal variable region of about 110 amino acids of the heavy and light chains. In this application, the term "scFv" generally refers to a fusion protein comprising at least one antibody fragment including a variable region comprising a light chain and at least one antibody fragment including a variable region comprising a heavy chain, wherein the light and heavy chain variable regions are adjacent (e.g., via a synthetic linker such as a short, flexible peptide linker) and are capable of being expressed as a single-chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived. Unless otherwise specified, as used in this application, the scFv may have the VL and VH variable regions in any order (e.g., relative to the N-terminus and C-terminus of the polypeptide), and the scFv may comprise VL-linker-VH or may comprise VH-linker-VL. In this application, the term “dAb” generally refers to an antigen-binding fragment consisting of a VH domain or a VL domain, for example, Ward et al. (Nature, 1989 Oct 12; 341(6242): 544-6), Holt et al., Trends Biotechnol., 2003, 21(11): 484-490. In this application, the term "VHH" generally refers to an antibody containing a variable antigen-binding domain of a heavy chain antibody (see Vanlandschoot P. et al., 2011, Antiviral Research 92, 389-407). VHH may also be referred to as a nanobody (Nb). In this application, the term "monoclonal antibody" generally refers to an antibody molecule preparation consisting of a single molecule. Monoclonal antibodies typically exhibit high specificity against a single antigenic site. Moreover, unlike conventional polyclonal antibody preparations (which usually contain different antibodies targeting different determinants), each monoclonal antibody can target a single determinant on an antigen. In addition to their specificity, monoclonal antibodies have the advantage that they can be synthesized through hybridoma culture without contamination by other immunoglobulins. The modifier "monoclonal" can indicate the characteristics of an antibody obtained from a substantially homogeneous group of antibodies and is not to be interpreted as requiring the antibody to be produced by any particular method. For example, the monoclonal antibodies used in this application can be prepared in hybridoma cells or by recombinant DNA methods. In this application, the term "chimeric antibody" generally refers to an antibody in which the variable region is derived from one species and the constant region is derived from another species. Typically, the variable region is derived from an antibody from a laboratory animal such as a rodent ("parental antibody") and the constant region is derived from a human antibody, such that the resulting chimeric antibody is less likely to elicit an adverse immune response in human individuals compared to parental (e.g., mouse-derived) antibodies. In this application, the term "humanized antibody" generally refers to an antibody in which some or all of the amino acids outside the CDR region of a non-human antibody (e.g., a mouse antibody) are replaced by corresponding amino acids derived from human immunoglobulins. Small additions, deletions, insertions, substitutions, or modifications of amino acids in the CDR region are also permissible, as long as they retain the antibody's ability to bind to a specific antigen. A humanized antibody may optionally contain at least a portion of the constant region of a human immunoglobulin. A "humanized antibody" may retain antigen specificity similar to that of the original antibody. The "humanized" form of a non-human (e.g., mouse) antibody may minimally contain a chimeric antibody with a sequence derived from a non-human immunoglobulin. In some cases, CDR region residues in a human immunoglobulin (receptor antibody) may be replaced with CDR region residues from a non-human species (donor antibody) (such as a mouse, rat, rabbit, or non-human primate) having the desired properties, affinity, and / or capabilities. In some cases, FR region residues in a human immunoglobulin may be replaced with corresponding non-human residues. Furthermore, humanized antibodies can contain amino acid modifications not found in receptor antibodies or in donor antibodies. These modifications can be made to further improve antibody performance, such as binding affinity. In this application, the term "fully human antibody" generally refers to an antibody that contains only the protein sequence of human immunoglobulins. If it is produced in mice, in mouse cells, or in hybridomas derived from mouse cells, then a fully human antibody may contain mouse glycans. Similarly, "mouse antibody," "mouse antibody," or "rat antibody" respectively refers to an antibody that contains only mouse or rat immunoglobulin sequences. Fully human antibodies can be generated in humans or in transgenic animals with human immunoglobulin germline sequences via phage display or other molecular biology methods. Exemplary techniques that can be used to manufacture antibodies are known in the art. In this application, the term "antigen-binding protein" generally refers to a protein containing a portion that binds to an antigen, and optionally, a scaffold or backbone portion that allows the antigen-binding portion to adopt a conformation that promotes the binding of the antigen-binding protein to the antigen. Examples of antigen-binding proteins include, but are not limited to, antibodies, antigen-binding fragments (Fab, Fab', F(ab)2, Fv fragments, F(ab')2, scFv, di-scFv, VHH, and / or dAb), immunoconjugates, multispecific antibodies (e.g., bispecific antibodies), antibody fragments, antibody derivatives, antibody analogs, or fusion proteins, as long as they exhibit the desired antigen-binding activity. The "antigen-binding protein" of this application may contain a portion that binds to an antigen and optionally, allow the antigen-binding portion to adopt a scaffold or backbone portion that promotes the binding of the antigen-binding portion to the antigen. The term "about" typically refers to a range of values ​​that are 20% more or less than a specific value. For example, "about X" includes a range of values ​​that are ±20%, ±10%, ±5%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1% of X, where X is a numerical value. Invention Details Early detection and treatment of Alzheimer's disease hinges on identifying its specific diagnostic biomarkers. The inventors discovered the presence of the DIR protein in the blood of Alzheimer's patients, while it was undetectable in the blood of healthy individuals. This result suggests that DIR could potentially serve as a blood biomarker for the diagnosis (and possibly early diagnosis) of Alzheimer's disease; simultaneously, the inventors further explored its… He also tested blood samples from patients with cognitive impairment and found that the DIR protein level was significantly elevated in the blood samples of patients with cognitive impairment such as MCI (mild cognitive impairment). Therefore, elevated DIR in the blood will be a new biomarker in the diagnosis and treatment of Alzheimer's disease. Specifically, in pathological states (such as tumors and neurodegenerative diseases), the diseased tissue lacks blood supply, leading to hypoxia, which causes a series of changes in gene expression, along with the appearance of aberrant splice variants. Identifying the specific genes and their splice variants could be the key to unlocking disease treatment. The inventors previously discovered that DIR is an abnormal protein formed by abnormal splicing in the human body, and it only exists in human tissues and cells. DIR is a key molecule that can adaptively regulate cellular and tissue function through high expression and secretion under hypoxic conditions. Therefore, the inventors hypothesized that DIR could potentially enter the bloodstream through the blood supply system of diseased tissue. Subsequently, the inventors further proved the validity of this hypothesis through the following experiments: First, they extracellularly transferred DIR plasmids into HEK293 cells and then detected a large amount of DIR protein in the culture medium, demonstrating that DIR can be secreted extracellularly. Subsequently, DIR was detected in the plasma of AD and MCI patients, while it was not detected or detected at very low levels in the plasma of normal individuals and non-AD patients. This result indicates that DIR specifically exists in the blood of AD and MCI patients, thus serving as a blood biomarker for AD diagnosis (such as early diagnosis). Simultaneously, tests on blood samples from other patients with cognitive impairment revealed significantly elevated DIR protein levels; therefore, blood DIR levels can serve as a novel biomarker in the diagnosis and treatment of AD (Alzheimer's disease). All numerical ranges provided in this application are intended to clearly include all values ​​falling between the endpoints of the range and the range of values ​​between them. Features mentioned in this application or in the embodiments may be combined. All features disclosed in this application may be used in any compositional form, and each feature disclosed in the specification may be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features. As used in this application, “containing,” “having,” or “including” includes “comprising,” “mainly composed of,” “substantially composed of,” and “composed of”; “mainly composed of,” “substantially composed of,” and “composed of” are subordinate concepts of “containing,” “having,” or “including.” In this application, the neurodegenerative disease may include acute neurodegenerative diseases and chronic neurodegenerative diseases. For example, the neurodegenerative disease may include neurodegenerative diseases caused by neuronal death and glial cell homeostasis, neurodegenerative diseases caused by aging, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegenerative diseases caused by impaired cell motility. In this application, the neurodegenerative disease may include Alzheimer's disease. For example, the neurodegenerative disease may include early Alzheimer's disease, mid-Alzheimer's disease, and / or late Alzheimer's disease. In this application, the cognitive impairment may include early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment. For example, the cognitive impairment may include cognitive impairment caused by normal aging, Lewis's physical dementia (LBD), frontotemporal dementia, and / or vascular dementia. For example, the inducing diseases of the cognitive impairment may include Alzheimer's disease, multiple infarct type, Parkinson's disease, AIDS, and / or Creutzfeldt-Jakob disease (CJD). In this application, the cognitive impairment may include early cognitive impairment (MCI) (e.g., loss of short-term memory, difficulty in expressing or understanding abstract things, mood swings or behavioral changes, difficulty in learning new things and following complex instructions, impaired judgment and / or need for reminders from others to take care of basic self-care), mid-term cognitive impairment (e.g., confusion between long-term memory and memory of current situation, difficulty in expressing oneself, behavioral and personality changes or emotional instability and / or need for assistance with self-care), or late-term cognitive impairment (e.g., memory loss, decline in physical activity and mental condition, inability to express or communicate effectively, inability to take care of oneself and / or disruption of the biological clock). In this application, the cognitive impairment may include having a disease that can cause or induce the cognitive impairment. For example, the subject may have Alzheimer's disease, multiple infarct type, Parkinson's disease, HIV / AIDS, and / or Creutzfeldt-Jakob disease (CJD). Diagnostic target DIR On one hand, this application provides the use of an intron-retained cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L), and / or a nucleic acid encoding said DIR, in disease diagnosis and / or disease progression assessment, wherein said disease may include cognitive impairment. On one hand, this application provides the use of an intron-retaining cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L), and / or a nucleic acid encoding said DIR, in disease diagnosis and / or disease progression assessment, wherein said disease may include neurodegenerative diseases. DDIT4L (DNA Damage Inducible Transcript 4 Like, SEQ ID NO:92) is a protein-coding gene associated with the mTOR signaling pathway. Its level in macrophages can be upregulated by oxidized LDL and hypoxia. The DDIT4L gene, after intron removal via normal splicing, yields a nucleotide sequence (SEQ ID NO: 94) encoding a 193aa long DDIT4L protein. However, the applicant unexpectedly discovered another special splicing mode in this gene: intron retention splicing. This special splicing mode yields a 2212nt nucleotide sequence, and because the introns can contain terminators, it ultimately yields an 84aa splice product peptide (SEQ ID NO: 1). In this application, the protein obtained through intron retention splicing is referred to as "QDLIR or DIR" (as shown in Figure 1a). As used in this application, unless otherwise stated or clearly determined, the term "DIR" can include mature mRNA, cleavage peptide-encoded molecules, or splicing product peptides (or DIR proteins) obtained by intron retention cleavage of the DDIT4L gene. When the cleavage product can be mRNA, it can be selected from: (a) nucleotide sequences as shown in SEQ ID NO: 93. (a) a nucleotide molecule that has a high sequence identity with the nucleotide molecule of SEQ ID NO:93 (e.g., the sequence identity can be at least 80%, 85%, 90%, 92%, 95%, 98%, 99%, 99.5%, 99.8%). When the cleavage product can be a DIR-encoded molecule, it can be selected from: (a) a nucleotide molecule with a sequence as shown in SEQ ID NO: 8; or (b) a nucleotide molecule with high sequence identity to the nucleotide molecule of SEQ ID NO: 8 (e.g., sequence identity can be at least 80%, 85%, 90%, 92%, 95%, 98%, 99%, 99.5%, 99.8%). When the cleavage product can be a DIR protein, it can be selected from: (a') a polypeptide molecule with the sequence shown in SEQ ID NO: 1; (b') a protein molecule with high sequence identity to the polypeptide molecule of SEQ ID NO: 1 (e.g., sequence identity of at least 80%, 85%, 90%, 92%, 95%, 98%, 99%, 99.5%, 99.8%); (c') a protein molecule translated from any nucleotide molecule as described in (a) or (b) above; or (d') a conserved variant polypeptide, or a homologous protein or polypeptide, or an active fragment thereof, of any of the protein molecules described in (a') to (c') above. Diagnostic substances and diagnostic kits On the other hand, this application provides a substance for detecting the intron retention cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) and / or the nucleic acid encoding said DIR, in the preparation of products for disease diagnosis and / or disease progression assessment, wherein said disease may include cognitive impairment. On the other hand, this application provides a substance for detecting the intron retention cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) and / or the nucleic acid encoding said DIR, in the preparation of products for disease diagnosis and / or disease progression assessment, wherein said disease may include neurodegenerative diseases. As used herein, the terms "detection substance," "detection reagent," or "reagent for detecting DIR" or "reagent for detecting DIR expression" are used interchangeably and refer to substances that are specifically targeted at DIR molecules and can be used to directly or indirectly detect the presence and / or content of DIR molecules. These detection substances can detect DIR at the gene or protein level. In this application, the substance may include an antigen-binding protein capable of specifically binding to DIR, a probe capable of specifically binding to DIR, primers capable of specifically amplifying nucleic acids encoding DIR, a gene chip capable of specifically detecting nucleic acids encoding DIR, an aptamer capable of specifically binding to nucleic acids encoding DIR, and / or a guide RNA capable of specifically binding to nucleic acids encoding DIR. In this application, the kit may include at least one (e.g., 1, 2, 3 or more) of the detection substances. For example, the kit may include at least one (e.g., 1, 2, 3 or more) antigen-binding protein (e.g., DIR antibody) capable of specifically binding to DIR. In this application, antigen-binding proteins with different amino acid sequences of at least one CDR can be considered as different types of antigen-binding proteins. Based on the sequence of the DIR molecule, those skilled in the art can prepare or obtain reagents specifically targeting the DIR molecule using conventional methods. For example, the detection reagents available in this application may include, but are not limited to, those with specific targeting properties against the DIR molecule. Detection methods include specific antigen-binding proteins (e.g., monoclonal antibodies), probes, gene chips, PCR primers, gRNA, etc. Furthermore, for ease of detection, the detection reagents of this application may also carry detectable markers, which may include, but are not limited to: radioactive isotopes, fluorophores, chemiluminescent components, enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, dyes, metal ions, ligands (e.g., biotin or haptens), etc. The detection reagents of this application may exist in solution, immobilized on a carrier (such as a substrate or adsorbent), or in other manner conventional in the art, as long as the manner of existence is suitable for the detection of DIR in biological samples. For example, when the detection reagents of this application can be nucleotide probes, they can exist in the form of a biochip (or "microarray"). In this application, the product may exist in the form of a reagent kit. This application also provides a product for the diagnosis of Alzheimer's disease and / or the assessment of the progression of Alzheimer's disease (e.g., grading or staging), which may include: a substance for detecting DIR levels, and optionally other substances for the diagnosis of Alzheimer's disease and / or the assessment of the progression of Alzheimer's disease (e.g., grading or staging), such as substances for detecting existing AD markers. In this application, the diagnostic kit may include an instruction manual describing methods for diagnosing cognitive impairment and / or assessing the disease progression of cognitive impairment using the diagnostic kit; and / or diagnosing neurodegenerative diseases and / or assessing the disease progression of neurodegenerative diseases. Depending on the requirements of the detection method used, appropriate DIR detection substances can be selected and formulated into products suitable for the detection method, such as kits. Those skilled in the art can adjust and modify the detection method and the reagents contained in the product according to actual conditions and needs. Therefore, this application also provides a product (such as a test kit) that may comprise: (i) one or more reagents for detecting DIR; and (ii) one or more substances optionally selected from the group consisting of: containers, instructions for use, positive controls, negative controls, buffers, auxiliaries or solvents, such as solutions for suspending or fixing cells, detectable labels or markers, solutions for facilitating nucleic acid hybridization, solutions for lysing cells, or solutions for purifying nucleic acids. In one example, this application provides a detection kit suitable for detecting the expression of DIR protein in biological samples by immunohistochemistry. The detection kit may include: a blocking solution, such as 10% goat serum; a primary antibody, such as a rabbit anti-human or mouse DIR monoclonal antibody; a secondary antibody, such as a labeled (e.g., HRP-labeled) or unlabeled goat anti-rabbit secondary antibody; a substrate buffer, such as DAB substrate buffer; a chromogenic solution; and optionally, a container containing the above reagents and an instruction manual. The detection kit of this application may also include an instruction manual, which describes how to use the kit for detection. The kit described in this application is for the detection of cognitive impairment and how to use the test results to diagnose cognitive impairment and / or assess the disease progression of cognitive impairment, and / or diagnose neurodegenerative diseases, and / or assess the disease progression of neurodegenerative diseases. For example, the kit described in this application can be used for the diagnosis of Alzheimer's disease (AD) and / or the assessment of AD progression (e.g., grading or staging). The product of this application may also include other reagents used clinically for the diagnosis and / or assessment of AD progression (e.g., grading or staging) in subjects, to assist or validate the results obtained by detecting DIR. Those skilled in the art can make routine selections according to specific needs. Diagnostic methods On the other hand, this application provides a method for diagnosing cognitive impairment and / or assessing the disease progression of cognitive impairment, which may include the following steps: detecting the content of intron-retaining cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) and / or the content of nucleic acid encoding said DIR in a sample derived from a subject in need. On the other hand, this application provides a method for diagnosing neurodegenerative diseases and / or assessing the disease progression of neurodegenerative diseases, which may include the following steps: detecting the content of intron-retaining cleavage product DIR of DNA damage-inducing transcript 4-like transcript (DDIT4L) and / or the content of nucleic acid encoding said DIR in a sample derived from a subject in need. In this application, the subject may include a mammal. In this application, the subject may include a cancer patient. In this application, the subject is in an elderly stage. In this application, the sample may include blood samples and / or tissue or cell samples. In this application, the sample may include whole blood, serum, plasma and / or cerebrospinal fluid. In this application, the method may include: comparing the content of the DIR and / or the nucleic acid encoding DIR in the sample of the subject with a normal control value, wherein the normal control value may include the content of the DIR and / or the nucleic acid encoding DIR in a normal subject. In this application, the method can be used with the kit described in this application and / or the detection substance described in this application to diagnose cognitive impairment and / or assess the disease progression of cognitive impairment. In this application, the normal subject may not suffer from the cognitive impairment. The normal subject may not suffer from the neurodegenerative disease. In this application, when the DIR of the subject's sample and / or the content of the nucleic acid encoding DIR is significantly higher than (e.g., it can be increased by at least about 20%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more) the normal control value, the subject is diagnosed as having the cognitive impairment and / or the neurodegenerative disease. In this application, the method may include: comparing the content of the DIR and / or the nucleic acid encoding the DIR in a sample of the subject with an earlier control value, wherein the earlier control value may include the content of the DIR and / or the nucleic acid encoding the DIR previously measured for the same subject. In this application, the subject has been diagnosed with the cognitive impairment and / or the neurodegenerative disease. For example, the subject has been diagnosed with the cognitive impairment; or, the subject has been confirmed to have the neurodegenerative disease. In this application, when the DIR of the subject's sample and / or the content of the nucleic acid encoding the DIR is significantly higher than (e.g., it can be increased by at least about 20%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more) the earlier control value, the subject is diagnosed as having an exacerbation of the cognitive impairment and / or the neurodegenerative disease. In this application, the method may further include the step of detecting the levels of biomarkers associated with cognitive impairment and / or neurodegenerative diseases in a sample derived from the subject. In this application, the biomarkers associated with cognitive impairment and / or neurodegenerative diseases may further include AD7C-NTP, pTau-181, pTau-217, and / or Aβ1-42. The detection results of the levels of these biomarkers can be used to assist in the diagnosis of cognitive impairment and / or the assessment of the disease progression of cognitive impairment, and / or the diagnosis of neurodegenerative diseases, and / or the assessment of the disease progression of neurodegenerative diseases. In this application, the method may further include the step of observing brain imaging of the subject. The results of the brain imaging may be used to assist in the diagnosis of cognitive impairment, and / or to assess the disease progression of cognitive impairment, and / or to diagnose neurodegenerative diseases, and / or to assess the disease progression of neurodegenerative diseases. Diagnostic System On the other hand, this application provides a system for diagnosing cognitive impairment and / or assessing the disease progression of cognitive impairment, which may include a substance for detecting the intron retention cleavage product DIR of DNA damage-induced transcript 4-like transcript (DDIT4L) and / or a substance encoding the nucleic acid of said DIR. On the other hand, this application provides a system for diagnosing neurodegenerative diseases and / or assessing the disease progression of neurodegenerative diseases, which may include a substance for detecting the intron retention cleavage product DIR of DNA damage-induced transcript 4-like transcript (DDIT4L) and / or a substance encoding the nucleic acid of said DIR. In this application, the system may include a detection module capable of detecting the content of the DIR and / or the nucleic acid encoding the DIR. In this application, the detection module detects the content of the DIR and / or the nucleic acid encoding the DIR in the sample obtained by the collection module. In this application, the detection module may include a substance capable of detecting the DIR and / or the content of the nucleic acid encoding the DIR. In this application, the substance may include an antigen-binding protein capable of specifically binding to DIR, a probe capable of specifically binding to DIR, primers capable of specifically amplifying nucleic acids encoding DIR, a gene chip capable of specifically detecting nucleic acids encoding DIR, an aptamer capable of specifically binding to nucleic acids encoding DIR, and / or a guide RNA capable of specifically binding to nucleic acids encoding DIR. In this application, the detection module may include at least one (e.g., 1, 2, 3 or more) of the detection substances. For example, the detection module may include at least one (e.g., 1, 2, 3 or more) antigen-binding protein (e.g., DIR antibody) capable of specifically binding to DIR. In this application, antigen-binding proteins with different amino acid sequences of at least one CDR can be considered as different types of antigen-binding proteins. In this application, the detection module may include an instrument capable of detecting the intron-retained cleavage product DIR of DNA damage-induced transcript 4-like transcript (DDIT4L), and / or the content of nucleic acids encoding the DIR. For example, the instrument may include instruments required for qPCR, ELISA, western blot, and / or gene chips. In this application, the detection module may include substances and / or instruments capable of detecting the levels of biomarkers associated with cognitive impairment and / or neurodegenerative diseases. In this application, the biomarkers associated with cognitive impairment and / or neurodegenerative diseases may further include AD7C-NTP, pTau-181, pTau-217, and / or Aβ1-42. For example, the substances may also include antibodies capable of specifically binding to the biomarkers, probes capable of specifically binding to the biomarkers, primers capable of specifically amplifying nucleic acids encoding the biomarkers, gene chips capable of specifically detecting nucleic acids encoding the biomarkers, aptamers capable of specifically binding to nucleic acids encoding the biomarkers, and / or guide RNA capable of specifically binding to nucleic acids encoding the biomarkers. For example, the instruments may include instruments required for qPCR, ELISA, western blot, and / or gene chips. In this application, the detection module outputs the content value of the DIR and / or the nucleic acid encoding the DIR. In this application, the system may include a judgment module, which is capable of judging the diagnosis result and / or disease progression result of the subject based on the content of the DIR and / or the nucleic acid encoding the DIR and a normal control value and / or an early control value; wherein the normal control value may include the content of the DIR and / or the nucleic acid encoding the DIR in a normal subject; wherein the early control value may include the content of the DIR and / or the nucleic acid encoding the DIR previously measured in the same subject. In this application, "before" can include at least 10 days ago, at least 20 days ago, at least 1 month ago, at least 6 months ago, at least 12 months ago, at least 24 months ago, or longer. In this application, the subject may have been diagnosed with the cognitive impairment and / or the neurodegenerative disease. Using the system described in this application, the subject's... The levels of the DIR and / or the nucleic acids encoding the DIR at different time stages can help diagnose the cognitive impairment and / or the disease progression of the neurodegenerative disease in the subject. In this application, the normal subject may not suffer from the cognitive impairment and / or the neurodegenerative disease. For example, when the DIR of the subject's sample, and / or the content of the nucleic acid encoding DIR, is significantly higher than (e.g., it can be increased by at least about 20%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more) the normal control value, the judgment module will diagnose the subject as having the cognitive impairment and / or the neurodegenerative disease. For example, when the subject's sample has a DIR, and / or the content of the nucleic acid encoding the DIR is significantly higher than (e.g., it can be increased by at least about 20%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 200%, at least about 500% or more) the earlier control value, the judgment module will diagnose the subject as having an exacerbation of the cognitive impairment and / or the neurodegenerative disease. In this application, the judgment module can output the diagnostic results of the subject. In this application, the system may include a display module capable of displaying the diagnostic results of the judgment module. For example, the diagnostic results displayed by the display module may include qualitative and / or quantitative results. In this application, the system may include a storage module, wherein the storage module is capable of storing the content value output by the detection module and / or the diagnostic result output by the judgment module. In this application, the system may include the following devices: (a) A device for acquiring and / or receiving DIR level data in a sample; (b) An apparatus for analyzing data to assess the diagnosis of AD and / or the progression of AD in the subject, wherein a DIR higher than a control level indicates that the subject has AD and / or has progressed in AD. In this application, the system may further include (a') means for collecting and / or receiving other clinical indicators or basic characteristic data of AD diagnosis and / or AD progression in a sample. In this application, the device described in (b) is used to combine DIR level data with other clinical indicators or basic characteristic data of AD diagnosis and / or AD progression to perform prognostic assessment of AD diagnosis and / or AD progression of the subject. Alternatively, in this application, the system may further include a device for analyzing other clinical indicators or basic characteristic data of AD diagnosis and / or AD progression; and / or for combining DIR level data with other clinical indicators or basic characteristic data of AD diagnosis and / or AD progression to analyze the AD diagnosis and / or AD progression of the subject. The apparatus for conducting the evaluation. In this application, the system may further include one or more devices selected from the group consisting of: devices for inputting and / or outputting and / or storing data; devices for outputting and / or storing analysis results, such as devices for uploading and / or storing analysis results to a cloud database or a corresponding cloud database device; and devices for intelligently analyzing and recommending treatment plans based on evaluation results. It should be understood that those skilled in the art may add other conventional devices or programs to the system as needed. Typically, AD diagnosis and / or assessment of AD progression (e.g., grading or staging) can be performed by detecting the level of DIR molecules in the subject or a sample obtained from the subject and comparing this level with a control level; if the comparison shows that the level of DIR molecules in the subject is higher than the control level, it suggests that the subject has AD or that AD has progressed. In some embodiments, the method of this application may also optionally include: obtaining a sample from the subject; and contacting the sample with a reagent or kit for detecting DIR levels. As used in this application, the term "control" may include a normal control or a control for a specific grade or stage of AD development. "Control" may refer to the level of a DIR molecule used as a reference, including but not limited to: the level of a DIR molecule measured in a non-AD normal biological sample of the same subject (e.g., a sample obtained from a non-AD patient or normal person of that subject), a population standard level determined statistically, or a standardized level. The term "control for a specific grade or stage of AD development" refers to the level of a DIR molecule measured in the same subject at a previously determined grade or stage of development, a population standard level determined statistically at that grade or stage, or a standardized level. DIR antigen-binding protein In this application, the antigen-binding protein may comprise LCDR2, which may comprise the amino acid sequence shown in SEQ ID NO:74. For example, the antigen-binding protein of this application may have DIR binding capability. For example, the CDR may be determined using the IMGT numbering scheme. X1X2S(SEQ ID NO.74), where X1 is A or Y, and X2 is A or Y. In this application, the LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26 or 16. In this application, the antigen-binding protein may comprise LCDR1, which may comprise the amino acid sequence shown in SEQ ID NO:73. For example, the antigen-binding protein of this application may have DIR binding capability. For example, the CDR may be determined by the IMGT numbering scheme. For example, the LCDR1 may comprise the LCDR1 in the light chain variable region of IR-II-1 to IR-II-10. Q X1X2D X3X4X5X6X7Y (SEQ ID NO.73), where X1 is missing or S, X2 is missing or V, X3 is missing or Y, X4 is missing or D, X5 is G or I, X6 is D, E or S, and X7 is N or S. In this application, the LCDR1 may contain the amino acid sequence shown in any one of SEQ ID NO:25, 52, and 15. In this application, the antigen-binding protein may comprise LCDR3, which may comprise the amino acid sequence shown in SEQ ID NO:75. For example, the antigen-binding protein of this application may have DIR binding capability. For example, the CDR may be determined by the IMGT numbering scheme. For example, the LCDR3 may comprise the LCDR3 in the light chain variable region of IR-II-1 to IR-II-10. X1Q X2X3X4X5P X6X7 (SEQ ID NO.75), wherein X1 is L or Q, X2 is S or Y, X3 is N, S or Y, X4 is D, E or K, X5 is D or L, X6 is F or R, and X7 is A or T. In this application, the LCDR3 may contain the amino acid sequence shown in any one of SEQ ID NO:27, 53, 67, 17. In this application, the antigen-binding protein may comprise LCDR3, LCDR2, and LCDR1. For example, LCDR2 of the antigen-binding protein may comprise the amino acid sequence shown in SEQ ID NO:74, LCDR1 may comprise the amino acid sequence shown in SEQ ID NO:73, and LCDR3 may comprise the amino acid sequence shown in SEQ ID NO:75. For example, the antigen-binding protein of this application may have DIR binding capability. For example, the CDR may be determined by the IMGT numbering scheme. For example, LCDR1-3 may comprise LCDR1-3 in the light chain variable region of IR-II-1 to IR-II-10. In this application, the antigen-binding protein may comprise LCDR3, LCDR2, and LCDR1. For example, LCDR1 of the antigen-binding protein may comprise the amino acid sequence shown in SEQ ID NO:25, LCDR2 may comprise the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may comprise the amino acid sequence shown in SEQ ID NO:27. For example, LCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:52, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:53. For example, LCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:52, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:67. For example, LCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:15, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:16, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:17. For example, the antigen-binding protein of this application may have DIR binding capability. For example, the CDR may be determined by the IMGT numbering scheme. For example, the LCDR1-3 may comprise LCDR1-3 in the heavy chain variable region of IR-II-1 to IR-II-10. In this application, the antigen-binding protein may comprise HCDR1, and HCDR1 may comprise the amino acid sequence shown in SEQ ID NO:70. For example, the antigen-binding protein of this application may have DIR binding ability. For example, the... CDRs can be determined by the IMGT numbering scheme. For example, HCDR1 can include HCDR1 in the heavy chain variable regions of IR-II-1 to IR-II-10. GYTFX1X2YX3(SEQ ID NO.70), where X1 is S or T, X2 is E, N, R or S, and X3 is T or W. In this application, the HCDR1 may contain the amino acid sequence shown in any one of SEQ ID NO:20, 35, 56, 10. In this application, the antigen-binding protein may comprise HCDR2, which may comprise the amino acid sequence shown in SEQ ID NO:71. For example, the antigen-binding protein of this application may have DIR binding capability. For example, the CDR may be determined by the IMGT numbering scheme. For example, HCDR1 may comprise HCDR2 in the heavy chain variable region of IR-II-1 to IR-II-10. I X1P X2X3X4X5X6T (SEQ ID NO.71), wherein X1 is L or Y, X2 is G or H, X3 is G, N or S, X4 is missing or Y, X5 is G or Y, and X6 is G, N, S or T. In this application, the HCDR2 may contain the amino acid sequence shown in any one of SEQ ID NO:21, 36, 42, 48, 11. In this application, the antigen-binding protein may comprise HCDR3, which may comprise the amino acid sequence shown in SEQ ID NO:72. For example, the antigen-binding protein of this application may have DIR binding capability. For example, the CDR may be determined by the IMGT numbering scheme. For example, the HCDR3 may comprise HCDR3 in the heavy chain variable region of IR-II-1 to IR-II-10. X1X2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 DY (SEQ ID NO. 72), where X1 is missing or A, X2 is missing or R, X3 is missing, S or T, X4 is missing, D, G or Y, X5 is missing, D, I, M or V, X6 is missing, G or I, X7 is missing, T or Y, X8 is missing, A, L or T, X9 is missing, R, S or T, X 10 For missing, G, or T, X 11 For missing, D, or E, X 12 For D or Y, X 13 For F, L, or Y, X 14 For A, T, or V, X 15 It can be F or M. In this application, the HCDR3 may contain the amino acid sequence shown in any one of SEQ ID NO:22, 30, 37, 43, 49, 57, 62, 12. In this application, the antigen-binding protein may comprise HCDR3, HCDR2, and HCDR1. For example, HCDR2 of the antigen-binding protein may comprise the amino acid sequence shown in SEQ ID NO:71, HCDR1 may comprise the amino acid sequence shown in SEQ ID NO:70, and HCDR3 may comprise the amino acid sequence shown in SEQ ID NO:72. For example, the antigen-binding protein of this application may have DIR binding capability. For example, the CDR may be determined by the IMGT numbering scheme. For example, HCDR1-3 may comprise HCDR1-3 in the heavy chain variable region of IR-II-1 to IR-II-10. For example, HCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:20, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:21, and HCDR3 may contain the amino acid sequence shown in SEQ ID NO:22. For example, HCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:20, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:21, and HCDR3 may contain the amino acid sequence shown in SEQ ID NO:30. For example, HCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:35, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:36, and HCDR3 may contain the amino acid sequence shown in SEQ ID NO:37. For example, HCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:20, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:42, and HCDR3 may contain the amino acid sequence shown in SEQ ID NO:43. For example, HCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:20, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:48, and HCDR3 may contain the amino acid sequence shown in SEQ ID NO:49. For example, HCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:56, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:36, and HCDR3 may contain the amino acid sequence shown in SEQ ID NO:57. For example, HCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:35, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:36, and HCDR3 may contain the amino acid sequence shown in SEQ ID NO:62. For example, HCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:35, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:42, and HCDR3 may contain the amino acid sequence shown in SEQ ID NO:37. For example, HCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:56, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:36, and HCDR3 may contain the amino acid sequence shown in SEQ ID NO:57. For example, HCDR1 of the antigen-binding protein may contain the amino acid sequence shown in SEQ ID NO:10, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:11, and HCDR3 may contain the amino acid sequence shown in SEQ ID NO:12. For example, the antigen-binding protein of this application may have DIR binding capability. For example, the CDR may be determined by the IMGT numbering scheme. For example, the HCDR1-3 may comprise HCDR1-3 in the heavy chain variable region of IR-II-1 to IR-II-10. In this application, the antigen-binding protein may include HCDR3, HCDR2, HCDR1, LCDR3, LCDR2, and LCDR1. For example, the antigen-binding protein HCDR1 described in this application may contain the amino acid sequence shown in SEQ ID NO:20, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:21, HCDR3 may contain the amino acid sequence shown in SEQ ID NO:22, LCDR1 may contain the amino acid sequence shown in SEQ ID NO:25, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:27. For example, the antigen-binding protein HCDR1 described in this application may contain the amino acid sequence shown in SEQ ID NO:20, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:21, HCDR3 may contain the amino acid sequence shown in SEQ ID NO:30, LCDR1 may contain the amino acid sequence shown in SEQ ID NO:25, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:27. For example, the antigen-binding protein HCDR1 described in this application may contain the amino acid sequence shown in SEQ ID NO:35, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:36, HCDR3 may contain the amino acid sequence shown in SEQ ID NO:37, LCDR1 may contain the amino acid sequence shown in SEQ ID NO:25, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:27. For example, the antigen-binding protein HCDR1 described in this application may contain the amino acid sequence shown in SEQ ID NO:20, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:42, HCDR3 may contain the amino acid sequence shown in SEQ ID NO:43, LCDR1 may contain the amino acid sequence shown in SEQ ID NO:25, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:27. For example, the antigen-binding protein HCDR1 described in this application may contain the amino acid sequence shown in SEQ ID NO:20, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:48, HCDR3 may contain the amino acid sequence shown in SEQ ID NO:49, LCDR1 may contain the amino acid sequence shown in SEQ ID NO:52, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:53. For example, the antigen-binding protein HCDR1 described in this application may contain the amino acid sequence shown in SEQ ID NO:56, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:36, HCDR3 may contain the amino acid sequence shown in SEQ ID NO:57, LCDR1 may contain the amino acid sequence shown in SEQ ID NO:25, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:27. For example, the antigen-binding protein HCDR1 described in this application may contain the amino acid sequence shown in SEQ ID NO:35. HCDR2 may contain the amino acid sequence shown in SEQ ID NO:36, HCDR3 may contain the amino acid sequence shown in SEQ ID NO:62, LCDR1 may contain the amino acid sequence shown in SEQ ID NO:25, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:27. For example, the antigen-binding protein HCDR1 described in this application may contain the amino acid sequence shown in SEQ ID NO:35, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:42, HCDR3 may contain the amino acid sequence shown in SEQ ID NO:37, LCDR1 may contain the amino acid sequence shown in SEQ ID NO:52, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:53. For example, the antigen-binding protein HCDR1 described in this application may contain the amino acid sequence shown in SEQ ID NO:56, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:36, HCDR3 may contain the amino acid sequence shown in SEQ ID NO:57, LCDR1 may contain the amino acid sequence shown in SEQ ID NO:52, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:26, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:67. For example, the antigen-binding protein HCDR1 described in this application may contain the amino acid sequence shown in SEQ ID NO:10, HCDR2 may contain the amino acid sequence shown in SEQ ID NO:11, HCDR3 may contain the amino acid sequence shown in SEQ ID NO:12, LCDR1 may contain the amino acid sequence shown in SEQ ID NO:15, LCDR2 may contain the amino acid sequence shown in SEQ ID NO:16, and LCDR3 may contain the amino acid sequence shown in SEQ ID NO:17. For example, the antigen-binding protein of this application may have DIR binding capability. For example, the CDR may be determined by the IMGT numbering scheme. For example, the HCDR1-3 may comprise the HCDR1-3 in the heavy chain variable region of IR-II-1 to IR-II-10; and the LCDR1-3 may comprise the LCDR1-3 in the light chain variable region of IR-II-1 to IR-II-10. In this application, the antigen-binding protein may include H-FR1, the C-terminus of which may be directly or indirectly linked to the N-terminus of HCDR1. In this application, the antigen-binding protein may include H-FR2, which may be located between HCDR1 and HCDR2. In this application, the antigen-binding protein may include H-FR3, which may be located between HCDR2 and HCDR3. In this application, the antigen-binding protein may include H-FR4, the N-terminus of which may be linked to the C-terminus of HCDR3. In this application, the antigen-binding protein may include H-FR1, H-FR2, H-FR3, and H-FR4. In this application, the antigen-binding protein may include L-FR1, the C-terminus of which may be directly or indirectly linked to the N-terminus of LCDR1. In this application, the antigen-binding protein may include L-FR1, the C-terminus of which may be directly or indirectly linked to the N-terminus of LCDR1. In this application, the antigen-binding protein may include L-FR2, which may be located between LCDR1 and LCDR2. In this application, the antigen-binding protein may include L-FR3, which may be located between LCDR2 and LCDR3. In this application, the antigen-binding protein may include L-FR4, the N-terminus of which may be directly or indirectly linked to the C-terminus of LCDR3. Connected. In this application, the antigen-binding protein may include L-FR1, L-FR2, L-FR3, and L-FR4. In this application, the antigen-binding protein may include a heavy chain variable region VH, which may contain the amino acid sequence shown in any one of SEQ ID NO: 13, 23, 31, 38, 44, 50, 58, 63, and 65. For example, the antigen-binding protein of this application may have DIR binding capability. In this application, the antigen-binding protein may include a light chain variable region (VL), which may contain the amino acid sequence shown in any one of SEQ ID NO: 18, 28, 33, 40, 46, 54, 60, and 68. For example, the antigen-binding protein of this application may have DIR binding capability. In this application, the antigen-binding protein may comprise the VH and VL. In some embodiments, the VH may comprise the amino acid sequence shown in SEQ ID NO:23, and the VL may comprise the amino acid sequence shown in SEQ ID NO:28. In some embodiments, the VH may contain the amino acid sequence shown in SEQ ID NO:31, and the VL may contain the amino acid sequence shown in SEQ ID NO:33. In some embodiments, the VH may contain the amino acid sequence shown in SEQ ID NO:38, and the VL may contain the amino acid sequence shown in SEQ ID NO:40. In some embodiments, the VH may contain the amino acid sequence shown in SEQ ID NO:44, and the VL may contain the amino acid sequence shown in SEQ ID NO:46. In some embodiments, the VH may contain the amino acid sequence shown in SEQ ID NO:50, and the VL may contain the amino acid sequence shown in SEQ ID NO:54. In some embodiments, the VH may contain the amino acid sequence shown in SEQ ID NO:58, and the VL may contain the amino acid sequence shown in SEQ ID NO:60. In some embodiments, the VH may contain the amino acid sequence shown in SEQ ID NO:63, and the VL may contain the amino acid sequence shown in SEQ ID NO:60. In some embodiments, the VH may contain the amino acid sequence shown in SEQ ID NO:65, and the VL may contain the amino acid sequence shown in SEQ ID NO:54. In some embodiments, the VH may contain the amino acid sequence shown in SEQ ID NO:58, and the VL may contain the amino acid sequence shown in SEQ ID NO:68. In some embodiments, the VH may contain the amino acid sequence shown in SEQ ID NO:13, and the VL may contain the amino acid sequence shown in SEQ ID NO:18. For example, the antigen-binding protein of this application may have DIR binding capability. In this application, the antigen-binding protein may include at least one CDR from the VH described in this application. In this application, the antigen-binding protein may include at least one CDR from the VL described herein. The CDR can be obtained according to any partitioning method. In this application, the CDR may encompass CDR sequences partitioned according to any CDR partitioning method; it may also encompass variants thereof. In this application, the antigen-binding protein may include HCDR1, HCDR2 and HCDR3 from the VH described in this application. In this application, the antigen-binding protein may comprise HCDR1, HCDR2, and HCDR3 as described in the VH of this application. The VH may comprise the amino acid sequence shown in any one of SEQ ID NO: 13, 23, 31, 38, 44, 50, 58, 63, and 65. For example, the antigen-binding protein of this application may have DIR binding capability. In this application, the CDR may cover CDR sequences partitioned according to any CDR partitioning method; it may also cover its variants. In this application, the antigen-binding protein may comprise LCDR1, LCDR2, and LCDR3 as described in the VL of this application. The VL may comprise the amino acid sequence shown in any one of SEQ ID NO: 18, 28, 33, 40, 46, 54, 60, and 68. For example, the antigen-binding protein of this application may have DIR binding capability. In this application, the CDR may cover CDR sequences partitioned according to any CDR partitioning method; it may also cover its variants. In this application, the antigen-binding protein may include an antibody heavy chain constant region. The antibody heavy chain constant region may be derived from the heavy chain constant regions of human IgG, IgA, IgD, IgE, and / or IgM. The antibody heavy chain constant region may be derived from the heavy chain constant region of human IgG. In some embodiments, the antigen-binding protein may include an antibody heavy chain constant region, and the antibody heavy chain constant region may be derived from the heavy chain constant regions of human IgG1, IgG2, IgG3, and / or IgG4. In some embodiments, the antigen-binding protein may include an antibody heavy chain constant region, and the antibody heavy chain constant region may be derived from the heavy chain constant region of human IgG1. In this application, the antigen-binding protein may include an antibody light chain constant region. The antibody light chain constant region may include a constant region derived from Igκ or a constant region derived from Igλ. The antibody light chain constant region may be derived from the human Igκ constant region. In this application, the antigen-binding protein may comprise an antibody or an antigen-binding fragment thereof. In some embodiments, the antigen-binding fragment may include Fab, Fab', Fv fragments, F(ab')2, F(ab)2, scFv, di-scFv, VHH and / or dAb. In some embodiments, the antibody may include a monoclonal antibody. In some embodiments, the antibody may include a murine antibody and / or a chimeric antibody. Furthermore, it should be noted that the antigen-binding protein described in this application may contain heavy chain and / or light chain sequences with one or more conserved sequence modifications. "Conserved sequence modification" refers to amino acid modifications that do not significantly affect or alter antibody binding properties. Such conserved modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into the antigen-binding protein described in this application using standard techniques known in the art, such as point mutations and PCR-mediated mutations. Conserved amino acid substitution involves replacing an amino acid residue with an amino acid residue having a similar side chain. Groups of amino acid residues with similar side chains are known in the art. These groups of amino acid residues include those with basic side chains (e.g., lysine, arginine, histidine), acidic side chains, and so on. The amino acids consist of polar side chains (e.g., aspartic acid, glutamic acid), nonpolar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), β-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). In some embodiments, one or more amino acid residues in the CDR region of the antigen-binding protein described in this application may be replaced with other amino acid residues from the same side chain group. Those skilled in the art will know that some conserved sequence modifications do not cause the antigen to lose its binding ability. For example, see Brummell et al., (1993) Biochem 32:1180-8; de Wildt et al., (1997) Prot. Eng. 10:835-41; Komissarov et al., (1997) J. Biol. Chem. 272:26864-26870; Hall et al., (1992) J. Immunol. 149:1605-12; Kelley and O'Connell (1993) Biochem. 32:6862-35; Adib-Conquy et al., (1998) Int. Immunol. 10:341-6 and Beers et al., (2000) Clin. Can. Res. 6:2835-43. The antigen-binding proteins described in this application can be identified, screened, or characterized by various assays known in the art. For example, the antigen-binding activity of the antigen-binding protein or fusion protein of this application can be tested by known methods such as enzyme-linked immunosorbent assay (ELISA), immunoblotting (e.g., Western blotting), flow cytometry (e.g., FACS), immunohistochemistry, immunofluorescence, etc. In this application, the antigen-binding protein is capable of specifically binding to DIR or its functionally active fragment. In this application, the antigen-binding protein is capable of specifically binding to DIR-II. In some embodiments, the DIR or its functionally active fragment may be a full-length DIR or its functionally active fragment, or a fragment that exerts the functional activity of a DIR (e.g., DIR-II). In some embodiments, the DIR or its functionally active fragment may be a separate DIR or its functionally active fragment, or a mixture of various forms of DIR or its functionally active fragments. For example, the DIR or its functionally active fragment may be a human DIR or its functionally active fragment. In some embodiments, the antigen-binding protein can be measured by ELISA to determine its binding activity to an antigen (e.g., DIR-II). For example, the antigen-binding protein may have the ability to bind to the antigen or its functional fragments at a value of about 10 ng / ml or higher (e.g., at least 15 ng / ml, at least 20 ng / ml, at least 25 ng / ml, at least 30 ng / ml, at least 35 ng / ml, at least 40 ng / ml, at least 45 ng / ml, at least 50 ng / ml, at least 55 ng / ml, at least 60 ng / ml, at least 65 ng / ml, at least 70 ng / ml, at least 75 ng / ml, at least 80 ng / ml, at least 85 ng / ml, at least 90 ng / ml, at least 95 ng / ml, at least 100 ng / ml, at least 500 ng / ml, at least 1000 ng / ml or higher). Drug screening methods On the other hand, this application provides a drug screening method, which may include the following steps: detecting changes in the content of DIR and / or nucleic acids encoding DIR in a subject after administration of a candidate drug, wherein the drug is used to prevent, treat and / or alleviate cognitive impairment and / or neurodegenerative diseases. In this application, when the candidate drug is administered, the content of DIR and / or the nucleic acid encoding DIR in the subject decreases, then the candidate drug has a therapeutic effect. In this application, the application may include injection. In this application, the drug may include small molecule drugs and / or biological macromolecule drugs. According to the disclosure in this application, the level of DIR is closely related to the presence and / or degree of cognitive impairment, and can therefore be used as an indicator for assessing AD diagnosis and / or AD progression (e.g., grading or staging). Furthermore, this application also provides a method for screening candidate drugs for treating Alzheimer's disease (AD), the method comprising testing the effect of the candidate drug on DIR levels in a subject or a sample obtained from the subject, wherein a decrease in DIR levels after use of the candidate drug indicates that the candidate drug has an effect on treating AD. The features involved in the candidate drug screening method of this application may be defined or described as in this application. In some embodiments, the candidate drug may be an inhibitor of DIR. This application reveals that DIR is specifically expressed in the blood and / or cerebrospinal fluid of AD patients. Importantly, DIR can be detected in small amounts of serum (approximately 100 μl), providing a promising diagnostic tool for early AD in clinical applications. Current results indicate a positive detection rate exceeding 90% for AD and MCI, demonstrating DIR's strong potential as a specific biomarker for early AD screening. Currently, pTau-181, pTau-217, and Aβ1-42, which are newly developed early AD screening tests used in clinical blood testing, have relatively low specificity and are quite expensive. In contrast, the AD early screening test based on DIR levels proposed in this application has a high detection rate, excellent specificity, and / or low cost, offering a price advantage. For example, the cost of DIR level detection via ELISA can be controlled to below 10 yuan per person. Therefore, the detection indicators and methods in this application have significant advantages in both effectiveness and cost compared to existing methods. Furthermore, this application found that DIR is highly specific and sensitive for the diagnosis of cognitive impairment and / or neurodegenerative diseases. It can distinguish potential AD and / or MCI patients even when there are no significant differences in targets such as pTau-181, pTau-217, and Aβ1-42, thus enabling effective diagnosis of patients at an earlier stage. In this application, the method can use the kit described in this application and / or the detection substance described in this application to detect changes in the levels of DIR and / or nucleic acids encoding DIR in a subject before and / or after administration of the candidate drug. In this application, the method can use at least one (e.g., 1, 2, 3, or more) of the detection substance to detect changes in the levels of DIR and / or nucleic acids encoding DIR in a subject before and / or after administration of the candidate drug. For example, the method can use at least one (e.g., 1, 2, 3, or more) antigen-binding protein (e.g., DIR antibody) capable of specifically binding to DIR. In this application, antigen-binding proteins with different amino acid sequences of at least one CDR can be considered as different types of antigen-binding proteins. Sequence list information: This application provides the following implementation methods: 1. The use of substances that detect the intron retention cleavage product DIR of DNA damage-inducible transcript 4 (DDIT4L) from subject samples in the preparation of products (e.g., kits or detection systems) for the diagnosis of Alzheimer's disease, diagnosis of mild cognitive impairment, and / or assessment of the progression of Alzheimer's disease (e.g., grading or staging) in said subjects. 2. The application as described in Embodiment 1, wherein: the splicing product is selected from the group consisting of: mRNA having the nucleotide sequence shown in SEQ ID NO:93; splicing product peptide having the nucleotide sequence shown in SEQ ID NO:8 encoding nucleic acid; or, splicing product peptide having the amino acid sequence shown in SEQ ID NO:1. 3. The application as described in Embodiment 1, wherein the early-onset Alzheimer's disease includes: early-stage Alzheimer's disease (amnesia period), mid-stage Alzheimer's disease (neurological disorder period), and late-stage Alzheimer's disease (severe dementia period). 4. The application as described in Embodiment 1, wherein the substance is selected from reagents, devices, or combinations thereof used for detecting DIR. 5. The application as described in Embodiment 1, wherein the substance is selected from: substances specific to the DIR, such as antibodies to the DIR (preferably monoclonal antibodies); DIR-specific probes, gene chips, PCR primers, gRNA, etc. 6. The application as described in Embodiment 1, wherein the sample is selected from: blood samples, such as whole blood, serum, plasma; cerebrospinal fluid. 7. The application as described in Embodiment 1, wherein an increase in the level of DIR in the sample compared to a normal control indicates that the subject has Alzheimer's disease or mild cognitive impairment; or, an increase in the level of DIR in the sample compared to a mild cognitive impairment control or a prior control level of a subject already diagnosed with Alzheimer's disease indicates that the subject's Alzheimer's disease has progressed (e.g., to a higher grade or stage). 8. A product (e.g., a kit or system) for the diagnosis of Alzheimer's disease, the diagnosis of mild cognitive impairment, and / or the assessment of the progression of Alzheimer's disease (e.g., grading or staging), comprising: (i) A substance for detecting the intron-retained cleavage product DIR of DNA damage-inducible transcript 4 (DDIT4L) in the target sample; and (ii) Optional, other substances used for the diagnosis of Alzheimer's disease, the diagnosis of mild cognitive impairment, and / or the assessment of the progression of Alzheimer's disease (e.g., grading or staging), such as detection substances for detecting existing Alzheimer's disease biomarkers. For example, in some cases: (i) contains one or more substances selected from the following group: Reagents, equipment, or combinations thereof used to detect the DIR; Substances for detecting said DIR at the gene and / or protein level, such as substances for use in one or more detection techniques or methods selected from the group consisting of: immunohistochemistry (e.g., immunofluorescence assay, chemiluminescence assay, reverse enzyme-linked immunosorbent assay, immunogold assay), Western blotting, Northern blotting, PCR, microarray assay; or Substances specific to the DIR, such as antibodies (preferably monoclonal antibodies); probes, gene chips, PCR primers, gRNAs specific to the cleavage products; and / or Other substances in (ii) are selected from: substances used to detect one or more other markers of Alzheimer's disease, such as AD7C-NTP, pTau-181, pTau-217, Aβ1-42; and / or reagents for imaging brain amyloid; and / or reagents for imaging diagnosis of the subject's brain. 9. A system for diagnosing Alzheimer's disease, diagnosing mild cognitive impairment, and / or assessing the progression of Alzheimer's disease (e.g., grading or staging), comprising the following devices: (a) A device for acquiring and / or receiving data on the intron retention cleavage product DIR level of DNA damage-inducible transcript 4 (DDIT4L) transcripts in a sample; (b) A device for analyzing data to diagnose Alzheimer's disease, mild cognitive impairment, and / or assess the progression of Alzheimer's disease (e.g., grading or staging) in the subject. Specifically, an increase in the DIR level in the sample compared to a normal control indicates that the subject has Alzheimer's disease or mild cognitive impairment; or, an increase in the DIR level in the sample compared to a mild cognitive impairment control or a previous control level of a subject already diagnosed with Alzheimer's disease indicates that the subject's Alzheimer's disease has progressed (e.g., to a higher grade or stage). 10. A method for screening drugs for the treatment of Alzheimer's disease, the method comprising: detecting the effect of a candidate drug on the level of intron retention shearing product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L) in a subject, wherein a decrease in the level after using the candidate drug indicates that the candidate drug has a therapeutic effect on Alzheimer's disease. Without being limited by any theory, the embodiments described below are merely for illustrating the detection methods and applications of this application, and are not intended to limit the scope of the invention. Example The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the present application. Those skilled in the art can make appropriate modifications and variations to the present application, and such modifications and variations are all within the scope of the present application. Experimental methods in the following examples that do not specify specific conditions can be performed using conventional methods in the art, such as those described in the "Experimental Methods in the Art". Follow the instructions in the "Laboratory Guide to Subcloning" (3rd edition, New York: Cold Spring Harbor Laboratory Press, 1989) or as recommended by the supplier. DNA sequencing methods are standard in the field and can also be provided by commercial companies. Unless otherwise stated, percentages and parts are by weight. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to one skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein may be used in the methods of this application. The preferred methods and materials described herein are for illustrative purposes only. Example 1: DIR protein is a secretory protein Experimental Materials and Methods Plasmid construction and cell transfection methods: Human DIR cDNA was cloned into the pCMV-flag vector to express the flag-DIR protein. In HEK293 cells (Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences), pCMV-flag and pCMV-flag-DIR plasmids were transfected using Lippo 3000 reagent. After 48 hours of cell culture, cells and culture medium were harvested, and appropriate amounts of lysis buffer were added to each. The cells were lysed by rotation at 4°C for 30 minutes, centrifuged at 12000g for 30 minutes, and the supernatant was collected. A small amount of lysis buffer was used for Western blotting analysis. Western Blot Experiment: The Western Blot experiment was performed according to the steps of SDS-PAGE electrophoresis, membrane transfer, immunoassay and chemiluminescence (the antibody used was purchased from Jier Biochemical (Shanghai) Co., Ltd.). Results and Discussion After culturing HEK293 cells for 48 hours, cells transfected with pCMV-flag-DIR plasmid showed a large amount of DIR expression, and a large amount of DIR was also detected in the cell culture medium (Figure 1b). This indicates that after DIR is transcribed and translated into protein in the cell, it can be secreted into the extracellular culture medium through the intracellular secretory pathway. Judging from the amount of secretion, some of the intracellularly synthesized DIR was secreted into the extracellular culture medium, which suggests that DIR may also be secreted into the extracellular environment in the human body and thus enter the blood circulation system. This provides a theoretical basis for it to become a blood biomarker under certain pathological conditions. Example 2: Changes in the level of DIR protein in the blood of AD patients Experimental Materials and Methods Tissue specimens: Venous blood specimens from AD and MCI patients, non-AD patients (patients with hypertension, coronary heart disease or diabetes) and normal individuals (a total of 58 samples), from Huashan Hospital Affiliated to Fudan University and Xuhui District Central Hospital. Methods for venous blood collection and plasma acquisition: The patient's cubital fossa vein was collected using vacuum blood collection technology into an EDTA vacuum tube. The tube was immediately and gently inverted 8 times to thoroughly mix the blood with the anticoagulant. The blood was then transported to the laboratory on ice, centrifuged at 1500g for 10 minutes at 4°C, and the supernatant was aspirated, aliquoted, and stored at -80°C. Plasma Western Blot Method: After aliquoting plasma and thawing on ice, dilute appropriately with PBS, add buffer, and incubate at 100°C. The tissue was denatured in a bath for 5 minutes, and subsequent steps were the same as those for tissue Western blotting. Plasma ELISA method: Plasma samples were diluted 1:1 with 1× dilution buffer (OBT1998G, Bio-Rad); then, 100 μl of blocking buffer was pipetted and blocked at 37°C for 1 hour; then, 100 μl of serially diluted standard and diluted plasma were added to the wells coated with capture antibody (Jier Biochemical, AB009458), changing the pipette tip each time; incubated at 37°C for 1.5 hours; the liquid in each well was removed, and the sample was washed 3 times with 100 μl of 1× washing buffer (BUF031C, Bio-Rad); 100 μl of detection antibody (i.e., DIR antibody IR-II-6, the amino acid sequence of its VH is shown in SEQ ID NO.58, and the amino acid sequence of its VL is shown in SEQ ID NO.60) was added to each well, and the sample was incubated at 37°C for 1 hour; the liquid in each well was removed, and 100 μl of detection antibody (i.e., DIR antibody IR-II-6, the amino acid sequence of its VH is shown in SEQ ID NO.58, and the amino acid sequence of its VL is shown in SEQ ID NO.60) was added to each well, and the sample was incubated at 37°C for 1 hour; the liquid in each well was removed, and the sample was washed 3 times with 100 μl of 1× washing buffer (BUF031C, Bio-Rad) was added to each well, and the sample was washed 3 times. Wash three times with 1× washing buffer; add 100 μl of 1× avidin-HRP solution to each well and incubate at 37°C for 1 hour; remove the liquid from each well and wash three times with 100 μl of 1× washing buffer; add 100 μl of 1× substrate reaction solution (BUF062C, purchased from Bio-Rad) to each well and incubate at room temperature in the dark for 10-30 minutes; detect the reaction at 655 nm using a microplate reader and establish a standard curve. Results and Discussion Blood samples were collected from patients with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI), non-AD patients, and healthy individuals. The results showed that DIR levels were highest in the blood samples of AD and MCI patients, and were detectable in approximately 95% of these patients. Blood samples from MCI patients also contained relatively high levels of DIR, which was detectable in about 90% of these patients. However, DIR was undetectable or detected in very small amounts in the blood samples of patients without cognitive impairment, and was undetectable in the blood samples of healthy individuals (Figure 2a). Using ELISA, it was found that the DIR level in the blood samples of AD patients was relatively high, reaching 10-100 ug / ml, while the DIR level in non-AD patients was at the pg / ml level, undetectable in normal individuals. Therefore, the DIR level in AD patients was 103-104 times higher than that in other patients. This suggests that DIR has very high specificity (Figures 2a and 2b). The above results indicate that DIR has a high concentration in the blood of patients with AD and MCI, and can be used as a blood biomarker to detect the presence of AD, especially for patients with mild cognitive impairment such as MCI. Furthermore, DIR levels are correlated with the severity of AD (see Figure 2b). Example 3: Methodological Study of DIR Protein Detection DIR protein (Jier Biochemistry, 752084) was prepared into a stock solution of 1 mg / ml using DPBS solution. Before the experiment, it was diluted with ELISA washing buffer (BUF031C, purchased from Bio-Rad) to prepare a standard DIR protein solution. The concentration of DIR protein standard was detected by ELISA, and a multinomial regression was used for fitting. The resulting standard curve is shown in Figure 3. The R-squared value of the regression model 2 A value of 0.99 indicates a high degree of fit; the shaded area shows the 95% confidence interval of the regression model. The narrow and long confidence interval is visible in the figure, indicating that the model has high reliability in estimating the DIR content in the sample. Example 4: R-°C curve of DIR as a clinical detection indicator Blood samples were collected from patients with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI), non-AD patients, and healthy individuals (same as in Example 2). ELISA tests were performed, and the results were analyzed using the "pROC" package of R software (version 3.6.2). A Logistic regression model was established based on the detected DIR concentration, and the ROC curve was obtained by using a bootstrap sampling method. The results are shown in Figure 4. The results show that a relatively ideal prediction result can be obtained by using only DIR single-parameter modeling, with AUC = 0.807 (95% confidence interval of 0.688-0.926). Example 5: Changes in the level of DIR protein in the blood of patients with different types of MCI Experimental Materials and Methods Tissue specimens: Venous blood specimens from patients with different types of MCI and normal follow-up patients, from Huashan Hospital Affiliated to Fudan University. Methods for collecting venous blood and obtaining plasma: Same as in Example 2. Plasma ELISA method: Same as in Example 2. MCI classification methods: aMCI-s: Amnesic MCI with impairment in a single cognitive domain; aMCI-m: Amnesic MCI with impairment in multiple cognitive domains; naMCI-s: Non-amnesic MCI with impairment in a single cognitive domain; naMCI-m: Non-amnesic MCI with impairment in multiple cognitive domains. In Example 5, there were 122 samples of patients with aMCI-m type; 85 samples of patients with aMCI-s type; 11 samples of patients with naMCI-m type; 88 samples of patients with naMCI-s type; and 279 samples of normal follow-up subjects. Results and Discussion Blood samples were collected from patients with different types of MCI and normal follow-up populations in clinical practice and tested. It was found that the DIR content in the blood samples of patients with aMCI-m type of MCI was elevated, which was significantly different from that in normal follow-up populations (Figure 5). Using ELISA, it was found that patients with aMCI-m type had higher levels of DIR in their blood, and patients with aMCI-m type were more likely to progress to AD than other types of MCI patients, suggesting that the DIR indicator has the ability to distinguish aMCI-m type. The above results indicate that DIR can serve as an effective diagnostic biomarker for AD. Example 6: Changes in the level of DIR protein in the blood of patients with different types of MCI Experimental Materials and Methods Tissue specimens: Venous blood specimens from patients with different types of MCI, AD patients, and normal follow-up subjects, obtained from Huashan Hospital Affiliated to Fudan University. Methods for collecting venous blood and obtaining plasma: Same as in Example 2. Plasma ELISA method: DIR was the same as in Example 2; Tau, Aβ40 and Aβ42 were tested by a triple reagent kit (catalog number: 101995) from Hangzhou Jingbai Biotechnology Co., Ltd., according to its operating procedures. MCI classification method: Same as in Example 5. Results and Discussion We collected blood samples from patients with different types of MCI, AD, and normal follow-up populations and tested them. We found that DIR levels were elevated in the blood samples of patients with aMCI-m type and AD patients, showing significant differences compared to normal follow-up populations and other MCI types. As for the indicators such as Tau, Aβ40, and Aβ42 in the blood samples, although some indicators (such as Aβ40) showed an increasing trend in the blood of patients with aMCI-m type and AD patients, no significant differences were detected between the groups (see Figure 6). ELISA analysis revealed elevated levels of DIR in the blood of patients with aMCI-m and AD. This indicates that, compared to existing auxiliary diagnostic markers such as Tau, Aβ40, and Aβ42, DIR can more clearly distinguish aMCI-m patients, AD patients from other types of MCI patients, or healthy individuals in the early stages. Therefore, DIR can serve as an effective diagnostic biomarker for aMCI-m and AD. Example 7: Comparison of DIR protein levels in patient plasma and cerebrospinal fluid Experimental Materials and Methods Tissue specimens: Venous blood and cerebrospinal fluid specimens were obtained from the same patient (one case each of cerebral edema, meningioma and glioma), and were all from Huashan Hospital Affiliated to Fudan University. Methods for collecting venous blood and obtaining plasma: Same as in Example 2. Method of cerebrospinal fluid collection: Cerebrospinal fluid is collected during the patient's surgery. Plasma and cerebrospinal fluid ELISA method: Same as in Example 2. Results and Discussion The levels of DIR in plasma and cerebrospinal fluid are highly consistent. 2 The value is 0.99 (see Figure 7). The DIR levels in the patient's blood were consistent with those in the cerebrospinal fluid using the ELISA method, indicating that the levels detected in the blood can directly reflect the DIR levels in the cerebrospinal fluid. This suggests that the DIR described in this application is also applicable as an effective diagnostic marker using cerebrospinal fluid as a sample. Example 8: Detection of binding activity of DIR antibodies The sequencing results of DIR antibodies IR-II-1 to IR-II-10 (IR-II-10 is A2D10) are shown in Table 1 below: Table 1 The binding activity of the above-mentioned IR-II-1 to IR-II-10 antibodies to the DIR-II fragment was detected. The specific method is as follows: The target fragment DIR-II was coated onto a 96-well plate using coating buffer and blocked with blocking buffer. Monoclonal antibody (1 mg / mL) was then diluted proportionally (1:2kJ, 1:6kJ, 1:18kJ, 1:54kJ, 1:162kJ, 1:486kJ, 1:1458kJ, 1:4374kJ), pipetteed into individual wells, and incubated at 37°C with gentle shaking for 2 hours, followed by three washes with washing buffer. Then, secondary antibody containing horseradish peroxidase (1:5kJ) was added, and the plate was incubated at 37°C. After three washes, an appropriate volume of TMB substrate solution was added, and the plate was incubated at 37°C for a specified time. The absorbance of the sample at 450 nm was then recorded using a microplate reader. The results are shown in Table 2 and Figure 8. These results indicate that the aforementioned IR-II-1 to IR-II-10 antibodies specifically bind to the DIR-II fragment at a working concentration of approximately 10 ng / ml or higher. Therefore, the aforementioned IR-II-1 to IR-II-10 antibodies can all be used for the detection of DIR protein, as well as the diagnosis of aMCI-m and AD. Table 2 All references to this application are incorporated herein by reference as if each reference were individually incorporated herein by reference. Furthermore, it should be understood that after reading the foregoing teachings of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. Use of the intron-retained cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L), and / or the nucleic acid encoding said DIR, in disease diagnosis and / or disease progression assessment, wherein said disease includes cognitive impairment.

2. Use of the intron-retaining cleavage product DIR of DNA damage-inducible transcript 4-like transcript (DDIT4L), and / or the nucleic acid encoding said DIR, in disease diagnosis and / or disease progression assessment, wherein said diseases include neurodegenerative diseases. disease.

3. The use according to any one of claims 1-2, wherein the DIR comprises ammonia as shown in SEQ ID NO:

1. amino acid sequence.

4. The use according to any one of claims 1-3, wherein the nucleic acid encoding DIR comprises the one shown in SEQ ID NO:

8. The nucleotide sequence.

5. The use according to any one of claims 1-4, wherein the nucleic acid encoding DIR comprises SEQ ID NO:93 The nucleotide sequence shown.

6. The use according to any one of claims 1-5, wherein the cognitive impairment includes cognitive impairment caused by normal aging, Lewis's physical dementia (LBD), and frontotemporal lobe cognitive impairment. Dementia and / or vascular dementia.

7. The use according to any one of claims 1-6, wherein the inducing diseases of the cognitive impairment include Alzheimer's disease, multiple infarct type, Parkinson's disease, and AIDS. And / or Creutzfeldt-Jakob disease (CJD).

8. The use according to any one of claims 1-7, wherein the cognitive impairment includes early cognitive impairment (MCI). Intermediate cognitive impairment and late cognitive impairment.

9. The use according to any one of claims 1-8, wherein the cognitive impairment includes amnesic M. CI (Multi-cognitive domain impairment) (aMCI-m).

10. The use according to any one of claims 2-9, wherein the neurodegenerative disease includes Acute neurodegenerative diseases and chronic neurodegenerative diseases.

11. The use according to any one of claims 2-10, wherein the neurodegenerative disease includes neurodegenerative diseases caused by neuronal death and glial cell homeostasis, neurodegenerative diseases caused by aging, neurodegenerative diseases caused by impaired CNS cell function, and neurodegenerative diseases caused by abnormal intercellular communication. Diseases and / or neurodegenerative diseases caused by impaired cell movement.

12. The use according to any one of claims 2-11, wherein the neurodegenerative disease includes Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), and muscular atrophy. Amyotrophic lateral sclerosis (ALS) and / or Huntington's disease (HD).

13. According to claims 2-12 The use of any one of the following, wherein the neurodegenerative disease includes Alzheimer's disease.

14. The use according to any one of claims 2-13, wherein the neurodegenerative disease includes early Alzheimer's disease, mid-Alzheimer's disease, and / or late Alzheimer's disease.

15. Use in the preparation of products for the diagnosis of and / or assessment of disease progression, including cognitive impairment, of DNA damage-inducible transcript 4-like transcript (DDIT4L) in the detection of intron-retained cleavage product DIR, and / or substances encoding said DIR nucleic acid.

16. Detection of the intron retention cleavage product DIR of DNA damage-inducible transcript 4 (DDIT4L) transcript, and / or the substance encoding the nucleic acid of said DIR, in the preparation of... Use in products for disease diagnosis and / or disease progression assessment, wherein the disease includes neurodegenerative diseases.

17. According to claim 15- The use of any one of the 16, wherein the DIR comprises the amino acid sequence shown in SEQ ID NO:

1.

18. According to claims 15-17 For any of the uses described above, wherein the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:

8.

19. According to claim 15- The use of any one of the 18, wherein the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:

93.

20. The use according to any one of claims 15-19, The cognitive impairments mentioned therein include cognitive impairments caused by normal aging, Lewis's physical dementia (LBD), frontotemporal dementia, and / or vascular dementia.

21. The use of any one of claims 15-20 The cognitive impairment-inducing diseases mentioned above include Alzheimer's disease, multiple infarct type, Parkinson's disease, AIDS, and / or Creutzfeldt-Jakob disease (CJD).

22. Root The use according to any one of claims 15-21, wherein the cognitive impairment includes early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment. obstacle.

23. The use according to any one of claims 15-22, wherein the cognitive impairment includes amnesic MCI (multi-cognitive domain impairment) (aMCI) -m)。 24. The use according to any one of claims 16-23, wherein the neurodegenerative disease includes acute neurodegenerative diseases and chronic neurodegenerative diseases.

25. The use according to any one of claims 16-24, wherein the neurodegenerative disease includes neurodegenerative diseases caused by neuronal death and glial cell homeostasis, and neurodegenerative diseases caused by aging. Neurodegenerative diseases, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegenerative diseases caused by impaired cell motility.

26. The claim 16-25 The intended use of the neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), and myocardial infarction. Amyotrophic lateral sclerosis (ALS) and / or Huntington's disease (HD).

27. The use according to any one of claims 16-26, wherein the neurodegenerative... Diseases include Alzheimer's disease.

28. The use according to any one of claims 16-27, wherein the neurodegenerative disease includes early-stage Alzheimer's disease and mid-stage Alzheimer's disease. And / or late-stage Alzheimer's disease.

29. The use according to any one of claims 15-28, wherein the substance comprises substances capable of detecting the DIR, and / or Reagents and / or devices for encoding the nucleic acid of the DIR.

30. The use according to any one of claims 15-29, wherein the substance comprises a reagent for specifically detecting the DIR and / or a nucleic acid encoding the DIR.

31. The use according to any one of claims 15-30, wherein the substance comprises an antigen-binding protein capable of specifically binding to DIR, a probe capable of specifically binding to DIR, and a substance capable of... Primers capable of specifically amplifying nucleic acids encoding DIR, gene chips capable of specifically detecting nucleic acids encoding DIR, aptamers capable of specifically binding nucleic acids encoding DIR, and / or capable of... Guide RNA that specifically binds to nucleic acids encoding DIR.

32. The use according to claim 31, wherein the antigen-binding protein comprises L CDR2, wherein LCDR2 contains the amino acid sequence shown in SEQ ID NO:

74.

33. The use according to claim 32, wherein the LCDR2 comprises SEQ I The amino acid sequence shown in D NO:26 or 16.

34. The use according to any one of claims 31-33, wherein the antigen-binding protein comprises L CDR1, wherein LCDR1 contains the amino acid sequence shown in SEQ ID NO:

73.

35. The use according to claim 34, wherein the LCDR1 comprises SEQ ID The amino acid sequence shown in any one of NO:25, 52, or 15.

36. The use according to any one of claims 31-35, wherein the antigen binding The protein contains LCDR3, which contains the amino acid sequence shown in SEQ ID NO:

75.

37. The claim 36 For use, the LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 27, 53, 67, 17.

38. The use according to any one of claims 31-37, wherein the antigen-binding protein comprises LCDR1, LCDR2, and LCDR3, wherein, a) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:25, the LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:27; b) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:52, the LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:53; c) LCDR1 contains the amino acid sequence shown in SEQ ID NO:52, LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and LCDR3 contains the amino acid sequence shown in SEQ ID NO:

67. amino acid sequence; or, d) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:15, and the LCDR2 contains SEQ ID NO:

15. The amino acid shown in NO:16 The sequence, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:

17.

39. The use according to any one of claims 31-38, wherein The antigen-binding protein described herein includes HCDR1, which contains the amino acid sequence shown in SEQ ID NO:

70.

40. The use according to claim 39, wherein the H CDR1 contains the amino acid sequence shown in any one of SEQ ID NO: 20, 35, 56, 10.

41. The use of any one of claims 31-40 The antigen-binding protein comprises HCDR2, which comprises the amino acid sequence shown in SEQ ID NO:

71.

42. The use according to claim 41, wherein The HCDR2 contains the amino acid sequence shown in any one of SEQ ID NO: 21, 36, 42, 48, 11.

43. The use according to any one of claims 31-42, wherein The antigen-binding protein described herein includes HCDR3, which contains the amino acid sequence shown in SEQ ID NO:

70.

44. According to rights The use as claimed in claim 43, wherein the HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 22, 30, 37, 43, 49, 57, 62, 12.

45. The use according to any one of claims 31-44, wherein the antigen-binding protein comprises HCDR1, HCDR2, and HCDR3, wherein, a) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:21, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:22; b) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:21, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:

30. c) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:37; d) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:42, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:43; e) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:48, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:49; f) HCDR1 contains the amino acid sequence shown in SEQ ID NO:56, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:57; g) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:62; h) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:42, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:37; i) HCDR1 contains the amino acid sequence shown in SEQ ID NO:56, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and the HCDR3 contains the amino acid sequence shown in SEQ ID NO:57; or, j) HCDR1 contains the amino acid sequence shown in SEQ ID NO:10, HCDR2 contains the amino acid sequence shown in SEQ ID NO:11, and the HCDR3 contains the amino acid sequence shown in SEQ ID NO:

12.

46. ​​The use according to any one of claims 31-45, wherein the antigen-binding protein comprises a heavy chain variable region VH, said VH comprising SEQ ID NO: 13, 23 The amino acid sequence shown in any one of 31, 38, 44, 50, 58, 63, 65.

47. The claim 31-46 The stated use, wherein the antigen-binding protein comprises a light chain variable region VL, the VL comprising the amino acid sequence shown in any one of SEQ ID NO: 18, 28, 33, 40, 46, 54, 60, 68.

48. The use according to any one of claims 31-47, wherein the antigen-binding protein comprises a heavy chain variable region VH and a light chain variable region VL, wherein: a) The VH contains the amino acid sequence shown in SEQ ID NO:23, and the VL contains the amino acid sequence shown in SEQ ID NO:28; b) The VH contains the amino acid sequence shown in SEQ ID NO:31, and the VL contains the amino acid sequence shown in SEQ ID NO:33; c) The VH contains the amino acid sequence shown in SEQ ID NO:38, and the VL contains the amino acid sequence shown in SEQ ID NO:40; d) The VH contains the amino acid sequence shown in SEQ ID NO:44, and the VL contains the amino acid sequence shown in SEQ ID NO:46; e) The VH contains the amino acid sequence shown in SEQ ID NO:50, and the VL contains the amino acid sequence shown in SEQ ID NO:

54. The amino acid sequence shown; f) The VH contains the amino acid sequence shown in SEQ ID NO:58, and the VL contains the amino acid sequence shown in SEQ ID NO:60; g) The VH contains the amino acid sequence shown in SEQ ID NO:63, and the VL contains the amino acid sequence shown in SEQ ID NO:60; h) The VH contains the amino acid sequence shown in SEQ ID NO:65, and the VL contains SEQ ID NO:

65. The amino acid sequence shown in NO:54; i) The VH contains the amino acid sequence shown in SEQ ID NO:58, and the VL contains SEQ ID N. The amino acid sequence shown at O:68; or, j) The VH contains the amino acid sequence shown in SEQ ID NO:13, and the VL contains SEQ ID NO:

13. The amino acid sequence shown in NO:

18.

49. The use according to any one of claims 31-48, wherein the antigen-binding protein comprises a heavy chain constant region, and the heavy chain constant region comprises components derived from... The constant region of IgG.

50. The use according to claim 49, wherein the heavy chain constant region comprises It is derived from the constant regions of the following histones: IgG1, IgG2, IgG3, and IgG4.

51. According to claim 31 For any of the following uses, the antigen-binding protein comprises a light chain constant region, and the light chain constant region comprises a constant region derived from Igκ or a constant region derived from Igλ.

52. The use according to claim 51, wherein... The constant regions of the light chain include those derived from human Igκ.

53. The use according to any one of claims 31-52, wherein the anti- Original binding proteins include antibodies or their antigen-binding fragments.

54. The use according to claim 53, The antigen-binding fragments are selected from the group consisting of: Fab, Fab', F(ab)2, Fv fragment, F(ab')2, scFv, di-scFv, VHH and / or dAb.

55. Use according to any one of claims 53-54 The antibody is selected from the group consisting of monoclonal antibodies, murine antibodies, and chimeric antibodies.

56. The use according to any one of claims 15-55, wherein the product comprises a diagnostic kit.

57. A diagnostic kit comprising the substance according to any one of claims 15-56 The diagnostic kit is used to diagnose cognitive impairment and / or assess the disease progression of cognitive impairment; and / or Used for diagnosing neurodegenerative diseases and / or assessing the disease progression of neurodegenerative diseases.

58. The diagnostic kit of claim 57, comprising a description of methods for diagnosing cognitive impairment and / or assessing the disease progression of cognitive impairment using the diagnostic kit; and / or diagnosing neurodegenerative diseases and / or assessing the disease progression of neurodegenerative diseases.

59. A method for diagnosing cognitive impairment and / or assessing the disease progression of cognitive impairment, comprising the step of: detecting in a sample derived from a subject in need of... DNA damage-inducible transcript 4-like transcript (DDIT4L) intron-retained cleavage product DIR, and / or the nucleus encoding said DIR. Acid content.

60. A method for diagnosing neurodegenerative diseases and / or assessing the disease progression of neurodegenerative diseases, comprising the following steps: detecting substances derived from... In the samples of the subjects, intron-retained cleavage products DIR of DNA damage-inducible transcript 4 (DDIT4L) transcript, and / or those encoding said DIR, were present. The content of nucleic acids.

61. The method according to any one of claims 59-60, wherein the DIR comprises the amino acid sequence shown in SEQ ID NO:

1.

62. According to claim 59 The method of any one of the following 61, wherein the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:

8.

63. The method according to any one of claims 59-62, wherein The nucleic acid encoding DIR described herein contains the nucleotide sequence shown in SEQ ID NO:

93.

64. The method according to any one of claims 59-63 The cognitive impairments mentioned therein include cognitive impairments caused by normal aging, Lewis's physical dementia (LBD), frontotemporal dementia, and / or vascular dementia. 6 5. The method according to any one of claims 59-64, wherein the cognitive impairment-inducing disease includes Alzheimer's disease, multiple infarct type, Parkinson's disease, etc. Chronic disease, AIDS, and / or Creutzfeldt-Jakob disease (CJD).

66. The method according to any one of claims 59-65, wherein the cognitive impairment includes early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment.

67. The method according to any one of claims 59-66, wherein the cognitive impairment includes amnesic MCI with multiple cognitive domain impairment (aMCI-m). )。 68. The method according to any one of claims 60-67, wherein the neurodegenerative disease includes acute neurodegenerative diseases and chronic neurodegenerative diseases.

69. The method according to any one of claims 60-68, wherein The neurodegenerative diseases described include those caused by neuronal death and glial cell homeostasis, and those caused by aging. Neurodegenerative diseases, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegenerative diseases caused by impaired cell motility. Neurodegenerative diseases.

70. The method according to any one of claims 60-69, wherein The neurodegenerative diseases mentioned include Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), and muscle atrophy. Amyotrophic lateral sclerosis (ALS) and / or Huntington's disease (HD).

71. According to claims The method of any one of 60-70, wherein the neurodegenerative disease includes Alzheimer's disease.

72. According to claim 6 The method of any one of 0-71, wherein the neurodegenerative disease includes early Alzheimer's disease, mid-Alzheimer's disease and / or Late stage of Alzheimer's disease.

73. The claim 59-72 Methods, wherein the subjects include mammals.

74. The method according to any one of claims 59-73, wherein the subject includes a tumor patient.

75. The method according to any one of claims 59-74 The method, in which the subjects were in an elderly stage.

76. The method according to any one of claims 59-75, wherein the sample This includes blood samples and / or tissue or cell samples.

77. According to the rights The method of any one of claims 59-76, wherein the sample comprises whole blood, serum, plasma and / or cerebrospinal fluid.

78. The method according to any one of claims 59-77, wherein the method The method includes: taking the DIR and / or the nucleic acid encoding the DIR from the subject's sample. The content of DIR was compared with the normal control value, wherein the normal control value included the content of DIR and / or the nucleic acid encoding DIR in normal subjects.

79. The method of claim 78, wherein the normal subject does not suffer from the The aforementioned cognitive impairment and / or the aforementioned neurodegenerative disease.

80. The method according to any one of claims 78-79, wherein, When the subject's sample has a DIR, and / or the kernel encoding the DIR. The acid content was significantly higher than the normal control value, and the subject was diagnosed with the cognitive impairment and / or the neurodegenerative disease.

81. The method according to any one of claims 59-80, wherein the method The method includes: comparing the content of the DIR and / or the nucleic acid encoding the DIR in a sample of the subject with an earlier control value, wherein the earlier control value includes the DIR previously measured in the same subject. The content of R and / or nucleic acids encoding DIR.

82. The method of claim 81, wherein the subject has been diagnosed with the cognitive impairment and / or the neurodegenerative disease.

83. According to claim 81- The method of any one of 82, wherein the subject is diagnosed with the cognitive impairment and / or the worsening of the neurodegenerative disease when the DIR and / or the content of the nucleic acid encoding the DIR in the subject's sample are significantly higher than the earlier control value.

84. The method according to any one of claims 59-83, further comprising the step of: detecting the levels of biomarkers associated with cognitive impairment and / or neurodegenerative diseases in a sample derived from the subject.

85. The method of claim 84, wherein the biomarkers associated with cognitive impairment and / or neurodegenerative diseases include AD7C-NTP, pTau-1 81, pTau-217 and / or Aβ1-42.

86. The method according to any one of claims 59-85, further comprising: The next step is to observe brain imaging of the subject.

87. A system for diagnosing cognitive impairment and / or assessing the disease progression of cognitive impairment, comprising the detection of DNA damage. The intron-retaining cleavage product DIR of injury-inducible transcript 4-like transcript (DDIT4L), and / or the substance encoding the nucleic acid of said DIR.

88. Diagnosis A system for diagnosing and / or assessing the progression of neurodegenerative diseases, comprising the detection of intron-retaining cleavage products DIR of DNA damage-induced transcript 4-like transcript (DDIT4L). , and / or substances encoding the nucleic acids of the DIR.

89. The system according to any one of claims 87-88, wherein the DIR comprises the amino acid sequence shown in SEQ ID NO:

1.

90. The system according to any one of claims 87-89, wherein the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:

8.

91. The system according to any one of claims 87-90, wherein the nucleic acid encoding DIR comprises the one shown in SEQ ID NO:

93. The nucleotide sequence.

92. The system according to any one of claims 87-91, wherein the cognitive impairment includes cognitive impairment caused by normal aging, l Leukemia, LBD, frontotemporal dementia, and / or vascular dementia.

93. The system according to any one of claims 87-92, wherein the cognitive impairment-inducing disease includes Alzheimer's disease, multiple infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD).

94. The system according to any one of claims 87-93, wherein the cognition The impairments include early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment.

95. The system according to any one of claims 87-94, wherein the cognitive impairment includes amnesic MCI (aMCI-m).

96. The system according to any one of claims 88-95, wherein the neurodegenerative disease includes acute neurodegenerative diseases. Degenerative diseases and chronic neurodegenerative diseases.

97. The system according to any one of claims 88-96, wherein the neurodegenerative disease comprises neuronal death. Neurodegenerative diseases caused by glial cell homeostasis, neurodegenerative diseases caused by aging, and neurodegenerative diseases caused by C Neurodegenerative diseases caused by impaired NS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegeneration caused by impaired cell motility. Sexually transmitted diseases.

98. The system according to any one of claims 88-97, wherein The neurodegenerative diseases mentioned include Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), and muscular dystrophy. Amyotrophic lateral sclerosis (ALS) and / or Huntington's disease (HD).

99. According to claim 88- The system of any one of the 98, wherein the neurodegenerative disease includes Alzheimer's disease.

100. According to claims 88-99 The system described in any one of the following statements, wherein the neurodegenerative disease includes early Alzheimer's disease, mid-Alzheimer's disease, and / or late Alzheimer's disease. Expect.

101. The system according to any one of claims 87-100, which is available in the form of a kit.

102. The claim 87-101 The system includes a collection module capable of collecting samples from subjects in need.

103. The system of claim 102, wherein the subject package Including mammals.

104. The system according to any one of claims 102-103, wherein the subject includes a cancer patient.

105. According to claim 102- The system of any one of 104, wherein the subject is in an elderly stage.

106. The system according to any one of claims 102-105, wherein the sample comprises a blood sample and / or a tissue or cell sample.

107. The system according to any one of claims 102-106, wherein the sample comprises whole blood, serum, plasma and / or cerebrospinal fluid.

108. According to claims The system according to any one of 87-107 includes a detection module capable of detecting the DIR and / or the content value of the nucleic acid encoding the DIR.

109. According to The system of claim 108, wherein the detection module detects the DIR and / or the encoded DIR in the sample obtained by the collection module. The content value of nucleic acid R.

110. The system according to any one of claims 108-109, wherein the detection module comprises the ability to detect the DIR and / or the content of nucleic acids encoding the DIR. The substance.

111. The system of claim 110, wherein the substance comprises an antigen-binding protein capable of specifically binding to DIR, and a protein capable of specifically binding to DIR. IR probes, primers capable of specifically amplifying nucleic acids encoding DIR, gene chips capable of specifically detecting nucleic acids encoding DIR, aptamers capable of specifically binding to nucleic acids encoding DIR, and / or specific... Guide RNA that binds to nucleic acids encoding DIR.

112. The system of claim 111, wherein the antigen-binding protein comprises LCDR2, and the L CDR2 contains the amino acid sequence shown in SEQ ID NO:

74.

113. The system of claim 112, wherein the LCDR2 comprises The amino acid sequence shown in SEQ ID NO:26 or 16.

114. The system according to any one of claims 112-113, wherein the antigen-binding protein comprises LCDR1, and the LCDR1 comprises the amino acid sequence shown in SEQ ID NO:

73.

115. The system of claim 114, wherein the LCDR1 comprises the amino acid sequence shown in any one of SEQ ID NO: 25, 52, 15.

116. The system according to any one of claims 111-115, wherein the antigen-binding protein comprises LCDR3, the LCDR3 comprising the amino acid sequence shown in SEQ ID NO:

75.

117. The system of claim 116, wherein the LCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 27, 53, 67, 17.

118. The system according to any one of claims 111-117, wherein the antigen-binding protein comprises LCDR1, LCDR2, and LCDR3, wherein, a) The LCDR1 includes SEQ The amino acid sequence shown in SEQ ID NO:25, LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and LCDR3 contains the amino acid sequence shown in SEQ ID NO:

27. amino acid sequence; b) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:52, and the LCDR2 contains the amino acid sequence shown in SEQ ID NO:

26. The amino acid sequence shown is provided, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:53; c) The LCDR1 contains the amino acid sequence shown in SEQ ID NO:

52. The LCDR2 contains the amino acid sequence shown in SEQ ID NO:26, and the LCDR3 contains the amino acid sequence shown in SEQ ID NO:67; or, d) LCDR1 contains the amino acid sequence shown in SEQ ID NO:15, LCDR2 contains the amino acid sequence shown in SEQ ID NO:16, and LCDR3 contains... Contains the amino acid sequence shown in SEQ ID NO:

17.

119. The system according to any one of claims 111-118, wherein the antigen-binding protein comprises HCDR1, and the HCD R1 contains the amino acid sequence shown in SEQ ID NO:

70.

120. The system of claim 119, wherein the HCDR1 comprises S The amino acid sequence shown in any one of EQ ID NO: 20, 35, 56, 10.

121. The system according to any one of claims 111-120, wherein the antigen-binding protein comprises HCDR2, and the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:

71.

122. The system of claim 121, wherein the HCDR2 comprises the amino acid sequence shown in any one of SEQ ID NO: 21, 36, 42, 48, 11.

123. The system according to any one of claims 111-122, wherein the antigen-binding protein comprises HCDR3, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:

70.

124. The system of claim 123, wherein the HCDR3 comprises the amino acid sequence shown in any one of SEQ ID NO: 22, 30, 37, 43, 49, 57, 62, 12.

125. The system according to any one of claims 111-124, wherein the antigen-binding protein comprises HCDR1, HCDR2, and HCDR3, wherein, a) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:21, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:22; b) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, and HCDR2 contains SEQ ID NO:

20. The amino acid sequence shown in NO:21, and the HCDR3 contains the amino acid sequence shown in SEQ ID NO:30; c) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:37; d) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:42, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:43; e) HCDR1 contains the amino acid sequence shown in SEQ ID NO:20, HCDR2 contains the amino acid sequence shown in SEQ ID NO:48, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:49; f) HCDR1 contains the amino acid sequence shown in SEQ ID NO:56, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:

56. The amino acid sequence shown in :57; g) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:36, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:

62. The amino acid sequence; h) HCDR1 contains the amino acid sequence shown in SEQ ID NO:35, HCDR2 contains the amino acid sequence shown in SEQ ID NO:42, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:

37. acid sequence; i) HCDR1 contains the amino acid sequence shown in SEQ ID NO:56, and HCDR2 contains the amino acid sequence shown in SEQ ID NO:

56. The amino acid sequence shown in SEQ ID NO:36, and the HCDR3 contains the amino acid sequence shown in SEQ ID NO:57; or, j) HCDR1 contains the amino acid sequence shown in SEQ ID NO:10, HCDR2 contains the amino acid sequence shown in SEQ ID NO:11, and HCDR3 contains the amino acid sequence shown in SEQ ID NO:

12.

126. The system according to any one of claims 111-125, wherein the antigen-binding protein comprises a heavy chain variable region VH, the VH comprising the amino acid sequence shown in any one of SEQ ID NO: 13, 23, 31, 38, 44, 50, 58, 63, 65.

127. The system according to any one of claims 111-126, wherein the antigen-binding protein comprises a light chain variable region VL, the VL comprising the amino acid sequence shown in any one of SEQ ID NO: 18, 28, 33, 40, 46, 54, 60, 68.

128. The system according to any one of claims 111-127, wherein the antigen-binding protein comprises a heavy chain variable region VH and a light chain variable region VL, wherein: a) The VH contains the amino acid sequence shown in SEQ ID NO:23, and the VL contains the amino acid sequence shown in SEQ ID NO:28; b) The VH contains the amino acid sequence shown in SEQ ID NO:31, and the VL contains the amino acid sequence shown in SEQ ID NO:33; c) The VH contains the amino acid sequence shown in SEQ ID NO:38, and the VL contains the amino acid sequence shown in SEQ ID NO:40; d) The V H contains the amino acid sequence shown in SEQ ID NO:44, and VL contains the amino acid sequence shown in SEQ ID NO:46; e) The VH includes S The amino acid sequence shown in EQ ID NO:50, and the VL contains the amino acid sequence shown in SEQ ID NO:54; f) The VH includes SEQ The amino acid sequence shown in SEQ ID NO:58, and the VL contains the amino acid sequence shown in SEQ ID NO:60; g) The VH contains the amino group represented by SEQ ID NO:

63. The acid sequence, and the VL contains the amino acid sequence shown in SEQ ID NO:60; h) The V H contains the amino acid sequence shown in SEQ ID NO:65, and VL contains the amino group shown in SEQ ID NO:

54. acid sequence; i) The VH contains the amino acid sequence shown in SEQ ID NO:58, and the VL contains the amino acid sequence shown in SEQ ID NO:68; or, j) The VH contains SEQ ID NO The amino acid sequence shown in SEQ ID NO:13, and the VL contains the amino acid sequence shown in SEQ ID NO:

18.

129. According to claims The system of any one of 111-128, wherein the antigen-binding protein comprises a heavy chain constant region, and the heavy chain constant region comprises a constant region derived from IgG.

130. The system of claim 129, wherein the heavy chain constant region comprises proteins derived from histones selected from the following The constant regions are: IgG1, IgG2, IgG3 and IgG4.

131. The system according to any one of claims 111-130, wherein the antigen-binding protein comprises a light chain constant region. Furthermore, the light chain constant region includes a constant region derived from Igκ or a constant region derived from Igλ.

132. The system of claim 131, wherein the light chain constant region comprises a constant region derived from human Igκ.

133. According to The system of any one of claims 111-132, wherein the antigen-binding protein comprises an antibody or an antigen-binding fragment thereof.

134. According to claim 1 The system of 33, wherein the antigen-binding fragment is selected from the group consisting of: Fab, Fab', F(ab)2, Fv fragment, F(ab')2, scFv, di-scFv, VHH and / or dAb.

135. The system according to any one of claims 133-134 The antibody is selected from the group consisting of monoclonal antibodies, murine antibodies, and chimeric antibodies.

136. The system according to any one of claims 108-135, wherein the detection module comprises the ability to detect four samples of DNA damage-induced transcripts. An instrument for measuring the content of intron-retaining cleavage products DIR of transcript (DDIT4L) and / or the nucleic acids encoding said DIR. 13 7. The system according to any one of claims 108-136, wherein the detection module comprises a substance and / or instrument capable of detecting the levels of biomarkers associated with cognitive impairment and / or neurodegenerative diseases.

138. The system of claim 137, wherein the cognitive impairment Biomarkers associated with impairment and / or neurodegenerative diseases include AD7C-NTP, pTau-181, pTau-217, and / or Aβ1-42.

139. The system according to any one of claims 108-138 The system, wherein the detection module outputs the content value of the DIR and / or the nucleic acid encoding the DIR.

140. The system according to any one of claims 87-139, comprising a determination module, the determination module being capable of determining the... The diagnostic result of the subject is determined by comparing the content of DIR and / or the nucleic acid encoding the DIR with normal control values ​​and / or early control values. and / or disease progression outcomes; Wherein, the normal control value includes the content of DIR and / or nucleic acid encoding DIR in normal subjects; wherein, the early The control values ​​include the levels of the DIR and / or the nucleic acids encoding the DIR previously measured for the same subject.

141. The system of claim 140, wherein the normal subject does not suffer from the cognitive impairment described above. Disorders and / or the aforementioned neurodegenerative diseases.

142. The system according to any one of claims 140-141, wherein when the DIR and / or the content of the nucleic acid encoding DIR in the subject's sample are significantly higher than the normal control value, the The assessment module diagnoses the subject as having the cognitive impairment and / or the neurodegenerative disease.

143. According to claims The system of any one of 140-142, wherein the subject has been diagnosed with the cognitive impairment and / or the neurodegenerative disease.

144. According to the rights The system described in any one of 140-143 is provided, wherein the levels of DIR and / or the nucleic acid encoding DIR in the subject's sample are significantly higher than those in the earlier control. The judgment module diagnoses the subject as having an exacerbated cognitive impairment and / or neurodegenerative disease.

145. The system according to any one of claims 140-144, wherein... The judgment module outputs the diagnostic results of the subject.

146. The system according to any one of claims 87-145, comprising a display module, wherein the display module is capable of displaying the diagnosis of the judgment module. The result is as follows.

147. The system according to any one of claims 87-146, comprising a storage module, wherein the storage module is capable of storing the output of the detection module. The content value, and / or the diagnostic result output by the judgment module.

148. A drug screening method comprising the following steps: detecting the effect of administration of a candidate drug on the recipient... Changes in the levels of DIR and / or nucleic acids encoding DIR in test subjects, wherein the drug is used to prevent, treat and / or alleviate cognitive impairment and / or neurodegenerative diseases.

149. The method of claim 148, wherein the DIR comprises the amino acid sequence shown in SEQ ID NO:

1.

150. The method according to any one of claims 148-149, wherein the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:

8.

151. The invention according to any one of claims 148-150 The method wherein the nucleic acid encoding DIR comprises the nucleotide sequence shown in SEQ ID NO:

93.

152. The method according to any one of claims 148-151, wherein the cognitive impairment includes cognitive impairment caused by normal aging. Lews' physical dementia (LBD), frontotemporal dementia, and / or vascular dementia.

153. According to claim 148- The method of any one of 152, wherein the inducing disease of the cognitive impairment includes Alzheimer's disease, multiple infarct type, Parkinson's disease, AIDS and / or Creutzfeldt-Jakob disease (CJD). 。 154. The claim 148-153 The method, wherein the cognitive impairment includes early cognitive impairment (MCI), intermediate cognitive impairment, and late cognitive impairment.

155. According to claims The method of any one of 148-154, wherein the cognitive impairment includes amnesic MCI with multiple cognitive impairments. Knowledge domain impaired (aMCI-m).

156. The method according to any one of claims 148-155, wherein the nerve Degenerative diseases include acute neurodegenerative diseases and chronic neurodegenerative diseases.

157. The method according to any one of claims 148-156, wherein the neurodegenerative disease includes neurodegenerative diseases caused by neuronal death and glial cell homeostasis, neurodegenerative diseases caused by aging, neurodegenerative diseases caused by impaired CNS cell function, neurodegenerative diseases caused by abnormal intercellular communication, and / or neurodegenerative diseases caused by impaired cell motility.

158. The method according to any one of claims 148-157, wherein the neurodegenerative disease includes Alzheimer's disease, Parkinson's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and / or Huntington's disease (HD).

159. The method according to any one of claims 148-158, wherein the neurodegenerative disease includes Alzheimer's disease.

160. The method according to any one of claims 148-159, wherein the neurodegenerative disease includes early Alzheimer's disease, mid-Alzheimer's disease, and / or late Alzheimer's disease.

161. The method according to any one of claims 148-160, wherein the candidate drug has a therapeutic effect when the content of DIR and / or nucleic acid encoding DIR is reduced in the subject after administration of the candidate drug.

162. The method according to any one of claims 148-161, wherein the application comprises injection.

163. The method according to any one of claims 148-162, wherein the drug comprises a small molecule drug and / or a biological macromolecule drug.

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