Biomarkers for early diagnosis of neurodegenerative diseases in patients with mild cognitive impairment

Abstract

The present invention relates to a composition and kit for early diagnosis of Alzheimer's disease that diagnose early whether a patient with mild cognitive impairment has progressed to Alzheimer's disease using a novel miRNA biomarker, a composition and kit for detailed diagnosis of Alzheimer's disease that diagnose the degree of progression of Alzheimer's disease in detail, and a method for providing information for early diagnosis or detailed diagnosis of Alzheimer's disease using the same. In the present invention, by presenting a novel biomarker capable of predicting Alzheimer's disease, a composition and kit for early diagnosis of Alzheimer's disease are provided, thereby enabling rapid and accurate diagnosis of Alzheimer's disease patients and providing appropriate treatment methods to patients according to the degree of progression of Alzheimer's disease.

Description

Technology Field

[0001] The present invention relates to a composition and kit for early diagnosis of Alzheimer's disease that diagnose the stage of progression to Alzheimer's disease in patients with mild cognitive impairment early using a novel miRNA biomarker, a composition and kit for detailed diagnosis of Alzheimer's disease that diagnose the degree of progression of Alzheimer's disease in detail, and a method for providing information for early diagnosis or detailed diagnosis of Alzheimer's disease using the same. Background Technology

[0002] Dementia is a representative disease of old age characterized by the acquired loss of intellectual ability and the gradual deterioration of personality due to cognitive impairment and behavioral and psychological symptoms (such as insomnia, binge eating, anxiety, agitation, depression, and delusions). Any disease capable of causing damage to overall brain function can be a cause of dementia. The commonly known Alzheimer's dementia, or Alzheimer's disease (AD), accounts for approximately 60% of all dementia cases; in this condition, nerve cells in the cerebral cortex or hippocampus degenerate or gradually decline, leading to the loss of brain tissue and brain atrophy. In some cases, vascular dementia occurs as brain cells die due to impaired cerebral blood circulation or cerebrovascular abnormalities.

[0003] It is estimated that more than 20% of the elderly aged 80 or older are affected by Alzheimer's disease, and the number is rapidly increasing as society ages. However, because Alzheimer's disease is caused by various etiological factors accompanied by the accumulation of amyloid-β in brain tissue, there is still no clear diagnostic or treatment method.

[0004] Currently, the diagnosis of Alzheimer's disease is primarily made through medical history interviews at the point when symptoms become clearly apparent. However, since Alzheimer's disease progresses 10 to 20 years before symptoms worsen, there is a problem in that early diagnosis based on symptoms alone is very difficult. Recently, high-performance imaging technologies such as amyloid-PET (positron emission tomography) and MRI (magnetic resonance imaging) are being used for the early diagnosis of Alzheimer's disease; however, the high cost and limitations of the equipment place a heavy burden on patients. In addition, while numerous studies are being conducted on cerebrospinal fluid detection methods for early diagnosis by detecting amyloid beta or tau proteins, known as biomarkers for Alzheimer's disease, these methods have limitations as a widely available early diagnosis technology because they involve significant discomfort for the subjects.

[0005] Recently, research on blood biomarkers for the diagnosis of Alzheimer's disease has been actively conducted worldwide. However, since Alzheimer's disease is a chronic disease with a wide variety of causes, early diagnosis is very difficult with only one or two types of biomarkers, and the results to date are extremely limited. In particular, there is a lack of biomarkers with high sensitivity for Alzheimer's disease, and conventional amyloid-β or tau proteins are showing limitations, such as constraints in crossing the blood-brain barrier (BBB). Therefore, there is an urgent need for research on non-invasive biomarkers that can screen with high reliability as new biomarkers. Prior art literature

[0006] Republic of Korea Application No. 10-2016-0107789 Republic of Korea Application No. 10-2018-0102177 The problem to be solved

[0007] The present invention aims to provide a composition for the early diagnosis of Alzheimer's disease in patients with mild cognitive impairment using a novel miRNA biomarker.

[0008] In addition, the present invention aims to provide a kit for early diagnosis of Alzheimer's disease comprising a composition for early diagnosis of Alzheimer's disease in patients with mild cognitive impairment.

[0009] In addition, the present invention aims to provide a method for providing information for the early diagnosis or detailed diagnosis of Alzheimer's disease using a novel miRNA biomarker. means of solving the problem

[0010] One aspect of the present invention is a composition for the early diagnosis of Alzheimer's disease comprising a preparation for measuring the expression levels of miRNAs hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, Mature-1322, Mature-639, and Mature-655,

[0011] The above-mentioned Mature-1322 is represented by SEQ ID NO. 1, the above-mentioned Mature-639 is represented by SEQ ID NO. 2, and the above-mentioned Mature-655 is represented by SEQ ID NO. 3. A composition is provided.

[0012] The term "Alzheimer's disease" as used in this invention refers to a degenerative brain disease in which neuritic plaques and neurofibrillary tangles associated with the deposition of beta-amyloid are observed as brain pathological findings, and macroscopically, general brain atrophy due to the loss of neurons is observed. Initially, a decline in memory is mainly observed, but as the disease progresses, not only is there a decline in cognitive function, but neuropsychiatric symptoms such as personality changes, agitation, depression, delusions, hallucinations, increased aggression, and sleep disorders are accompanied and worsen.

[0013] The term "mild cognitive impairment" as used in this invention refers to a state that exhibits a clear, objective decline in cognitive function, although it is not sufficient to diagnose dementia. As aging progresses, symptoms such as memory loss and reduced attention span appear; mild cognitive impairment corresponds to a stage between Alzheimer's disease and normal aging. Although patients diagnosed with mild cognitive impairment have a higher probability of progressing to dementia compared to the general population, not all patients with mild cognitive impairment progress to dementia; some revert to normal aging, while others maintain their mild cognitive impairment. Therefore, the development of methods to diagnose Alzheimer's disease at the early stages of mild cognitive impairment is recognized as a critical technology in the field of early diagnosis. In particular, diagnostic technologies based on blood analysis are considered even more important for early diagnosis due to their simplicity and affordability.

[0014] In the present invention, miRNA can be used as a biomarker for the early diagnosis of the progression to Alzheimer's disease in patients with mild cognitive impairment. Here, a biomarker generally refers to a substance detectable in biological samples and includes all organic biomolecules such as polypeptides, proteins, nucleic acids, genes, lipids, glycolipids, glycoproteins, and sugars that can identify biological changes.

[0015] The term "miRNA" used in this invention refers to 21 to 23 non-coding RNAs that regulate gene expression after transcription by promoting the degradation of target RNAs or inhibiting their translation. Generally, miRNA is produced in a mature form after being transcribed as a precursor of about 70-80 nucleotides in length with a hairpin structure called pre-miRNA, and then cleaved by Dicer, an RNAse III enzyme. More than 30% of human miRNAs exist in clusters, and after being transcribed as a single precursor, the final mature miRNA is formed through a cleaving process.

[0016] These miRNAs consist of specific miRNAs that show specific changes in expression levels according to the worsening of symptoms in patients with cognitive impairment through next-generation sequencing (NGS), and can be presented as biomarkers for the early diagnosis of Alzheimer's disease.

[0017] The aforementioned NGS possesses the multiplexing capability to perform hundreds of thousands of reactions simultaneously and enables sequencing with small sample volumes. While specific application techniques vary slightly depending on the commercially available technology, NGS generally utilizes clonal amplification, massively parallel sequencing, and novel sequencing methods with mechanisms of action different from the Sanger method. Commercialized technologies include the FLX model sequencer, an improved version of the 454 GS released by Roche in 2007; the Genome Analyzer HiSeq released by Illumina in 2006; and SOLiD released by Applied Biosystems in 2007. These three platforms commonly adopt clonal amplification technology, abandoning complex library construction and cloning processes; utilize massively parallel sequencing technology capable of processing large volumes at once; and eliminate the cumbersome electrophoresis process by determining base sequences through sequencing by synthesis via cyclic sequencing. In addition, it uses an algorithm that arranges short reads using the shotgun method to find duplicate parts and complete the whole.

[0018] The 349 miRNAs for the early diagnosis of Alzheimer's disease in patients with mild cognitive impairment include not only previously identified miRNAs but also novel miRNAs that were first identified as miRNAs by the inventors.

[0019] The above novel miRNAs have not been reported in existing references, and include Mature-1322 indicated by SEQ ID NO. 1, Mature-639 indicated by SEQ ID NO. 2, Mature-655 indicated by SEQ ID NO. 3, Mature-1259 indicated by SEQ ID NO. 4, Mature-240 indicated by SEQ ID NO. 5, Mature-626 indicated by SEQ ID NO. 6, Mature-1251 indicated by SEQ ID NO. 7, Mature-1331 indicated by SEQ ID NO. 8, Mature-168 indicated by SEQ ID NO. 9, Mature-169 indicated by SEQ ID NO. 10, Mature-176 indicated by SEQ ID NO. 11, Mature-181 indicated by SEQ ID NO. 12, Mature-326 indicated by SEQ ID NO. 13, Mature-509 indicated by SEQ ID NO. 14, Mature-565 indicated by SEQ ID NO. 15, Mature-567 indicated by SEQ ID NO. 16, Mature-893 indicated by SEQ ID NO. 17, and Mature-1363 indicated by SEQ ID NO. 18. Mature-600 indicated by sequence number 19, Mature-65 indicated by sequence number 20, Mature-759 indicated by sequence number 21, Mature-1121 indicated by sequence number 22, Mature-1390 indicated by sequence number 23, Mature-154 indicated by sequence number 24, Mature-173 indicated by sequence number 25, Mature-184 indicated by sequence number 26, Mature-191 indicated by sequence number 27, Mature-208 indicated by sequence number 28, Mature-289 indicated by sequence number 29, Mature-298 indicated by sequence number 30, Mature-322 indicated by sequence number 31, Mature-330 indicated by sequence number 32, Mature-392 indicated by sequence number 33, Mature-394 indicated by sequence number 34, Mature-452 indicated by sequence number 35, Mature-611 indicated by sequence number 36,Mature-627 designated by sequence number 37, Mature-667 designated by sequence number 38, Mature-808 designated by sequence number 39, Mature-847 designated by sequence number 40, and Mature-896 designated by sequence number 41 are included.

[0020] These 349 miRNAs include hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, Mature-1322, Mature-639, and Mature-655 as biomarkers for the early diagnosis of Alzheimer's disease in patients with mild cognitive impairment, and one or more of the remaining biomarkers may be additionally included and used as needed.

[0021] More specifically, among 349 miRNAs, it is desirable to use a miRNA alone or a combination of miRNAs that have a statistically significant difference in expression (p < 0.05) for a more accurate diagnosis of Alzheimer's disease.

[0022] In the present invention, early diagnosis or detailed diagnosis may mean providing information on which stage the diagnosed individual belongs to when the progression of Alzheimer's disease is classified into a normal stage, a mild cognitive impairment stage, a transitional stage from mild cognitive impairment to Alzheimer's disease, and a moderate to severe Alzheimer's disease stage.

[0023] More specifically, in the present invention, early diagnosis or detailed diagnosis of Alzheimer's disease means not only distinguishing between normal individuals and individuals with Alzheimer's disease, but also diagnosing whether individuals with mild cognitive impairment have the potential to progress to Alzheimer's disease and / or distinguishing between individuals of the following seven groups.

[0024] Specifically, the diagnostic composition of the present invention is capable of distinguishing between normal individuals (Group 7), individuals with early-onset Alzheimer's disease who are amyloid PET positive (Early-onset Alzheimer's disease with positive amyloid PET, Group 1), individuals with late-onset Alzheimer's disease who are amyloid PET positive (late-onset Alzheimer's disease with positive amyloid PET, Group 2), individuals with mild cognitive impairment who are amyloid PET negative (MCI with negative amyloid PET, Group 3), individuals with mild cognitive impairment who are amyloid PET negative but possess the ApoE 44 gene (MCI with negative amyloid PET but with ApoE 44, Group 4), individuals with mild cognitive impairment who are amyloid PET positive (MCI with positive amyloid PET, Group 5), and individuals with non-Alzheimer's dementia (Non-AD dementia, Group 6).

[0025] According to one embodiment of the present invention, the diagnosis of Alzheimer's disease may distinguish between a normal stage and a moderate to severe stage of Alzheimer's disease.Distinguishing between the above normal stage and the moderate to severe Alzheimer's disease stage is Mature-1322, Mature-655, Mature-639, hsa-miR-32-5p, hsa-miR-33a-5p, hsa-miR-33b-5p, hsa-miR-17-3p, hsa-miR-199a-5p, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p, hsa-miR-3613-5p, hsa-miR-374a-3p, hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-1306-5p, hsa-miR-141-3p, hsa-miR-1537-5p, hsa-miR-188-5p, hsa-miR-197-3p, hsa-miR-20a-3p, hsa-miR-20a-5p, hsa-miR-363-3p, hsa-miR-4687-5p, hsa-miR-496, hsa-miR-579-5p, Mature-1259, Mature-240, Mature-626, hsa-miR-142-3p, hsa-miR-184, hsa-miR-21-5p, hsa-miR-3200-3p, hsa-miR-328-3p, hsa-miR-376a-5p, hsa-miR-424-5p, hsa-miR-4433b-5p, hsa-miR-450a-5p, This can be done using a preparation that measures the expression level of one or more miRNAs selected from the group consisting of hsa-miR-5100, hsa-miR-548am-5p, hsa-miR-548au-5p, hsa-miR-548c-5p, hsa-miR-548o-5p, hsa-miR-590-3p, hsa-miR-6511a-3p, hsa-miR-6793-3p, hsa-miR-6858-3p, hsa-miR-766-3p, hsa-miR-8072, Mature-600, Mature-65, Mature-759, hsa-miR-3620-3p, hsa-miR-4701-5p, hsa-miR-490-3p, and hsa-miR-95-5p.Preferably, Mature-1322, Mature-655, Mature-639, hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, hsa-let-7g-3p, hsa-miR-188-5p, Mature-1259, Mature-240, hsa-miR-11400, Mature-626, hsa-miR-1537-5p, Mature-759, Mature-600, hsa-miR-21-5p, hsa-miR-142-3p, hsa-miR-184, hsa-miR-4433b-5p, hsa-miR-424-5p, hsa-miR-8072, hsa-miR-6858-3p, hsa-miR-6511a-3p, hsa-miR-766-3p, hsa-miR-5100, hsa-miR-548au-5p, hsa-miR-548o-5p, hsa-miR-548c-5p, hsa-miR-548am-5p, hsa-miR-328-3p, Mature-65, hsa-miR-3200-3p, It may be done using a preparation that measures the expression level of one or more miRNAs selected from the group consisting of hsa-miR-376a-5p, hsa-miR-450a-5p, hsa-miR-6793-3p and hsa-miR-590-3p.More preferably, Mature-1322, Mature-655, Mature-639, hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, Mature-759, Mature-600, hsa-miR-21-5p, hsa-miR-142-3p, hsa-miR-184, It may be done using a preparation that measures the expression level of one or more miRNAs selected from the group consisting of hsa-miR-4433b-5p, hsa-miR-424-5p, hsa-miR-8072, hsa-miR-6858-3p and hsa-miR-6511a-3p.

[0026] According to one embodiment of the present invention, the diagnosis of Alzheimer's disease may distinguish between a normal stage and a transition stage from mild cognitive impairment to Alzheimer's disease. Distinguishing the above normal stage and the transition stage from mild cognitive field to Alzheimer's disease is Mature-1322, Mature-655, Mature-639, hsa-miR-32-5p, hsa-miR-33a-5p, hsa-miR-33b-5p, hsa-miR-17-3p, hsa-miR-199a-5p, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p, hsa-miR-3613-5p, hsa-miR-374a-3p, hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-1306-5p, hsa-miR-141-3p, hsa-miR-1537-5p, hsa-miR-188-5p, hsa-miR-197-3p, hsa-miR-20a-3p, hsa-miR-20a-5p, hsa-miR-363-3p, hsa-miR-4687-5p, hsa-miR-496, hsa-miR-579-5p, Mature-1259, Mature-240, Mature-626, hsa-let-7a-3p, hsa-let-7i-3p, hsa-miR-101-3p, hsa-miR-101-5p, hsa-miR-10399-5p, hsa-miR-103a-1-5p, hsa-miR-1228-5p, hsa-miR-126-5p, hsa-miR-1271-5p, hsa-miR-1287-5p, hsa-miR-1307-5p, hsa-miR-136-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-146b-3p, hsa-miR-148a-3p, hsa-miR-148b-3p, hsa-miR-148b-5p, hsa-miR-150-3p, hsa-miR-154-5p, hsa-miR-15a-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1-3p, hsa-miR-16-5p,hsa-miR-181a-3p, hsa-miR-181c-5p, hsa-miR-1908-3p, hsa-miR-199b-5p, hsa-miR-19b-1-5p, hsa-miR-2110, hsa-miR-21-3p, hsa-miR-22-5p, hsa-miR-2355-3p, hsa-miR-2355-5p, hsa-miR-26b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29c-5p, hsa-miR-301b-5p, hsa-miR-30e-3p, hsa-miR-32-3p, hsa-miR-337-3p hsa-miR-337-5p, hsa-miR-340-3p, hsa-miR-340-5p, hsa-miR-369-3p, hsa-miR-369-5p, hsa-miR-370-5p, hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-376c-3p, hsa-miR-378a-5p, hsa-miR-380-3p, hsa-miR-381-3p, hsa-miR-4286, hsa-miR-4463, hsa-miR-4473, hsa-miR-452-5p, hsa-miR-454-5p, hsa-miR-4644, hsa-miR-4654 hsa-miR-4732-5p, hsa-miR-4799-5p, hsa-miR-483-3p, hsa-miR-487a-3p, hsa-miR-487b-3p, hsa-miR-497-5p, hsa-miR-542-3p, hsa-miR-548ap-5p, hsa-miR-548av-3p, hsa-miR-548j-5p, hsa-miR-548o-3p, hsa-miR-551b-3p, hsa-miR-556-3p, hsa-miR-556-5p, hsa-miR-5698, hsa-miR-590-5p, hsa-miR-598-3p, hsa-miR-642a-3p hsa-miR-642b-3p, hsa-miR-654-3p, hsa-miR-656-3p, hsa-miR-660-5p, hsa-miR-671-5p, hsa-miR-6885-5p,hsa-miR-744-3p, hsa-miR-8485, hsa-miR-939-5p, hsa-miR-98-3p, hsa-miR-99a-3p, Mature-1251, Mature-1331, Mature-168, Mature-169, Mature-176, Mature-181, Mature-326, Mature-509, Mature-565, Mature-567, Mature-893, hsa-miR-142-3p, hsa-miR-184, hsa-miR-21-5p, hsa-miR-3200-3p, hsa-miR-328-3p, hsa-miR-376a-5p, hsa-miR-424-5p, hsa-miR-4433b-5p, hsa-miR-450a-5p, hsa-miR-5100, hsa-miR-548am-5p, hsa-miR-548au-5p, hsa-miR-548c-5p, hsa-miR-548o-5p, hsa-miR-590-3p, hsa-miR-6511a-3p, hsa-miR-6793-3p, hsa-miR-6858-3p, hsa-miR-766-3p, hsa-miR-8072, Mature-600, Mature-65, Mature-759, hsa-let-7f-1-3p, hsa-let-7f-2-3p, hsa-let-7g-5p, hsa-let-7i-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-3p, hsa-miR-107, hsa-miR-10a-5p, hsa-miR-12136, hsa-miR-1226-3p, hsa-miR-1229-3p, hsa-miR-1260b, hsa-miR-126-3p, hsa-miR-127-5p, hsa-miR-1277-3p, hsa-miR-1277-5p, hsa-miR-128-3p, hsa-miR-1292-5p, hsa-miR-130a-3p, hsa-miR-133b, hsa-miR-1343-3p, hsa-miR-139-3p hsa-miR-140-3p, hsa-miR-142-5p, hsa-miR-143-5p,hsa-miR-144-5p, hsa-miR-145-3p, hsa-miR-145-5p, hsa-miR-146a-3p, hsa-miR-154-3p, hsa-miR-155-5p, hsa-miR-15b-3p, hsa-miR-181a-2-3p, hsa-miR-181a-5p, hsa-miR-18a-5p, hsa-miR-1908-5p, hsa-miR-1914-3p, hsa-miR-192-3p, hsa-miR-192-5p, hsa-miR-194-5p, hsa-miR-195-5p, hsa-miR-199a-3p, hsa-miR-199b-3p hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-200a-3p, hsa-miR-210-3p, hsa-miR-219a-5p, hsa-miR-221-5p, hsa-miR-22-3p, hsa-miR-224-5p, hsa-miR-23a-5p, hsa-miR-23b-3p, hsa-miR-23c, hsa-miR-24-1-5p, hsa-miR-24-2-5p, hsa-miR-24-3p, hsa-miR-26a-1-3p, hsa-miR-26a-2-3p, hsa-miR-29b-1-5p, hsa-miR-301a-3p hsa-miR-301b-3p, hsa-miR-30d-3p, hsa-miR-30e-5p, hsa-miR-3136-5p, hsa-miR-3138, hsa-miR-3143, hsa-miR-3154, hsa-miR-3173-5p, hsa-miR-3179, hsa-miR-320a-3p, hsa-miR-320b, hsa-miR-320c, hsa-miR-320d, hsa-miR-320e, hsa-miR-330-3p, hsa-miR-331-3p, hsa-miR-338-3p, hsa-miR-33a-3p, hsa-miR-370-3p hsa-miR-374b-3p, hsa-miR-374c-5p, hsa-miR-376a-2-5p, hsa-miR-376a-3p, hsa-miR-376b-3p, hsa-miR-377-3p,hsa-miR-382-3p, hsa-miR-411-3p, hsa-miR-411-5p, hsa-miR-423-5p, hsa-miR-425-3p, hsa-miR-429, hsa-miR-4306, hsa-miR-432-5p, hsa-miR-4446-3p, hsa-miR-4485-5p, hsa-miR-4498, hsa-miR-451a, hsa-miR-4524a-3p, hsa-miR-4533, hsa-miR-4659b-3p, hsa-miR-4662a-5p, hsa-miR-4665-5p, hsa-miR-4685-3p, hsa-miR-4748 hsa-miR-484, hsa-miR-486-3p, hsa-miR-493-5p, hsa-miR-495-3p, hsa-miR-5010-5p, hsa-miR-501-5p, hsa-miR-502-3p, hsa-miR-532-5p, hsa-miR-539-3p, hsa-miR-545-3p, hsa-miR-548aa, hsa-miR-548ad-5p, hsa-miR-548ae-5p, hsa-miR-548ap-3p, hsa-miR-548ay-5p, hsa-miR-548d-3p, hsa-miR-548d-5p, hsa-miR-548f-3p hsa-miR-548h-3p, hsa-miR-548t-3p, hsa-miR-548z, hsa-miR-576-5p, hsa-miR-598-5p, hsa-miR-616-3p, hsa-miR-625-5p, hsa-miR-628-5p, hsa-miR-641, hsa-miR-6511b-3p, hsa-miR-6515-5p, hsa-miR-6516-5p, hsa-miR-654-5p, hsa-miR-6735-5p, hsa-miR-6754-5p, hsa-miR-6763-5p, hsa-miR-6767-5p, hsa-miR-6779-5p hsa-miR-6783-5p, hsa-miR-6802-5p, hsa-miR-6809-5p, hsa-miR-6810-3p, hsa-miR-6837-5p, hsa-miR-6873-5p,hsa-miR-6875-5p, hsa-miR-6876-5p, hsa-miR-6877-5p, hsa-miR-7109-3p, hsa-miR-7-1-3p, hsa-miR-7151-3p, hsa-miR-760, hsa-miR-874-3p, hsa-miR-877-3p, hsa-miR-92a-1-5p, hsa-miR-92b-3p, hsa-miR-92b-5p, hsa-miR-99b-5p, Mature-1121, Mature-1390, Mature-154, Mature-173, Mature-184, Mature-191, Mature-208, Mature-289, Mature-298, Mature-322, Mature-330, This can be done using a reagent that measures the expression level of one or more miRNAs selected from the group consisting of Mature-392, Mature-394, Mature-452, Mature-611, Mature-627, Mature-667, Mature-808, Mature-847 and Mature-896. Preferably, Mature-1322, Mature-655, Mature-639, hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, hsa-let-7g-3p, hsa-miR-188-5p, Mature-1259, Mature-240, hsa-miR-11400, Mature-626, hsa-miR-1537-5p, hsa-miR-671-5p, Mature-565, hsa-miR-4463, hsa-miR-337-5p, hsa-miR-27a-3p, hsa-miR-15a-3p, hsa-miR-642a-3p, Mature-326, hsa-miR-21-3p,hsa-miR-340-5p, hsa-miR-32-3p, hsa-miR-598-3p, hsa-miR-8485, hsa-miR-148b-5p, hsa-let-7a-3p, hsa-miR-15b-5p, hsa-miR-590-5p, Mature-1251, hsa-miR-642b-3p, Mature-509, hsa-miR-199b-5p, hsa-miR-369-5p, hsa-miR-2355-3p, hsa-miR-4644, hsa-miR-27b-3p, hsa-miR-154-5p, hsa-miR-369-3p, hsa-miR-337-3p, hsa-miR-1307-5p hsa-miR-143-3p, hsa-let-7i-3p, hsa-miR-19b-1-5p, hsa-miR-374b-5p, hsa-miR-939-5p, hsa-miR-4286, hsa-miR-454-5p, hsa-miR-146b-3p, hsa-miR-556-3p, hsa-miR-101-5p, hsa-miR-1908-3p, hsa-miR-487a-3p, hsa-miR-660-5p, hsa-miR-98-3p, hsa-miR-181c-5p, hsa-miR-4732-5p, hsa-miR-548j-5p, hsa-miR-548ap-5p hsa-miR-497-5p, hsa-miR-144-3p, Mature-759, Mature-600, hsa-miR-21-5p, hsa-miR-142-3p, hsa-miR-184, hsa-miR-4433b-5p, hsa-miR-424-5p, hsa-miR-8072, hsa-miR-6858-3p, hsa-miR-6511a-3p, hsa-miR-766-3p, hsa-miR-5100, hsa-miR-548au-5p, hsa-miR-548o-5p, hsa-miR-548c-5p, hsa-miR-548am-5p, hsa-miR-328-3p, Mature-65, hsa-miR-3200-3p, hsa-miR-376a-5p, hsa-miR-450a-5p, hsa-miR-6793-3p, hsa-miR-590-3p,hsa-miR-1277-3p, hsa-miR-144-5p, hsa-miR-1343-3p, hsa-miR-4485-5p, hsa-miR-423-5p, hsa-miR-4665-5p, hsa-miR-451a, hsa-miR-33a-3p, hsa-miR-6810-3p, Mature-184, hsa-miR-26a-2-3p, hsa-miR-192-5p, hsa-miR-338-3p, hsa-miR-320c, hsa-miR-330-3p, hsa-miR-320d, hsa-miR-616-3p, hsa-miR-6877-5p, hsa-miR-6511b-3p, It may be done using a preparation that measures the expression level of one or more miRNAs selected from the group consisting of hsa-miR-545-3p, hsa-miR-210-3p, hsa-miR-30e-5p, hsa-miR-15b-3p, hsa-miR-19a-3p, hsa-miR-374b-3p, hsa-miR-625-5p, hsa-miR-24-2-5p, hsa-miR-320b, hsa-miR-377-3p, hsa-miR-576-5p, Mature-289, hsa-miR-301b-3p, hsa-miR-19b-3p and hsa-miR-548f-3p. More preferably, Mature-1322, Mature-655, Mature-639, hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, hsa-miR-671-5p, Mature-565, hsa-miR-4463, hsa-miR-337-5p, hsa-miR-27a-3p, hsa-miR-15a-3p, hsa-miR-642a-3p, Mature-326, hsa-miR-21-3p,hsa-miR-340-5p, hsa-miR-32-3p, hsa-miR-598-3p, hsa-miR-8485, hsa-miR-148b-5p, hsa-let-7a-3p, hsa-miR-15b-5p, hsa-miR-590-5p, Mature-1251, hsa-miR-642b-3p, Mature-509, hsa-miR-199b-5p, hsa-miR-369-5p, hsa-miR-2355-3p, hsa-miR-4644, Mature-759, Mature-600, hsa-miR-21-5p, hsa-miR-142-3p, hsa-miR-184, hsa-miR-4433b-5p, A preparation for measuring the expression levels of one or more miRNAs selected from the group consisting of hsa-miR-424-5p, hsa-miR-8072, hsa-miR-6858-3p, hsa-miR-6511a-3p, hsa-miR-1277-3p, hsa-miR-144-5p, hsa-miR-1343-3p, hsa-miR-4485-5p, hsa-miR-423-5p, hsa-miR-4665-5p, hsa-miR-451a, hsa-miR-33a-3p, hsa-miR-6810-3p, Mature-184, hsa-miR-26a-2-3p, hsa-miR-192-5p, hsa-miR-338-3p, and hsa-miR-320c It may be accomplished by using

[0027] According to one embodiment of the present invention, the diagnosis of Alzheimer's disease may distinguish between the mild cognitive impairment stage and the transition stage from mild cognitive impairment to Alzheimer's disease. Distinguishing the above mild cognitive impairment and the transition stage from mild cognitive impairment to Alzheimer's disease is Mature-1322, Mature-655, Mature-639, hsa-miR-32-5p, hsa-miR-33a-5p, hsa-miR-33b-5p, hsa-miR-17-3p, hsa-miR-199a-5p, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p, hsa-miR-3613-5p, hsa-miR-374a-3p, hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-1306-5p, hsa-miR-141-3p, hsa-miR-1537-5p, hsa-miR-188-5p, hsa-miR-197-3p, hsa-miR-20a-3p, hsa-miR-20a-5p, hsa-miR-363-3p, hsa-miR-4687-5p, hsa-miR-496, hsa-miR-579-5p, Mature-1259, Mature-240, Mature-626, hsa-let-7a-3p, hsa-let-7i-3p, hsa-miR-101-3p, hsa-miR-101-5p, hsa-miR-10399-5p, hsa-miR-103a-1-5p, hsa-miR-1228-5p, hsa-miR-126-5p, hsa-miR-1271-5p, hsa-miR-1287-5p, hsa-miR-1307-5p, hsa-miR-136-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-146b-3p, hsa-miR-148a-3p, hsa-miR-148b-3p, hsa-miR-148b-5p, hsa-miR-150-3p, hsa-miR-154-5p, hsa-miR-15a-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1-3p, hsa-miR-16-5p,hsa-miR-181a-3p, hsa-miR-181c-5p, hsa-miR-1908-3p, hsa-miR-199b-5p, hsa-miR-19b-1-5p, hsa-miR-2110, hsa-miR-21-3p, hsa-miR-22-5p, hsa-miR-2355-3p, hsa-miR-2355-5p, hsa-miR-26b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29c-5p, hsa-miR-301b-5p, hsa-miR-30e-3p, hsa-miR-32-3p, hsa-miR-337-3p hsa-miR-337-5p, hsa-miR-340-3p, hsa-miR-340-5p, hsa-miR-369-3p, hsa-miR-369-5p, hsa-miR-370-5p, hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-376c-3p, hsa-miR-378a-5p, hsa-miR-380-3p, hsa-miR-381-3p, hsa-miR-4286, hsa-miR-4463, hsa-miR-4473, hsa-miR-452-5p, hsa-miR-454-5p, hsa-miR-4644, hsa-miR-4654 hsa-miR-4732-5p, hsa-miR-4799-5p, hsa-miR-483-3p, hsa-miR-487a-3p, hsa-miR-487b-3p, hsa-miR-497-5p, hsa-miR-542-3p, hsa-miR-548ap-5p, hsa-miR-548av-3p, hsa-miR-548j-5p, hsa-miR-548o-3p, hsa-miR-551b-3p, hsa-miR-556-3p, hsa-miR-556-5p, hsa-miR-5698, hsa-miR-590-5p, hsa-miR-598-3p, hsa-miR-642a-3p hsa-miR-642b-3p, hsa-miR-654-3p, hsa-miR-656-3p, hsa-miR-660-5p, hsa-miR-671-5p, hsa-miR-6885-5p,This can be done using a preparation that measures the expression level of one or more miRNAs selected from the group consisting of hsa-miR-744-3p, hsa-miR-8485, hsa-miR-939-5p, hsa-miR-98-3p, hsa-miR-99a-3p, Mature-1251, Mature-1331, Mature-168, Mature-169, Mature-176, Mature-181, Mature-326, Mature-509, Mature-565, Mature-567, Mature-893, hsa-miR-1255a, hsa-miR-134-3p, hsa-miR-214-3p, hsa-miR-2392, hsa-miR-4271, hsa-miR-431-3p, hsa-miR-99a-5p, and Mature-1363. Preferably, Mature-1322, Mature-655, Mature-639, hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, hsa-let-7g-3p, hsa-miR-188-5p, Mature-1259, Mature-240, hsa-miR-11400, Mature-626, hsa-miR-1537-5p, hsa-miR-671-5p, Mature-565, hsa-miR-4463, hsa-miR-337-5p, hsa-miR-27a-3p, hsa-miR-15a-3p, hsa-miR-642a-3p, Mature-326, hsa-miR-21-3p, hsa-miR-340-5p, hsa-miR-32-3p, hsa-miR-598-3p, hsa-miR-8485, hsa-miR-148b-5p, hsa-let-7a-3p, hsa-miR-15b-5p, hsa-miR-590-5p,Mature-1251, hsa-miR-642b-3p, Mature-509, hsa-miR-199b-5p, hsa-miR-369-5p, hsa-miR-2355-3p, hsa-miR-4644, hsa-miR-27b-3p, hsa-miR-154-5p, hsa-miR-369-3p, hsa-miR-337-3p, hsa-miR-1307-5p, hsa-miR-143-3p, hsa-let-7i-3p, hsa-miR-19b-1-5p, hsa-miR-374b-5p, hsa-miR-939-5p, hsa-miR-4286, hsa-miR-454-5p, It may be done using a preparation that measures the expression level of one or more miRNAs selected from the group consisting of hsa-miR-146b-3p, hsa-miR-556-3p, hsa-miR-101-5p, hsa-miR-1908-3p, hsa-miR-487a-3p, hsa-miR-660-5p, hsa-miR-98-3p, hsa-miR-181c-5p, hsa-miR-4732-5p, hsa-miR-548j-5p, hsa-miR-548ap-5p, hsa-miR-497-5p, hsa-miR-144-3p, hsa-miR-4271 and hsa-miR-2392. More preferably, Mature-1322, Mature-655, Mature-639, hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, hsa-miR-671-5p, Mature-565, hsa-miR-4463, hsa-miR-337-5p, hsa-miR-27a-3p, hsa-miR-15a-3p, hsa-miR-642a-3p, Mature-326, hsa-miR-21-3p,It may be performed using a preparation that measures the expression level of one or more miRNAs selected from the group consisting of hsa-miR-340-5p, hsa-miR-32-3p, hsa-miR-598-3p, hsa-miR-8485, hsa-miR-148b-5p, hsa-let-7a-3p, hsa-miR-15b-5p, hsa-miR-590-5p, Mature-1251, hsa-miR-642b-3p, Mature-509, hsa-miR-199b-5p, hsa-miR-369-5p, hsa-miR-2355-3p, hsa-miR-4644, hsa-miR-4271, and hsa-miR-2392.

[0028] According to one embodiment of the present invention, through a composition for the early diagnosis of Alzheimer's disease comprising a preparation for measuring the expression levels of miRNAs hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, Mature-1322, Mature-639, and Mature-655, the differentiation and diagnosis of Group 5 and Group 7; and the differentiation and diagnosis of Group 3 and Group 5; and / or differentiation and diagnosis of the above Group 2 and Group 7 are possible. The same applies when the above composition further includes one or more agents for measuring miRNA expression levels selected from the group consisting of hsa-let-7g-3p, hsa-miR-188-5p, Mature-1259, Mature-240, hsa-miR-11400, Mature-626 and hsa-miR-1537-5p; and / or when the above composition further includes one or more agents for measuring miRNA expression levels selected from the group consisting of hsa-miR-4687-5p, hsa-miR-106b-5p, hsa-miR-20a-5p, hsa-miR-579-5p, hsa-miR-141-3p, hsa-miR-1306-5p and hsa-miR-363-3p.

[0029] 상기 조성물에 hsa-let-7a-3p, hsa-let-7i-3p, hsa-miR-101-3p, hsa-miR-101-5p, hsa-miR-10399-5p, hsa-miR-103a-1-5p, hsa-miR-1228-5p, hsa-miR-126-5p, hsa-miR-1271-5p, hsa-miR-1287-5p, hsa-miR-1307-5p, hsa-miR-136-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-146b-3p, hsa-miR-148a-3p, hsa-miR-148b-3p, hsa-miR-148b-5p, hsa-miR-150-3p, hsa-miR-154-5p, hsa-miR-15a-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1-3p, hsa-miR-16-5p, hsa-miR-181a-3p, hsa-miR-181c-5p, hsa-miR-1908-3p, hsa-miR-199b-5p, hsa-miR-19b-1-5p, hsa-miR-2110, hsa-miR-21-3p, hsa-miR-22-5p hsa-miR-2355-3p, hsa-miR-2355-5p, hsa-miR-26b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29c-5p, hsa-miR-301b-5p, hsa-miR-30e-3p, hsa-miR-32-3p, hsa-miR-337-3p, hsa-miR-337-5p, hsa-miR-340-3p, hsa-miR-340-5p, hsa-miR-369-3p, hsa-miR-369-5p, hsa-miR-370-5p, hsa-miR-374a-5p, hsa-miR-374b-5p hsa-miR-376c-3p, hsa-miR-378a-5p, hsa-miR-380-3p, hsa-miR-381-3p, hsa-miR-4286, hsa-miR-4463, hsa-miR-4473, hsa-miR-452-5p, hsa-miR-454-5p,hsa-miR-4644, hsa-miR-4654, hsa-miR-4732-5p, hsa-miR-4799-5p, hsa-miR-483-3p, hsa-miR-487a-3p, hsa-miR-487b-3p, hsa-miR-497-5p, hsa-miR-542-3p, hsa-miR-548ap-5p, hsa-miR-548av-3p, hsa-miR-548j-5p, hsa-miR-548o-3p, hsa-miR-551b-3p, hsa-miR-556-3p, hsa-miR-556-5p, hsa-miR-5698, hsa-miR-590-5p, One or more selected from the group consisting of hsa-miR-598-3p, hsa-miR-642a-3p, hsa-miR-642b-3p, hsa-miR-654-3p, hsa-miR-656-3p, hsa-miR-660-5p, hsa-miR-671-5p, hsa-miR-6885-5p, hsa-miR-744-3p, hsa-miR-8485, hsa-miR-939-5p, hsa-miR-98-3p, hsa-miR-99a-3p, Mature-1251, Mature-1331, Mature-168, Mature-169, Mature-176, Mature-181, Mature-326, Mature-509, Mature-565, Mature-567, and Mature-893 If a preparation for measuring miRNA expression levels is further included, differentiation and diagnosis of Group 5 and Group 7; and / or differentiation and diagnosis of Group 3 and Group 5 are possible.

[0030] When the above composition includes a preparation for measuring the expression level of one or more miRNAs selected from the group consisting of hsa-miR-1255a, hsa-miR-134-3p, hsa-miR-214-3p, hsa-miR-2392, hsa-miR-4271, hsa-miR-431-3p, hsa-miR-99a-5p, and Mature-1363, it is possible to distinguish and diagnose Group 3 and Group 5.

[0031] In the composition, hsa-miR-142-3p, hsa-miR-184, hsa-miR-21-5p, hsa-miR-3200-3p, hsa-miR-328-3p, hsa-miR-376a-5p, hsa-miR-424-5p, hsa-miR-4433b-5p, hsa-miR-450a-5p, hsa-miR-5100, hsa-miR-548am-5p, hsa-miR-548au-5p, hsa-miR-548c-5p, hsa-miR-548o-5p, hsa-miR-590-3p, hsa-miR-6511a-3p, hsa-miR-6793-3p, hsa-miR-6858-3p, If a preparation for measuring the expression level of one or more selected from the group consisting of hsa-miR-766-3p, hsa-miR-8072, Mature-600, Mature-65 and Mature-759 is further included, differentiation and diagnosis of Group 5 and Group 7; and / or differentiation and diagnosis of Group 2 and Group 7 are possible.

[0032] 상기 조성물에 hsa-let-7f-1-3p, hsa-let-7f-2-3p, hsa-let-7g-5p, hsa-let-7i-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-3p, hsa-miR-107, hsa-miR-10a-5p, hsa-miR-12136, hsa-miR-1226-3p, hsa-miR-1229-3p, hsa-miR-1260b, hsa-miR-126-3p, hsa-miR-127-5p, hsa-miR-1277-3p, hsa-miR-1277-5p, hsa-miR-128-3p, hsa-miR-1292-5p, hsa-miR-130a-3p, hsa-miR-133b, hsa-miR-1343-3p, hsa-miR-139-3p, hsa-miR-140-3p, hsa-miR-142-5p, hsa-miR-143-5p, hsa-miR-144-5p, hsa-miR-145-3p, hsa-miR-145-5p, hsa-miR-146a-3p, hsa-miR-154-3p, hsa-miR-155-5p, hsa-miR-15b-3p, hsa-miR-181a-2-3p, hsa-miR-181a-5p hsa-miR-18a-5p, hsa-miR-1908-5p, hsa-miR-1914-3p, hsa-miR-192-3p, hsa-miR-192-5p, hsa-miR-194-5p, hsa-miR-195-5p, hsa-miR-199a-3p, hsa-miR-199b-3p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-200a-3p, hsa-miR-210-3p, hsa-miR-219a-5p, hsa-miR-221-5p, hsa-miR-22-3p, hsa-miR-224-5p, hsa-miR-23a-5p hsa-miR-23b-3p, hsa-miR-23c, hsa-miR-24-1-5p, hsa-miR-24-2-5p, hsa-miR-24-3p, hsa-miR-26a-1-3p, hsa-miR-26a-2-3p, hsa-miR-29b-1-5p,hsa-miR-301a-3p, hsa-miR-301b-3p, hsa-miR-30d-3p, hsa-miR-30e-5p, hsa-miR-3136-5p, hsa-miR-3138, hsa-miR-3143, hsa-miR-3154, hsa-miR-3173-5p, hsa-miR-3179, hsa-miR-320a-3p, hsa-miR-320b, hsa-miR-320c, hsa-miR-320d, hsa-miR-320e, hsa-miR-330-3p, hsa-miR-331-3p, hsa-miR-338-3p, hsa-miR-33a-3p hsa-miR-370-3p, hsa-miR-374b-3p, hsa-miR-374c-5p, hsa-miR-376a-2-5p, hsa-miR-376a-3p, hsa-miR-376b-3p, hsa-miR-377-3p, hsa-miR-382-3p, hsa-miR-411-3p, hsa-miR-411-5p, hsa-miR-423-5p, hsa-miR-425-3p, hsa-miR-429, hsa-miR-4306, hsa-miR-432-5p, hsa-miR-4446-3p, hsa-miR-4485-5p, hsa-miR-4498 hsa-miR-451a, hsa-miR-4524a-3p, hsa-miR-4533, hsa-miR-4659b-3p, hsa-miR-4662a-5p, hsa-miR-4665-5p, hsa-miR-4685-3p, hsa-miR-4748, hsa-miR-484, hsa-miR-486-3p, hsa-miR-493-5p, hsa-miR-495-3p, hsa-miR-5010-5p, hsa-miR-501-5p, hsa-miR-502-3p, hsa-miR-532-5p, hsa-miR-539-3p, hsa-miR-545-3p, hsa-miR-548aa, hsa-miR-548ad-5p, hsa-miR-548ae-5p, hsa-miR-548ap-3p, hsa-miR-548ay-5p, hsa-miR-548d-3p, hsa-miR-548d-5p,hsa-miR-548f-3p, hsa-miR-548h-3p, hsa-miR-548t-3p, hsa-miR-548z, hsa-miR-576-5p, hsa-miR-598-5p, hsa-miR-616-3p, hsa-miR-625-5p, hsa-miR-628-5p, hsa-miR-641, hsa-miR-6511b-3p, hsa-miR-6515-5p, hsa-miR-6516-5p, hsa-miR-654-5p, hsa-miR-6735-5p, hsa-miR-6754-5p, hsa-miR-6763-5p, hsa-miR-6767-5p, hsa-miR-6779-5p, hsa-miR-6783-5p, hsa-miR-6802-5p, hsa-miR-6809-5p, hsa-miR-6810-3p, hsa-miR-6837-5p, hsa-miR-6873-5p, hsa-miR-6875-5p, hsa-miR-6876-5p, hsa-miR-6877-5p, hsa-miR-7109-3p, hsa-miR-7-1-3p, hsa-miR-7151-3p, hsa-miR-760, hsa-miR-874-3p, hsa-miR-877-3p, hsa-miR-92a-1-5p, hsa-miR-92b-3p, If a preparation for measuring the expression level of one or more types of miRNA selected from the group consisting of hsa-miR-92b-5p, hsa-miR-99b-5p, Mature-1121, Mature-1390, Mature-154, Mature-173, Mature-184, Mature-191, Mature-208, Mature-289, Mature-298, Mature-322, Mature-330, Mature-392, Mature-394, Mature-452, Mature-611, Mature-627, Mature-667, Mature-808, Mature-847, and Mature-896 is further included, differentiation and diagnosis of Group 5 and Group 7 are possible.

[0033] If the above composition further includes one or more agents for measuring miRNA expression levels selected from the group consisting of hsa-miR-3620-3p, hsa-miR-4701-5p, hsa-miR-490-3p and hsa-miR-95-5p, it is possible to distinguish and diagnose Group 2 and Group 7.

[0035] The miRNA according to the present invention can measure its expression level in biological samples.

[0036] The term "biological sample" as used in the present invention refers to a sample containing cells and tissues, as well as organic biomolecules such as nucleic acids, genes, peptides, amino acids, proteins, lipids, sugars, glycolipids, and glycoproteins, which are derived from living organisms and capable of identifying biological changes. In the present invention, the sample is not limited to any other samples containing miRNA.

[0037] According to one embodiment of the present invention, the biological sample may be one or more selected from the group consisting of blood, plasma, serum, lymph fluid, saliva, urine, and tissue.

[0038] The above preparation may be a substance that binds to miRNA.

[0039] According to one embodiment of the present invention, the formulation may be one or more selected from the group consisting of primers, probes, and antisense oligonucleotides that specifically bind to miRNA.

[0040] As used in this invention, "specifically binding" means having superior binding affinity to a target substance compared to other substances, to the extent that the presence of the target substance can be detected by binding.

[0041] The term "primer" used in the present invention refers to a single-strand oligonucleotide having a short free 3-terminal hydroxyl group, capable of forming base pairs with a complementary template, and functioning as a starting point for template strand replication. The primer can initiate DNA synthesis in the presence of reagents for a polymerization reaction (i.e., DNA polymerase or reverse transcriptase) and four different nucleoside triphosphates at an appropriate buffer solution and temperature. Additionally, the primer consists of sense and antisense nucleic acids having a sequence of 7 to 50 nucleotides, and may have a sequence of 15 to 30 nucleotides at a level that does not alter the basic properties of the primer acting as a starting point for DNA synthesis.

[0042] The term "probe" used in the present invention refers to a linear oligomer of natural or modified monomer or linkages, comprising deoxyribonucleotide and ribonucleotide, capable of specifically hybridizing to a target nucleotide sequence, and is naturally occurring or artificially synthesized.

[0044] Another aspect of the present invention provides a kit for early diagnosis of Alzheimer's disease comprising the aforementioned composition for early diagnosis of Alzheimer's disease.

[0045] The "kit for early diagnosis of Alzheimer's disease in patients with mild cognitive impairment" used in the present invention refers to a substance capable of early diagnosis of Alzheimer's disease through biological samples collected from a test subject, thereby enabling rapid, accurate, and convenient diagnosis of the progression to Alzheimer's disease in patients with mild cognitive impairment. In the present invention, the kit for early diagnosis of Alzheimer's disease in patients with mild cognitive impairment comprises a preparation capable of measuring miRNA expression levels, and it is preferable that the preparation comprises a primer or a primer set.

[0046] According to one embodiment of the present invention, the kit may further include a reagent for nucleic acid amplification.

[0047] The above nucleic acid amplification reagent may include conventional PCR reagents known in the art, and may include, for example, nucleoside triphosphate, (deoxy)ribonuclease inhibitor, heat-resistant polymerase and reaction buffer, but is not limited thereto.

[0048] The above nucleoside triphosphate refers to a molecule in which a purine or pyrimidine nucleoside is bonded to ribose or deoxyribose and bonded to three phosphate groups, and includes (deoxy)adenosine triphosphate ((deoxy)adenosine triphosphate, ATP or dATP), (deoxy)guanosine triphosphate ((deoxy)guanosine triphosphate, GTP or dGTP), (deoxy)cytidine triphosphate ((deoxy)cytidine triphosphate, CTP or dCTP), and (deoxy)thymidine triphosphate ((deoxy)thymidine triphosphate, TTP or dTTP).

[0049] The above reaction buffer may be a Taq polymerase buffer, a PCR buffer, etc., and is a compound added to an amplification reaction that alters the stability, activity, and / or longevity of one or more components of the amplification reaction by adjusting the pH of the amplification reaction. Such reaction buffers may further include additives to optimize an efficient PCR reaction.

[0050] According to one embodiment of the present invention, the kit may be one or more selected from the group consisting of PCR, RT-PCR kit, real-time PCR kit and microarray chip kit.

[0051] According to one embodiment of the present invention, the kit may further include a reagent for nucleic acid separation.

[0052] The above nucleic acid isolation reagent is a conventional RNA or miRNA extraction reagent known in the art and may include a salt capable of cell lysis, a surfactant, a metal ion, a sugar, a reducing agent (e.g., DTT), etc.

[0053] The kit according to the present invention may include, without limitation, a diagnostic kit based on conventional gene quantitative analysis.

[0054] For example, when the above kit is applied to a PCR amplification process, the kit of the present invention may optionally include reagents required for PCR amplification, such as a buffer, DNA polymerase, DNA polymerase cofactor, and dNTPs. Additionally, the kit according to the present invention may be manufactured into a plurality of separate packages or compartments containing the above-mentioned reagent components, and the kit of the present invention may be a diagnostic kit containing essential elements required to perform DNA or RNA chip analysis.

[0056] Another aspect of the present invention comprises: a) collecting a biological sample from an individual requiring diagnosis; b) measuring the expression level of one or more miRNAs selected from the group consisting of hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, Mature-1322, Mature-639, and Mature-655 in the collected biological sample; and c) a method for providing information for early diagnosis or detailed diagnosis of Alzheimer's disease, comprising the step of comparing the measured miRNA expression level with a control group.

[0057] Steps a) through c) above will be examined in detail below, and details common to the previously mentioned content will be omitted to avoid excessive complexity.

[0058] Step a) above is the process of collecting biological samples from subjects who require testing for Alzheimer's disease.

[0059] According to one embodiment of the present invention, the process of collecting the biological sample in step a) may be non-invasively or naturally excreted, separated, or collected from a subject who requires testing for the presence of Alzheimer's disease.

[0060] According to one embodiment of the present invention, the biological sample of step a) may be one or more selected from the group consisting of blood, plasma, serum, lymph fluid, saliva, urine, and tissue.

[0061] Step b) above is a process of measuring the expression level along with the presence of biomarker miRNA in the collected biological sample.

[0062] According to one embodiment of the present invention, the detailed diagnosis of Alzheimer's disease may be to distinguish between a normal stage and a moderate to severe Alzheimer's disease stage, and to this end, step b) is a miRNA in the biological sample, namely hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-1306-5p, hsa-miR-141-3p, hsa-miR-1537-5p, hsa-miR-188-5p, hsa-miR-20a-5p, hsa-miR-363-3p, hsa-miR-4687-5p, hsa-miR-579-5p, Mature-1259, Mature-240, Mature-626, hsa-miR-142-3p, hsa-miR-184, hsa-miR-21-5p, hsa-miR-3200-3p, hsa-miR-328-3p, hsa-miR-376a-5p, hsa-miR-424-5p, hsa-miR-4433b-5p, hsa-miR-450a-5p, hsa-miR-5100, hsa-miR-548am-5p, hsa-miR-548au-5p, hsa-miR-548c-5p, hsa-miR-548o-5p, hsa-miR-590-3p, hsa-miR-6511a-3p, hsa-miR-6793-3p, hsa-miR-6858-3p, hsa-miR-766-3p, hsa-miR-8072, Mature-600, Mature-65, It may be to further measure the expression levels of one or more selected from the group consisting of Mature-759, hsa-miR-3620-3p, hsa-miR-4701-5p, hsa-miR-490-3p and hsa-miR-95-5p.Preferably, step b) above involves miRNAs in the biological sample, namely hsa-let-7g-3p, hsa-miR-188-5p, Mature-1259, Mature-240, hsa-miR-11400, Mature-626, hsa-miR-1537-5p, Mature-759, Mature-600, hsa-miR-21-5p, hsa-miR-142-3p, hsa-miR-184, hsa-miR-4433b-5p, hsa-miR-424-5p, hsa-miR-8072, hsa-miR-6858-3p, hsa-miR-6511a-3p, hsa-miR-766-3p, hsa-miR-5100, hsa-miR-548au-5p, It may be to further measure the expression levels of one or more selected from the group consisting of hsa-miR-548o-5p, hsa-miR-548c-5p, hsa-miR-548am-5p, hsa-miR-328-3p, Mature-65, hsa-miR-3200-3p, hsa-miR-376a-5p, hsa-miR-450a-5p, hsa-miR-6793-3p and hsa-miR-590-3p. More preferably, step b) may further measure the expression level of one or more selected from the group consisting of miRNAs Mature-759, Mature-600, hsa-miR-21-5p, hsa-miR-142-3p, hsa-miR-184, hsa-miR-4433b-5p, hsa-miR-424-5p, hsa-miR-8072, hsa-miR-6858-3p and hsa-miR-6511a-3p in the biological sample.

[0063] In addition, according to one embodiment of the present invention, the detailed diagnosis of Alzheimer's disease may distinguish between a normal stage and a transition stage from mild cognitive impairment to Alzheimer's disease, and to this end, the above step b) is a miRNA in the biological sample, which is hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-1306-5p, hsa-miR-141-3p, hsa-miR-1537-5p, hsa-miR-188-5p, hsa-miR-20a-5p, hsa-miR-363-3p, hsa-miR-4687-5p, hsa-miR-579-5p, Mature-1259, Mature-240, Mature-626, hsa-let-7a-3p, hsa-let-7i-3p, hsa-miR-101-3p, hsa-miR-101-5p, hsa-miR-10399-5p, hsa-miR-103a-1-5p, hsa-miR-1228-5p, hsa-miR-126-5p, hsa-miR-1271-5p, hsa-miR-1287-5p, hsa-miR-1307-5p, hsa-miR-136-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-146b-3p, hsa-miR-148a-3p, hsa-miR-148b-3p, hsa-miR-148b-5p, hsa-miR-150-3p, hsa-miR-154-5p, hsa-miR-15a-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1-3p, hsa-miR-16-5p, hsa-miR-181a-3p, hsa-miR-181c-5p, hsa-miR-1908-3p, hsa-miR-199b-5p, hsa-miR-19b-1-5p, hsa-miR-2110, hsa-miR-21-3p, hsa-miR-22-5p, hsa-miR-2355-3p, hsa-miR-2355-5p, hsa-miR-26b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29c-5p, hsa-miR-301b-5p,hsa-miR-30e-3p, hsa-miR-32-3p, hsa-miR-337-3p, hsa-miR-337-5p, hsa-miR-340-3p, hsa-miR-340-5p, hsa-miR-369-3p, hsa-miR-369-5p, hsa-miR-370-5p, hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-376c-3p, hsa-miR-378a-5p, hsa-miR-380-3p, hsa-miR-381-3p, hsa-miR-4286, hsa-miR-4463, hsa-miR-4473, hsa-miR-452-5p, hsa-miR-454-5p, hsa-miR-4644, hsa-miR-4654, hsa-miR-4732-5p, hsa-miR-4799-5p, hsa-miR-483-3p, hsa-miR-487a-3p, hsa-miR-487b-3p, hsa-miR-497-5p, hsa-miR-542-3p, hsa-miR-548ap-5p, hsa-miR-548av-3p, hsa-miR-548j-5p, hsa-miR-548o-3p, hsa-miR-551b-3p, hsa-miR-556-3p, hsa-miR-556-5p, hsa-miR-5698, hsa-miR-590-5p, hsa-miR-598-3p, hsa-miR-642a-3p, hsa-miR-642b-3p, hsa-miR-654-3p, hsa-miR-656-3p, hsa-miR-660-5p, hsa-miR-671-5p, hsa-miR-6885-5p, hsa-miR-744-3p, hsa-miR-8485, hsa-miR-939-5p, hsa-miR-98-3p, hsa-miR-99a-3p, Mature-1251, Mature-1331, Mature-168, Mature-169, Mature-176, Mature-181, Mature-326, Mature-509, Mature-565, Mature-567, Mature-893, hsa-miR-142-3p, hsa-miR-184, hsa-miR-21-5p,hsa-miR-3200-3p, hsa-miR-328-3p, hsa-miR-376a-5p, hsa-miR-424-5p, hsa-miR-4433b-5p, hsa-miR-450a-5p, hsa-miR-5100, hsa-miR-548am-5p, hsa-miR-548au-5p, hsa-miR-548c-5p, hsa-miR-548o-5p, hsa-miR-590-3p, hsa-miR-6511a-3p, hsa-miR-6793-3p, hsa-miR-6858-3p, hsa-miR-766-3p, hsa-miR-8072, Mature-600, Mature-65 Mature-759, hsa-let-7f-1-3p, hsa-let-7f-2-3p, hsa-let-7g-5p, hsa-let-7i-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-3p, hsa-miR-107, hsa-miR-10a-5p, hsa-miR-12136, hsa-miR-1226-3p, hsa-miR-1229-3p, hsa-miR-1260b, hsa-miR-126-3p, hsa-miR-127-5p, hsa-miR-1277-3p, hsa-miR-1277-5p, hsa-miR-128-3p, hsa-miR-1292-5p, hsa-miR-130a-3p, hsa-miR-133b, hsa-miR-1343-3p, hsa-miR-139-3p, hsa-miR-140-3p, hsa-miR-142-5p, hsa-miR-143-5p, hsa-miR-144-5p, hsa-miR-145-3p, hsa-miR-145-5p, hsa-miR-146a-3p, hsa-miR-154-3p, hsa-miR-155-5p, hsa-miR-15b-3p, hsa-miR-181a-2-3p, hsa-miR-181a-5p, hsa-miR-18a-5p hsa-miR-1908-5p, hsa-miR-1914-3p, hsa-miR-192-3p, hsa-miR-192-5p, hsa-miR-194-5p, hsa-miR-195-5p,hsa-miR-199a-3p, hsa-miR-199b-3p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-200a-3p, hsa-miR-210-3p, hsa-miR-219a-5p, hsa-miR-221-5p, hsa-miR-22-3p, hsa-miR-224-5p, hsa-miR-23a-5p, hsa-miR-23b-3p, hsa-miR-23c, hsa-miR-24-1-5p, hsa-miR-24-2-5p, hsa-miR-24-3p, hsa-miR-26a-1-3p, hsa-miR-26a-2-3p hsa-miR-29b-1-5p, hsa-miR-301a-3p, hsa-miR-301b-3p, hsa-miR-30d-3p, hsa-miR-30e-5p, hsa-miR-3136-5p, hsa-miR-3138, hsa-miR-3143, hsa-miR-3154, hsa-miR-3173-5p, hsa-miR-3179, hsa-miR-320a-3p, hsa-miR-320b, hsa-miR-320c, hsa-miR-320d, hsa-miR-320e, hsa-miR-330-3p, hsa-miR-331-3p, hsa-miR-338-3p hsa-miR-33a-3p, hsa-miR-370-3p, hsa-miR-374b-3p, hsa-miR-374c-5p, hsa-miR-376a-2-5p, hsa-miR-376a-3p, hsa-miR-376b-3p, hsa-miR-377-3p, hsa-miR-382-3p, hsa-miR-411-3p, hsa-miR-411-5p, hsa-miR-423-5p, hsa-miR-425-3p, hsa-miR-429, hsa-miR-4306, hsa-miR-432-5p, hsa-miR-4446-3p, hsa-miR-4485-5p hsa-miR-4498, hsa-miR-451a, hsa-miR-4524a-3p, hsa-miR-4533, hsa-miR-4659b-3p, hsa-miR-4662a-5p, hsa-miR-4665-5p,hsa-miR-4685-3p, hsa-miR-4748, hsa-miR-484, hsa-miR-486-3p, hsa-miR-493-5p, hsa-miR-495-3p, hsa-miR-5010-5p, hsa-miR-501-5p, hsa-miR-502-3p, hsa-miR-532-5p, hsa-miR-539-3p, hsa-miR-545-3p, hsa-miR-548aa, hsa-miR-548ad-5p, hsa-miR-548ae-5p, hsa-miR-548ap-3p, hsa-miR-548ay-5p, hsa-miR-548d-3p hsa-miR-548d-5p, hsa-miR-548f-3p, hsa-miR-548h-3p, hsa-miR-548t-3p, hsa-miR-548z, hsa-miR-576-5p, hsa-miR-598-5p, hsa-miR-616-3p, hsa-miR-625-5p, hsa-miR-628-5p, hsa-miR-641, hsa-miR-6511b-3p, hsa-miR-6515-5p, hsa-miR-6516-5p, hsa-miR-654-5p, hsa-miR-6735-5p, hsa-miR-6754-5p, hsa-miR-6763-5p hsa-miR-6767-5p, hsa-miR-6779-5p, hsa-miR-6783-5p, hsa-miR-6802-5p, hsa-miR-6809-5p, hsa-miR-6810-3p, hsa-miR-6837-5p, hsa-miR-6873-5p, hsa-miR-6875-5p, hsa-miR-6876-5p, hsa-miR-6877-5p, hsa-miR-7109-3p, hsa-miR-7-1-3p, hsa-miR-7151-3p, hsa-miR-760, hsa-miR-874-3p, hsa-miR-877-3p, hsa-miR-92a-1-5p hsa-miR-92b-3p, hsa-miR-92b-5p, hsa-miR-99b-5p, Mature-1121, Mature-1390, Mature-154, Mature-173, Mature-184,It may be possible to further measure the expression level of one or more selected from the group consisting of Mature-191, Mature-208, Mature-289, Mature-298, Mature-322, Mature-330, Mature-392, Mature-394, Mature-452, Mature-611, Mature-627, Mature-667, Mature-808, Mature-847 and Mature-896. Preferably, step b) above involves miRNAs hsa-let-7g-3p, hsa-miR-188-5p, Mature-1259, Mature-240, hsa-miR-11400, Mature-626, hsa-miR-1537-5p, hsa-miR-671-5p, Mature-565, hsa-miR-4463, hsa-miR-337-5p, hsa-miR-27a-3p, hsa-miR-15a-3p, hsa-miR-642a-3p, Mature-326, hsa-miR-21-3p, hsa-miR-340-5p, hsa-miR-32-3p, hsa-miR-598-3p, hsa-miR-8485, hsa-miR-148b-5p, in the biological sample, hsa-let-7a-3p, hsa-miR-15b-5p, hsa-miR-590-5p, Mature-1251, hsa-miR-642b-3p, Mature-509, hsa-miR-199b-5p, hsa-miR-369-5p, hsa-miR-2355-3p, hsa-miR-4644, hsa-miR-27b-3p, hsa-miR-154-5p, hsa-miR-369-3p, hsa-miR-337-3p, hsa-miR-1307-5p, hsa-miR-143-3p, hsa-let-7i-3p, hsa-miR-19b-1-5p, hsa-miR-374b-5p, hsa-miR-939-5p, hsa-miR-4286, hsa-miR-454-5p, hsa-miR-146b-3p, hsa-miR-556-3p, hsa-miR-101-5p, hsa-miR-1908-3p,hsa-miR-487a-3p, hsa-miR-660-5p, hsa-miR-98-3p, hsa-miR-181c-5p, hsa-miR-4732-5p, hsa-miR-548j-5p, hsa-miR-548ap-5p, hsa-miR-497-5p, hsa-miR-144-3p, Mature-759, Mature-600, hsa-miR-21-5p, hsa-miR-142-3p, hsa-miR-184, hsa-miR-4433b-5p, hsa-miR-424-5p, hsa-miR-8072, hsa-miR-6858-3p, hsa-miR-6511a-3p, hsa-miR-766-3p, hsa-miR-5100, hsa-miR-548au-5p, hsa-miR-548o-5p, hsa-miR-548c-5p, hsa-miR-548am-5p, hsa-miR-328-3p, Mature-65, hsa-miR-3200-3p, hsa-miR-376a-5p, hsa-miR-450a-5p, hsa-miR-6793-3p, hsa-miR-590-3p, hsa-miR-1277-3p, hsa-miR-144-5p, hsa-miR-1343-3p, hsa-miR-4485-5p, hsa-miR-423-5p hsa-miR-4665-5p, hsa-miR-451a, hsa-miR-33a-3p, hsa-miR-6810-3p, Mature-184, hsa-miR-26a-2-3p, hsa-miR-192-5p, hsa-miR-338-3p, hsa-miR-320c, hsa-miR-330-3p, hsa-miR-320d, hsa-miR-616-3p, hsa-miR-6877-5p, hsa-miR-6511b-3p, hsa-miR-545-3p, hsa-miR-210-3p, hsa-miR-30e-5p, hsa-miR-15b-3p, hsa-miR-19a-3p, hsa-miR-374b-3p, hsa-miR-625-5p, hsa-miR-24-2-5p, hsa-miR-320b, hsa-miR-377-3p, hsa-miR-576-5p,It may be to further measure the expression levels of one or more selected from the group consisting of Mature-289, hsa-miR-301b-3p, hsa-miR-19b-3p and hsa-miR-548f-3p. More preferably, step b) is a miRNA in the biological sample, hsa-miR-671-5p, Mature-565, hsa-miR-4463, hsa-miR-337-5p, hsa-miR-27a-3p, hsa-miR-15a-3p, hsa-miR-642a-3p, Mature-326, hsa-miR-21-3p, hsa-miR-340-5p, hsa-miR-32-3p, hsa-miR-598-3p, hsa-miR-8485, hsa-miR-148b-5p, hsa-let-7a-3p, hsa-miR-15b-5p, hsa-miR-590-5p, Mature-1251, hsa-miR-642b-3p, Mature-509, hsa-miR-199b-5p, hsa-miR-369-5p, hsa-miR-2355-3p, hsa-miR-4644, Mature-759, Mature-600, hsa-miR-21-5p, hsa-miR-142-3p, hsa-miR-184, hsa-miR-4433b-5p, hsa-miR-424-5p, hsa-miR-8072, hsa-miR-6858-3p, hsa-miR-6511a-3p, hsa-miR-1277-3p, hsa-miR-144-5p, hsa-miR-1343-3p, hsa-miR-4485-5p, hsa-miR-423-5p, It may further involve measuring the expression levels of one or more selected from the group consisting of hsa-miR-4665-5p, hsa-miR-451a, hsa-miR-33a-3p, hsa-miR-6810-3p, Mature-184, hsa-miR-26a-2-3p, hsa-miR-192-5p, hsa-miR-338-3p, and hsa-miR-320c.

[0064] In addition, according to one embodiment of the present invention, the detailed diagnosis of Alzheimer's disease may distinguish between the mild cognitive impairment stage and the transition stage from mild cognitive impairment to Alzheimer's disease, and to this end, the above step b) is a miRNA in the biological sample, which is hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-1306-5p, hsa-miR-141-3p, hsa-miR-1537-5p, hsa-miR-188-5p, hsa-miR-20a-5p, hsa-miR-363-3p, hsa-miR-4687-5p, hsa-miR-579-5p, Mature-1259, Mature-240, Mature-626, hsa-let-7a-3p, hsa-let-7i-3p, hsa-miR-101-3p, hsa-miR-101-5p, hsa-miR-10399-5p, hsa-miR-103a-1-5p, hsa-miR-1228-5p, hsa-miR-126-5p, hsa-miR-1271-5p, hsa-miR-1287-5p, hsa-miR-1307-5p, hsa-miR-136-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-146b-3p, hsa-miR-148a-3p, hsa-miR-148b-3p, hsa-miR-148b-5p, hsa-miR-150-3p, hsa-miR-154-5p, hsa-miR-15a-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1-3p, hsa-miR-16-5p, hsa-miR-181a-3p, hsa-miR-181c-5p, hsa-miR-1908-3p, hsa-miR-199b-5p, hsa-miR-19b-1-5p, hsa-miR-2110, hsa-miR-21-3p, hsa-miR-22-5p, hsa-miR-2355-3p, hsa-miR-2355-5p, hsa-miR-26b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29c-5p, hsa-miR-301b-5p,hsa-miR-30e-3p, hsa-miR-32-3p, hsa-miR-337-3p, hsa-miR-337-5p, hsa-miR-340-3p, hsa-miR-340-5p, hsa-miR-369-3p, hsa-miR-369-5p, hsa-miR-370-5p, hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-376c-3p, hsa-miR-378a-5p, hsa-miR-380-3p, hsa-miR-381-3p, hsa-miR-4286, hsa-miR-4463, hsa-miR-4473, hsa-miR-452-5p, hsa-miR-454-5p, hsa-miR-4644, hsa-miR-4654, hsa-miR-4732-5p, hsa-miR-4799-5p, hsa-miR-483-3p, hsa-miR-487a-3p, hsa-miR-487b-3p, hsa-miR-497-5p, hsa-miR-542-3p, hsa-miR-548ap-5p, hsa-miR-548av-3p, hsa-miR-548j-5p, hsa-miR-548o-3p, hsa-miR-551b-3p, hsa-miR-556-3p, hsa-miR-556-5p, hsa-miR-5698, hsa-miR-590-5p, hsa-miR-598-3p, hsa-miR-642a-3p, hsa-miR-642b-3p, hsa-miR-654-3p, hsa-miR-656-3p, hsa-miR-660-5p, hsa-miR-671-5p, hsa-miR-6885-5p, hsa-miR-744-3p, hsa-miR-8485, hsa-miR-939-5p, hsa-miR-98-3p, hsa-miR-99a-3p, Mature-1251, Mature-1331, Mature-168, Mature-169, Mature-176, Mature-181, Mature-326, Mature-509, Mature-565, Mature-567, Mature-893, hsa-miR-1255a, hsa-miR-134-3p, hsa-miR-214-3p,It may be to further measure the expression levels of one or more selected from the group consisting of hsa-miR-2392, hsa-miR-4271, hsa-miR-431-3p, hsa-miR-99a-5p and Mature-1363. Preferably, step b) above involves miRNAs hsa-let-7g-3p, hsa-miR-188-5p, Mature-1259, Mature-240, hsa-miR-11400, Mature-626, hsa-miR-1537-5p, hsa-miR-671-5p, Mature-565, hsa-miR-4463, hsa-miR-337-5p, hsa-miR-27a-3p, hsa-miR-15a-3p, hsa-miR-642a-3p, Mature-326, hsa-miR-21-3p, hsa-miR-340-5p, hsa-miR-32-3p, hsa-miR-598-3p, hsa-miR-8485, hsa-miR-148b-5p, in the biological sample, hsa-let-7a-3p, hsa-miR-15b-5p, hsa-miR-590-5p, Mature-1251, hsa-miR-642b-3p, Mature-509, hsa-miR-199b-5p, hsa-miR-369-5p, hsa-miR-2355-3p, hsa-miR-4644, hsa-miR-27b-3p, hsa-miR-154-5p, hsa-miR-369-3p, hsa-miR-337-3p, hsa-miR-1307-5p, hsa-miR-143-3p, hsa-let-7i-3p, hsa-miR-19b-1-5p, hsa-miR-374b-5p, hsa-miR-939-5p, hsa-miR-4286, hsa-miR-454-5p, hsa-miR-146b-3p, hsa-miR-556-3p, hsa-miR-101-5p, hsa-miR-1908-3p, hsa-miR-487a-3p, hsa-miR-660-5p, hsa-miR-98-3p, hsa-miR-181c-5p, hsa-miR-4732-5p, hsa-miR-548j-5p, hsa-miR-548ap-5p,It may be to further measure the expression levels of one or more selected from the group consisting of hsa-miR-497-5p, hsa-miR-144-3p, hsa-miR-4271 and hsa-miR-2392. More preferably, step b) is a miRNA in the biological sample, hsa-miR-671-5p, Mature-565, hsa-miR-4463, hsa-miR-337-5p, hsa-miR-27a-3p, hsa-miR-15a-3p, hsa-miR-642a-3p, Mature-326, hsa-miR-21-3p, hsa-miR-340-5p, hsa-miR-32-3p, hsa-miR-598-3p, hsa-miR-8485, hsa-miR-148b-5p, hsa-let-7a-3p, hsa-miR-15b-5p, hsa-miR-590-5p, Mature-1251, hsa-miR-642b-3p, Mature-509, It may further involve measuring the expression levels of one or more selected from the group consisting of hsa-miR-199b-5p, hsa-miR-369-5p, hsa-miR-2355-3p, hsa-miR-4644, hsa-miR-4271, and hsa-miR-2392.

[0065] According to one embodiment of the present invention, the miRNA expression level of step b) may be measured by one or more methods selected from the group consisting of polymerase chain reaction (PCR), reverse transcription polymerase chain reaction (RT-PCR), competitive RT-PCR, real-time RT-PCR, nuclease protection assay, in situ hybridization, microarray, and Northern blot.

[0066] It is preferable to use the composition or kit for early or detailed diagnosis of Alzheimer's disease according to the present invention described above for such miRNA expression levels.

[0067] Step c) above is a process of determining whether there is Alzheimer's disease by comparing the miRNA expression level measured in the biological sample with a control group. Specifically, it may include a step of increasing or decreasing the miRNA expression level measured in the biological sample; and measuring the presence and degree of overexpression or underexpression.

[0068] According to one embodiment of the present invention, step c) is in an individual Mature-1322, Mature-639, Mature-655, hsa-miR-1306-5p, hsa-miR-197-3p, hsa-miR-4687-5p, Mature-1259, Mature-240, Mature-626, hsa-miR-184, hsa-miR-328-3p, hsa-miR-4433b-5p, hsa-miR-5100, hsa-miR-6511a-3p, hsa-miR-6793-3p, hsa-miR-6858-3p, hsa-miR-766-3p, hsa-miR-8072, Mature-600, Mature-65, Mature-759, hsa-miR-3620-3p, If the expression level of one or more selected miRNAs in the group consisting of hsa-miR-4701-5p and hsa-miR-95-5p is higher than that of the control group, it may be diagnosed as a moderate to severe stage of Alzheimer's disease.

[0069] According to one embodiment of the present invention, step c) comprises, in an individual, hsa-let-7g-3p, hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-141-3p, hsa-miR-1537-5p, hsa-miR-17-3p, hsa-miR-188-5p, hsa-miR-199a-5p, hsa-miR-20a-3p, hsa-miR-20a-5p, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p, hsa-miR-32-5p, hsa-miR-33a-5p, hsa-miR-33b-5p, hsa-miR-3613-5p, It may be diagnosed as a moderate to severe stage of Alzheimer's disease if the expression level of one or more selected miRNAs from the group consisting of hsa-miR-363-3p, hsa-miR-374a-3p, hsa-miR-496, hsa-miR-579-5p, hsa-miR-142-3p, hsa-miR-21-5p, hsa-miR-3200-3p, hsa-miR-376a-5p, hsa-miR-424-5p, hsa-miR-450a-5p, hsa-miR-548am-5p, hsa-miR-548au-5p, hsa-miR-548c-5p, hsa-miR-548o-5p, hsa-miR-590-3p, and hsa-miR-490-3p is lower than that of the control group. there is.

[0070] 본 발명의 일 구체예에 따르면, 상기 c) 단계는 개체에서 Mature-1322, Mature-639, Mature-655, hsa-miR-1228-5p, hsa-miR-1306-5p, hsa-miR-150-3p, hsa-miR-1908-3p, hsa-miR-197-3p, hsa-miR-2110, hsa-miR-4463, hsa-miR-4644, hsa-miR-4654, hsa-miR-4687-5p, hsa-miR-4732-5p, hsa-miR-483-3p, hsa-miR-5698, hsa-miR-642a-3p, hsa-miR-642b-3p, hsa-miR-671-5p, hsa-miR-6885-5p, hsa-miR-8485, hsa-miR-939-5p, Mature-1259, Mature-168, Mature-169, Mature-176, Mature-181, Mature-240, Mature-326, Mature-565, Mature-567, Mature-626, Mature-893, hsa-miR-12136, hsa-miR-1226-3p, hsa-miR-1229-3p, hsa-miR-1260b, hsa-miR-1292-5p, hsa-miR-1343-3p, hsa-miR-139-3p, hsa-miR-155-5p, hsa-miR-1908-5p, hsa-miR-1914-3p, hsa-miR-23a-5p, hsa-miR-29b-1-5p, hsa-miR-3138, hsa-miR-3154, hsa-miR-3173-5p, hsa-miR-3179, hsa-miR-320a-3p, hsa-miR-320b, hsa-miR-320c, hsa-miR-320d, hsa-miR-320e, hsa-miR-330-3p, hsa-miR-423-5p, hsa-miR-4306, hsa-miR-432-5p hsa-miR-4446-3p, hsa-miR-4485-5p, hsa-miR-4498, hsa-miR-4533, hsa-miR-4665-5p, hsa-miR-4685-3p,hsa-miR-4748, hsa-miR-484, hsa-miR-486-3p, hsa-miR-5010-5p, hsa-miR-501-5p, hsa-miR-616-3p, hsa-miR-6511b-3p, hsa-miR-6515-5p, hsa-miR-654-5p, hsa-miR-6735-5p, hsa-miR-6754-5p, hsa-miR-6763-5p, hsa-miR-6767-5p, hsa-miR-6779-5p, hsa-miR-6802-5p, hsa-miR-6809-5p, hsa-miR-6810-3p, hsa-miR-6837-5p, hsa-miR-6873-5p, hsa-miR-6875-5p, hsa-miR-6876-5p, hsa-miR-6877-5p, hsa-miR-7109-3p, hsa-miR-7151-3p, hsa-miR-760, hsa-miR-874-3p, hsa-miR-877-3p, hsa-miR-92a-1-5p, hsa-miR-92b-3p, hsa-miR-92b-5p, Mature-1121, Mature-1390, Mature-154, Mature-184, Mature-191, Mature-208, Mature-289, Mature-298, Mature-322, Mature-330, Mature-392, Mature-394, Mature-452, If the expression level of one or more selected miRNAs from the group consisting of Mature-611, Mature-627, Mature-667, Mature-808, Mature-847, Mature-896, hsa-miR-184, hsa-miR-328-3p, hsa-miR-4433b-5p, hsa-miR-5100, hsa-miR-6511a-3p, hsa-miR-6793-3p, hsa-miR-6858-3p, hsa-miR-766-3p, hsa-miR-8072, Mature-600, Mature-65, and Mature-759 is higher than that of the control group, it may be diagnosed as a transitional stage from mild cognitive impairment to Alzheimer's disease.

[0071] 본 발명의 일 구체예에 따르면, 상기 c) 단계는 개체에서 hsa-let-7a-3p, hsa-let-7g-3p, hsa-let-7i-3p, hsa-miR-101-3p, hsa-miR-101-5p, hsa-miR-10399-5p, hsa-miR-103a-1-5p, hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-126-5p, hsa-miR-1271-5p, hsa-miR-1287-5p, hsa-miR-1307-5p, hsa-miR-136-3p, hsa-miR-140-5p, hsa-miR-141-3p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-146b-3p, hsa-miR-148a-3p, hsa-miR-148b-3p, hsa-miR-148b-5p, hsa-miR-1537-5p, hsa-miR-154-5p, hsa-miR-15a-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1-3p, hsa-miR-16-5p, hsa-miR-17-3p, hsa-miR-181a-3p hsa-miR-181c-5p, hsa-miR-188-5p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19b-1-5p, hsa-miR-20a-3p, hsa-miR-20a-5p, hsa-miR-21-3p, hsa-miR-22-5p, hsa-miR-2355-3p, hsa-miR-2355-5p, hsa-miR-26b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p, hsa-miR-29c-5p hsa-miR-301b-5p, hsa-miR-30e-3p, hsa-miR-32-3p, hsa-miR-32-5p, hsa-miR-337-3p, hsa-miR-337-5p, hsa-miR-33a-5p, hsa-miR-33b-5p, hsa-miR-340-3p, hsa-miR-340-5p,hsa-miR-3613-5p, hsa-miR-363-3p, hsa-miR-369-3p, hsa-miR-369-5p, hsa-miR-370-5p, hsa-miR-374a-3p, hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-376c-3p, hsa-miR-378a-5p, hsa-miR-380-3p, hsa-miR-381-3p, hsa-miR-4286, hsa-miR-4473, hsa-miR-452-5p, hsa-miR-454-5p, hsa-miR-4799-5p, hsa-miR-487a-3p hsa-miR-487b-3p, hsa-miR-496, hsa-miR-497-5p, hsa-miR-542-3p, hsa-miR-548ap-5p, hsa-miR-548av-3p, hsa-miR-548j-5p, hsa-miR-548o-3p, hsa-miR-551b-3p, hsa-miR-556-3p, hsa-miR-556-5p, hsa-miR-579-5p, hsa-miR-590-5p, hsa-miR-598-3p, hsa-miR-654-3p, hsa-miR-656-3p, hsa-miR-660-5p, hsa-miR-744-3p hsa-miR-98-3p, hsa-miR-99a-3p, Mature-1251, Mature-1331, Mature-509, hsa-let-7f-1-3p, hsa-let-7f-2-3p, hsa-let-7g-5p, hsa-let-7i-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-3p, hsa-miR-107, hsa-miR-10a-5p, hsa-miR-126-3p, hsa-miR-127-5p, hsa-miR-1277-3p, hsa-miR-1277-5p, hsa-miR-128-3p, hsa-miR-130a-3p, hsa-miR-133b, hsa-miR-140-3p, hsa-miR-142-5p, hsa-miR-143-5p, hsa-miR-144-5p, hsa-miR-145-3p,hsa-miR-145-5p, hsa-miR-146a-3p, hsa-miR-154-3p, hsa-miR-15b-3p, hsa-miR-181a-2-3p, hsa-miR-181a-5p, hsa-miR-18a-5p, hsa-miR-192-3p, hsa-miR-192-5p, hsa-miR-194-5p, hsa-miR-195-5p, hsa-miR-199a-3p, hsa-miR-199b-3p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-200a-3p, hsa-miR-210-3p, hsa-miR-219a-5p hsa-miR-221-5p, hsa-miR-22-3p, hsa-miR-224-5p, hsa-miR-23b-3p, hsa-miR-23c, hsa-miR-24-1-5p, hsa-miR-24-2-5p, hsa-miR-24-3p, hsa-miR-26a-1-3p, hsa-miR-26a-2-3p, hsa-miR-301a-3p, hsa-miR-301b-3p, hsa-miR-30d-3p, hsa-miR-30e-5p, hsa-miR-3136-5p, hsa-miR-3143, hsa-miR-331-3p, hsa-miR-338-3p hsa-miR-33a-3p, hsa-miR-370-3p, hsa-miR-374b-3p, hsa-miR-374c-5p, hsa-miR-376a-2-5p, hsa-miR-376a-3p, hsa-miR-376b-3p, hsa-miR-377-3p, hsa-miR-382-3p, hsa-miR-411-3p, hsa-miR-411-5p, hsa-miR-425-3p, hsa-miR-429, hsa-miR-451a, hsa-miR-4524a-3p, hsa-miR-4659b-3p, hsa-miR-4662a-5p, hsa-miR-493-5p hsa-miR-495-3p, hsa-miR-502-3p, hsa-miR-532-5p, hsa-miR-539-3p, hsa-miR-545-3p, hsa-miR-548aa, hsa-miR-548ad-5p,hsa-miR-548ae-5p, hsa-miR-548ap-3p, hsa-miR-548ay-5p, hsa-miR-548d-3p, hsa-miR-548d-5p, hsa-miR-548f-3p, hsa-miR-548h-3p, hsa-miR-548t-3p, hsa-miR-548z, hsa-miR-576-5p, hsa-miR-598-5p, hsa-miR-625-5p, hsa-miR-628-5p, hsa-miR-641, hsa-miR-6516-5p, hsa-miR-6783-5p, hsa-miR-7-1-3p, hsa-miR-99b-5p, Mature-173, If the expression level of one or more selected miRNAs from the group consisting of hsa-miR-142-3p, hsa-miR-21-5p, hsa-miR-3200-3p, hsa-miR-376a-5p, hsa-miR-424-5p, hsa-miR-450a-5p, hsa-miR-548am-5p, hsa-miR-548au-5p, hsa-miR-548c-5p, hsa-miR-548o-5p, and hsa-miR-590-3p is lower than that of the control group, it may be diagnosed as a transitional stage from mild cognitive impairment to Alzheimer's disease.

[0072] According to one embodiment of the present invention, in the case where the control group is a patient with mild cognitive impairment, step c) comprises, in the individual, hsa-let-7a-3p, hsa-let-7g-3p, hsa-let-7i-3p, hsa-miR-101-3p, hsa-miR-101-5p, hsa-miR-10399-5p, hsa-miR-103a-1-5p, hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-126-5p, hsa-miR-1271-5p, hsa-miR-1287-5p, hsa-miR-1307-5p, hsa-miR-136-3p, hsa-miR-140-5p, hsa-miR-141-3p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-146b-3p, hsa-miR-148a-3p, hsa-miR-148b-3p, hsa-miR-148b-5p, hsa-miR-1537-5p, hsa-miR-154-5p, hsa-miR-15a-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1-3p, hsa-miR-16-5p, hsa-miR-17-3p, hsa-miR-181a-3p, hsa-miR-181c-5p, hsa-miR-188-5p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-19b-1-5p, hsa-miR-20a-3p, hsa-miR-20a-5p, hsa-miR-21-3p, hsa-miR-22-5p, hsa-miR-2355-3p, hsa-miR-2355-5p, hsa-miR-26b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p, hsa-miR-29c-5p, hsa-miR-301b-5p, hsa-miR-30e-3p, hsa-miR-32-3p, hsa-miR-32-5p, hsa-miR-337-3p, hsa-miR-337-5p, hsa-miR-33a-5p, hsa-miR-33b-5p, hsa-miR-340-3p,hsa-miR-340-5p, hsa-miR-3613-5p, hsa-miR-363-3p, hsa-miR-369-3p, hsa-miR-369-5p, hsa-miR-370-5p, hsa-miR-374a-3p, hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-376c-3p, hsa-miR-378a-5p, hsa-miR-380-3p, hsa-miR-381-3p, hsa-miR-4286, hsa-miR-4473, hsa-miR-452-5p, hsa-miR-454-5p, hsa-miR-4799-5p, hsa-miR-487a-3p, hsa-miR-487b-3p, hsa-miR-496, hsa-miR-497-5p, hsa-miR-542-3p, hsa-miR-548ap-5p, hsa-miR-548av-3p, hsa-miR-548j-5p, hsa-miR-548o-3p, hsa-miR-551b-3p, hsa-miR-556-3p, hsa-miR-556-5p, hsa-miR-579-5p, hsa-miR-590-5p, hsa-miR-598-3p, hsa-miR-654-3p, hsa-miR-656-3p, hsa-miR-660-5p, If the expression level of one or more selected miRNAs in the group consisting of hsa-miR-744-3p, hsa-miR-98-3p, hsa-miR-99a-3p, Mature-1251, Mature-1331, Mature-509, hsa-miR-134-3p, hsa-miR-431-3p, hsa-miR-99a-5p, and Mature-1363 is higher than that of the control group, it may be diagnosed as a transitional stage from mild cognitive impairment to Alzheimer's disease.

[0073] According to one embodiment of the present invention, in the case where the control group is a patient with mild cognitive impairment, step c) comprises, in the individual Mature-1322, Mature-639, Mature-655, hsa-miR-1228-5p, hsa-miR-1306-5p, hsa-miR-150-3p, hsa-miR-1908-3p, hsa-miR-197-3p, hsa-miR-2110, hsa-miR-4463, hsa-miR-4644, hsa-miR-4654, hsa-miR-4687-5p, hsa-miR-4732-5p, hsa-miR-483-3p, hsa-miR-5698, hsa-miR-642a-3p, hsa-miR-642b-3p, If the expression level of one or more selected miRNAs in the group consisting of hsa-miR-671-5p, hsa-miR-6885-5p, hsa-miR-8485, hsa-miR-939-5p, Mature-1259, Mature-168, Mature-169, Mature-176, Mature-181, Mature-240, Mature-326, Mature-565, Mature-567, Mature-626, Mature-893, hsa-miR-1255a, hsa-miR-214-3p, hsa-miR-2392 and hsa-miR-4271 is lower than that of the control group, it may be diagnosed as a transitional stage from mild cognitive impairment to Alzheimer's disease.

[0074] According to one embodiment of the present invention, the control group may be a normal person, an individual without symptoms suspected of having Alzheimer's disease or who has not been diagnosed with Alzheimer's disease, or a sample obtained therefrom.

[0075] In addition, the specific description regarding the above diagnostic composition applies equally to the invention regarding the above kit and diagnostic method. Effects of the invention

[0076] The present invention provides a composition and kit for diagnosing Alzheimer's disease by presenting a novel biomarker capable of early diagnosis of the onset of Alzheimer's disease in patients with mild cognitive impairment, thereby enabling rapid and accurate determination of whether patients with mild cognitive impairment progress to the dementia stage and providing appropriate treatment methods.

[0077] In addition, the present invention can accurately determine the condition of Alzheimer's disease patients and provide appropriate treatment and prescriptions by presenting biomarkers capable of detailed diagnosis according to the degree of progression of Alzheimer's disease. Brief explanation of the drawing

[0078] Figure 1 shows a population composed of 7 groups divided according to the progression of Alzheimer's disease. Figure 2 shows the process of sequencing RNA in NGS analysis. Figure 3 shows the number of biomarkers discovered through differences in miRNA expression levels in seven groups according to the progression of Alzheimer's disease. Figures 4 to 6 relate to heatmaps of two-way hierarchical clustering using Z-scores. Figure 7 is a volcano plot between group 2 and group 7. Figure 8 is a volcano plot between group 3 and group 5. Figure 9 is a volcano plot between group 5 and group 7. Specific details for implementing the invention

[0079] The present invention will be described in more detail below with reference to the attached drawings. However, this description is provided merely as an example to aid in understanding the invention, and the scope of the invention is not limited by this exemplary description.

[0081] Example 1: Population Selection

[0082] Normal control subjects who underwent Alzheimer's disease screening, including the MMSE, from April 2020 to February 2021 G7 ) 10 patients, patients with early-onset Alzheimer's disease who are amyloid PET positive G1 ) 10 people, patients with late-onset Alzheimer's disease who are amyloid PET positive G2 ) 10 patients, among patients with mild cognitive impairment, amyloid PET negative (MCI with negative amyloid PET, G3 ), among patients with mild cognitive impairment who are amyloid PET negative but possess the ApoE 44 gene (MCI with negative amyloid PET but with ApoE 44, G4 ) 5 patients, patients with mild cognitive impairment who are amyloid PET positive (MCI with positive amyloid PET, G5 ) and patients with non-Alzheimer's dementia (Non-AD dementia, G6 ) 5 people were selected and divided into 7 groups (Fig. 1), and among them, 6 people in G1, 8 people in G2, 9 people in G3, 4 people in G4, 6 people in G5, 3 people in G6, and 10 people in G7 whose NGS was successfully analyzed were formed into the population (Table 1).

[0083] division ID gender years MMSE Amyloid PET Normal Control (G7) 19 female 72 28 25 female 73 30 77 female 73 29 21 female 74 30 7 female 75 28 12 other 75 30 30 female 76 30 26 female 77 27 39 other 79 18 49 female 82 29 Early onset Alzheimer's disease with Positive amyloid PET (G1) ADAM2C 002 other 65 Positive ADAM2C 022 female 52 Positive ADAM2C 091 female 63 Positive ADAM2C 106 female 61 Positive ADAM2C 262 other 61 Positive ADAM2C 450 other 58 Positive Late onset Alzheimer's disease with Positive amyloid PET (G2) ADAM2C 042 female 70 Positive ADAM2C 043 female 81 Positive ADAM2C 090 other 78 Positive ADAM2C 112 other 76 Positive ADAM2C 115 other 76 Positive ADAM2C 140 other 81 Positive ADAM2C 229 female 70 Positive ADAM2C 265 female 80 Positive MCI with Negative amyloid PET (G3) ADAM2C 277 other 74 Negaitve ADAM2C 011 female 76 Negative ADAM2C 138 other 54 Negative ADAM2C 219 female 50 Negative ADAM2C 225 female 64 Negative ADAM2C 414 other 83 Negative ADAM2C 737 other 74 Negative ADAM2C 858 other 59 Negative ADAM2C 907 female 64 Negative MCI with Negative amyloid PET but with ApoE 44 (G4) ADAM2C 135 female 75 Negative ADAM2C 310 female 72 Negative ADAM2C 423 female 67 Negative MCI with Positive amyloid PET (G5) ADAM2C 024 F 73 Positive ADAM2C 030 M 79 Positive ADAM2C 031 F 79 Positive ADAM2C 072 F 76 Positive ADAM2C 101 F 73 Positive ADAM2C 806 F 72 Positive Non-AD dementia (G6) ADAM2C 105 M 75 Negative ADAM2C 284 F 66 Negative ADAM2C 457 F 57 Negative

[0085] Example 2: Plasma Separation

[0086] To obtain biomarkers associated with the progression of Alzheimer's disease by analyzing differences in miRNA expression levels among the aforementioned groups, blood samples were collected from the population of Example 1. 25 ml of venous blood was collected and transferred into two 9 ml EDTA vacutainer tubes, two 2.5 ml PAXgene tubes, and a 2 ml SST tube; blood collection was performed using a butterfly needle (21G needle). If using a butterfly needle is difficult, a vacutainer needle and vacutainer holder may be used, but using a standard syringe may cause errors in the test results. After collection, the blood was placed in the EDTA container first, followed by the PAXgene tube and SST tube. 9 ml of blood was filled into the EDTA vacutainer tube; since the concentration of the anticoagulant may vary, a constant amount was always collected. To prevent hemolysis, blood was collected slowly, and the specimen placed in an EDTA vacutainer tube was gently inverted 8 to 10 times to ensure sufficient mixing of the blood and anticoagulant. Centrifugation of the sample was then initiated within one hour of collection. The subsequent process was to be completed within two hours. The EDTA vacutainer tube was centrifuged at 1500 × G for 10 minutes at 20°C; while rapid acceleration was acceptable, deceleration was strictly performed slowly without using the brakes. After centrifugation, the plasma was separated using a disposable dropper to prevent mixing with blood cells (up to 0.5 cm above the blood cell layer) and placed into a 15 ml conical tube. Subsequently, the plasma from both EDTA vacutainer tubes was collected into a single conical tube. Afterward, the conical tube was briefly vortexed, and 350 µl of plasma was divided and placed into 0.5 ml self-standing microtubes.

[0088] 실시예 3: RNA의 분리

[0089] QIAzol® Lysis Reagent (Cat. No. 79306) and miRNeasy® Serum / Plasma Kit were used for RNA isolation from plasma, and the provided protocol was followed, as described below.

[0090] Trizol (x 5 vol.) was added to the plasma sample, mixed, and incubated at room temperature for 5 minutes to homogenize the sample. Subsequently, chloroform was added and mixed, then centrifuged at 12,000 g at 4°C for 15 minutes, followed by the addition of ethanol (x 1.5 vol.) to perform phase separation. RNA wash and elution: The sample was loaded onto an RNeasy MinElute spin column connected to a vacuum manifold, followed by the addition of RWT buffer and 80% ethanol. After centrifugation at 12,000 g for 30 seconds, RNase-free water was added to the column, incubated at room temperature for 3 minutes, and centrifuged at maximum speed for 1 minute.

[0092] 실시예 4: miRNA 서열분석 및 데이터 가공

[0093] miRBase v22.1 and RNAcentral 14.0 were used for NGS analysis. Single-end reads with a read length of 51 were used, Illumina’s SMARTer smRNA-Seq was used as the library kit, and the sequencer was the Illumina platform. The RNA sequencing process is shown in Figure 3.

[0094] After sequencing, the raw data was separated according to data quality, and adapter sequences underwent additional trimming. Trimmed reads and non-adaptor reads were processed to analyze long targets of 50 bp or longer, and the processed reads were collected to form a cluster. These clusters had a 100% match in sequence and read length, and a provisional ID was assigned to this cluster.

[0095] To eliminate the influence of large amounts of rRNA, reads were removed by comparing them to their rRNA sequences. The rRNA-removed reads were then compared with the reference genome in miRbase v22.1 and with RNAcentral 14.0, a non-coding RNA database. They were classified as registered miRNAs or into other classes of RNA (tRNA, snRNA, snoRNA, etc.). Prediction of new miRNAs (labeled as Mature) was performed using miRDeep2. Read counts for each miRNA were derived by extracting them from mapped miRNAs, and information regarding miRNAs expressed differently was analyzed using statistical techniques.

[0096] For each sample, information on base, GC(%), Q20(%), and Q(30%) was calculated, and two trimming processes were performed.

[0097] - GC (%): GC content

[0098] - Q20 (%): % of bases with a phred quality of 20 or higher

[0099] - Q30 (%): % of bases with a phred quality of 20 or higher

[0101] 실시예 5: 차등 발현 miRNA 분석

[0102] To diagnose the progression of Alzheimer's disease in detail, and specifically to discover miRNA biomarkers for diagnosing the moment of transition to Alzheimer's disease in patients with mild cognitive impairment, differential expression miRNA analysis was performed among the samples of each group in Example 1. For the differential expression miRNA analysis, the number of mature miRNA reads obtained from the miRDeep2 Quantifier module was used as raw data. For statistical analysis, p-values ​​were calculated using EdgeR analysis.

[0103] To specifically distinguish patients with mild cognitive impairment who are progressing to Alzheimer's disease, comparisons were made between the group of patients with late-onset Alzheimer's disease with positive amyloid PET (G2) and the normal control group (G7), patients with mild cognitive impairment who are also amyloid PET positive (MCI with positive amyloid PET, G5) and the normal control group (G7), and patients with mild cognitive impairment who are also amyloid PET negative (MCI with negative amyloid PET, G3) and patients with mild cognitive impairment who are also amyloid PET positive (MCI with positive amyloid PET, G5), and miRNAs with p < 0.05 were selected through EdgeR analysis.

[0104] When classified according to the degree of progression of Alzheimer's disease into normal stage, mild cognitive impairment stage, transition stage from mild cognitive impairment to Alzheimer's, and moderate to severe Alzheimer's stage, severe Alzheimer's can be diagnosed using miRNAs belonging to a region that is selected exclusively in the comparison between G2 and G7 (Fig. 3A); moderate Alzheimer's can be diagnosed using miRNAs belonging to a region that is selected in both the comparison between G2 and G7 and the comparison between G5 and G7 (Fig. 3D and F); mild Alzheimer's can be diagnosed using miRNAs belonging to a region that is selected in the comparison between G5 and G7 relative to normal individuals, but excludes those selected in the comparison between G2 and G7 (Fig. 3B and E); and mild Alzheimer's and mild cognitive impairment can be distinguished using miRNAs belonging to a region that is selected in the comparison between G3 and G5 (Fig. 3C, E, and F).

[0105] The analysis results are shown in Tables 2 to 5 below. In the comparison between G2 and G7, 57 miRNAs with p < 0.001 were selected; in the comparison between G5 and G7, 337 miRNAs with p < 0.05 were selected; and in the comparison between G3 and G5, 141 miRNAs with p < 0.01 were selected. Among these, 53 miRNAs were selected in common between the comparison between G2 and G7 and between G5 and G7 (Fig. 2 D and F), 133 miRNAs were selected in common between the comparison between G5 and G7 and between G3 and G5 (Fig. 2 E and F), and 30 miRNAs were selected in all three group comparisons (Fig. 2 F). A total of 349 miRNA markers were selected in the second NGS analysis.

[0106] A G3-G5, p G2-G7, p G5-G7,p hsa-miR-3620-3p 0.7005 0.0005 0.0506 hsa-miR-4701-5p 0.0897 0.0000 0.8178 hsa-miR-490-3p 0.7081 0.0008 0.0598 hsa-miR-95-5p 0.8702 0.0002 0.3958

[0107] D+F G3-G5, p G2-G7, p G5-G7,p hsa-let-7g-3p 0.0002 0.0002 0.0000 hsa-miR-106b-5p 0.0014 0.0004 0.0000 hsa-miR-11400 0.0003 0.0000 0.0000 hsa-miR-1306-5p 0.0031 0.0000 0.0000 hsa-miR-141-3p 0.0026 0.0002 0.0000 hsa-miR-1537-5p 0.0009 0.0002 0.0000 hsa-miR-17-3p 0.0000 0.0000 0.0000 hsa-miR-188-5p 0.0002 0.0005 0.0000 hsa-miR-197-3p 0.0000 0.0000 0.0000 hsa-miR-199a-5p 0.0000 0.0002 0.0000 hsa-miR-20a-3p 0.0001 0.0004 0.0000 hsa-miR-20a-5p 0.0022 0.0003 0.0018 hsa-miR-29a-3p 0.0000 0.0001 0.0000 hsa-miR-29b-3p 0.0000 0.0001 0.0000 hsa-miR-29c-3p 0.0000 0.0000 0.0000 hsa-miR-32-5p 0.0000 0.0000 0.0000 hsa-miR-33a-5p 0.0000 0.0000 0.0000 hsa-miR-33b-5p 0.0000 0.0000 0.0000 hsa-miR-3613-5p 0.0000 0.0000 0.0000 hsa-miR-363-3p 0.0036 0.0000 0.0001 hsa-miR-374a-3p 0.0000 0.0000 0.0000 hsa-miR-4687-5p 0.0011 0.0008 0.0000 hsa-miR-496 0.0001 0.0001 0.0001 hsa-miR-579-5p 0.0025 0.0009 0.0015 Mature-1259 0.0002 0.0000 0.0000 Mature-1322 0.0000 0.0000 0.0000 Mature-240 0.0002 0.0001 0.0030 Mature-626 0.0003 0.0003 0.0000 Mature-639 0.0000 0.0000 0.0000 Mature-655 0.0000 0.0000 0.0000 hsa-miR-142-3p 0.0589 0.0002 0.0000 hsa-miR-184 0.5273 0.0001 0.0000 hsa-miR-21-5p 0.0168 0.0003 0.0000 hsa-miR-3200-3p 0.3502 0.0003 0.0036 hsa-miR-328-3p 0.6746 0.0003 0.0012 hsa-miR-376a-5p 0.4749 0.0003 0.0057 hsa-miR-424-5p 0.0290 0.0008 0.0000 hsa-miR-4433b-5p 0.4081 0.0000 0.0000 hsa-miR-450a-5p 0.0287 0.0007 0.0070 hsa-miR-5100 0.9907 0.0002 0.0004 hsa-miR-548am-5p 0.3663 0.0009 0.0010 hsa-miR-548au-5p 0.3889 0.0006 0.0010 hsa-miR-548c-5p 0.3665 0.0009 0.0010 hsa-miR-548o-5p 0.3667 0.0009 0.0010 hsa-miR-590-3p 0.3145 0.0005 0.0099 hsa-miR-6511a-3p 0.0392 0.0006 0.0001 hsa-miR-6793-3p 0.8983 0.0007 0.0086 hsa-miR-6858-3p 0.1661 0.0001 0.0000 hsa-miR-766-3p 0.8807 0.0000 0.0002 hsa-miR-8072 0.4200 0.0007 0.0000 Mature-600 0.9475 0.0000 0.0000 Mature-65 0.1245 0.0000 0.0014 Mature-759 0.0977 0.0000 0.0000

[0108] B+E G3-G5, p G2-G7, p G5-G7,p hsa-let-7a-3p 0.0001 0.2688 0.0000 hsa-let-7i-3p 0.0003 0.0012 0.0000 hsa-miR-101-3p 0.0041 0.0017 0.0000 hsa-miR-101-5p 0.0007 0.0811 0.0002 hsa-miR-10399-5p 0.0025 0.0143 0.0003 hsa-miR-103a-1-5p 0.0064 0.0964 0.0002 hsa-miR-1228-5p 0.0035 0.8364 0.0000 hsa-miR-126-5p 0.0053 0.0201 0.0000 hsa-miR-1271-5p 0.0028 0.5427 0.0023 hsa-miR-1287-5p 0.0080 0.0348 0.0021 hsa-miR-1307-5p 0.0003 0.6731 0.0006 hsa-miR-136-3p 0.0024 0.1724 0.0001 hsa-miR-140-5p 0.0024 0.0793 0.0001 hsa-miR-143-3p 0.0003 0.0271 0.0000 hsa-miR-144-3p 0.0010 0.2741 0.0000 hsa-miR-146b-3p 0.0006 0.4334 0.0002 hsa-miR-148a-3p 0.0049 0.0998 0.0007 hsa-miR-148b-3p 0.0014 0.0167 0.0005 hsa-miR-148b-5p 0.0000 0.0021 0.0000 hsa-miR-150-3p 0.0043 0.3847 0.0004 hsa-miR-154-5p 0.0002 0.1299 0.0003 hsa-miR-15a-3p 0.0000 0.0036 0.0000 hsa-miR-15a-5p 0.0100 0.0125 0.0000 hsa-miR-15b-5p 0.0001 0.0036 0.0000 hsa-miR-16-1-3p 0.0012 0.0169 0.0002 hsa-miR-16-5p 0.0082 0.0434 0.0004 hsa-miR-181a-3p 0.0042 0.2007 0.0001 hsa-miR-181c-5p 0.0009 0.0313 0.0000 hsa-miR-1908-3p 0.0008 0.0312 0.0000 hsa-miR-199b-5p 0.0001 0.0033 0.0000 hsa-miR-19b-1-5p 0.0004 0.0166 0.0001 hsa-miR-2110 0.0050 0.4125 0.0025 hsa-miR-21-3p 0.0000 0.0098 0.0000 hsa-miR-22-5p 0.0058 0.0149 0.0024 hsa-miR-2355-3p 0.0001 0.0024 0.0001 hsa-miR-2355-5p 0.0011 0.1004 0.0001 hsa-miR-26b-3p 0.0052 0.2810 0.0002 hsa-miR-27a-3p 0.0000 0.0024 0.0000 hsa-miR-27b-3p 0.0002 0.0126 0.0000 hsa-miR-29c-5p 0.0011 0.0703 0.0001 hsa-miR-301b-5p 0.0060 0.0390 0.0036 hsa-miR-30e-3p 0.0039 0.0298 0.0001 hsa-miR-32-3p 0.0000 0.0091 0.0000 hsa-miR-337-3p 0.0003 0.0968 0.0000 hsa-miR-337-5p 0.0000 0.0058 0.0000 hsa-miR-340-3p 0.0014 0.1559 0.0000 hsa-miR-340-5p 0.0000 0.0334 0.0000 hsa-miR-369-3p 0.0002 0.0131 0.0002 hsa-miR-369-5p 0.0001 0.0832 0.0004 hsa-miR-370-5p 0.0044 0.4161 0.0136 hsa-miR-374a-5p 0.0021 0.4192 0.0000 hsa-miR-374b-5p 0.0005 0.0206 0.0000 hsa-miR-376c-3p 0.0077 0.5514 0.0012 hsa-miR-378a-5p 0.0088 0.1212 0.0119 hsa-miR-380-3p 0.0031 0.0175 0.0011 hsa-miR-381-3p 0.0060 0.0051 0.0001 hsa-miR-4286 0.0005 0.8044 0.0154 hsa-miR-4463 0.0000 0.0457 0.0067 hsa-miR-4473 0.0075 0.2583 0.0034 hsa-miR-452-5p 0.0091 0.1159 0.0014 hsa-miR-454-5p 0.0005 0.6561 0.0001 hsa-miR-4644 0.0001 0.2231 0.0468 hsa-miR-4654 0.0050 0.2575 0.0002 hsa-miR-4732-5p 0.0010 0.5777 0.0097 hsa-miR-4799-5p 0.0093 0.2332 0.0094 hsa-miR-483-3p 0.0023 0.2935 0.0123 hsa-miR-487a-3p 0.0008 0.4026 0.0126 hsa-miR-487b-3p 0.0020 0.0490 0.0032 hsa-miR-497-5p 0.0010 0.0066 0.0000 hsa-miR-542-3p 0.0032 0.0330 0.0000 hsa-miR-548ap-5p 0.0010 0.2415 0.0002 hsa-miR-548av-3p 0.0018 0.2356 0.0034 hsa-miR-548j-5p 0.0010 0.2415 0.0002 hsa-miR-548o-3p 0.0047 0.4100 0.0025 hsa-miR-551b-3p 0.0028 0.0459 0.0129 hsa-miR-556-3p 0.0006 0.0503 0.0000 hsa-miR-556-5p 0.0014 0.0015 0.0000 hsa-miR-5698 0.0029 0.1257 0.0024 hsa-miR-590-5p 0.0001 0.0284 0.0000 hsa-miR-598-3p 0.0000 0.0016 0.0000 hsa-miR-642a-3p 0.0000 0.2822 0.0001 hsa-miR-642b-3p 0.0001 0.2354 0.0004 hsa-miR-654-3p 0.0028 0.0599 0.0029 hsa-miR-656-3p 0.0041 1.0000 0.0213 hsa-miR-660-5p 0.0008 0.0044 0.0000 hsa-miR-671-5p 0.0000 0.0039 0.0000 hsa-miR-6885-5p 0.0012 0.0072 0.0000 hsa-miR-744-3p 0.0049 0.5697 0.0128 hsa-miR-8485 0.0000 0.0032 0.0000 hsa-miR-939-5p 0.0005 0.0579 0.0001 hsa-miR-98-3p 0.0009 0.4773 0.0005 hsa-miR-99a-3p 0.0031 0.0229 0.0097 Mature-1251 0.0001 0.2253 0.0002 Mature-1331 0.0038 0.9925 0.0073 Mature-168 0.0035 0.0064 0.0000 Mature-169 0.0035 0.0064 0.0000 Mature-176 0.0035 0.0064 0.0000 Mature-181 0.0035 0.0064 0.0000 Mature-326 0.0000 0.1849 0.0166 Mature-509 0.0001 0.1455 0.0000 Mature-565 0.0000 0.0141 0.0004 Mature-567 0.0078 0.1856 0.0338 Mature-893 0.0017 0.5675 0.0039 hsa-let-7f-1-3p 0.0143 0.8255 0.0319 hsa-let-7f-2-3p 0.0567 0.9763 0.0040 hsa-let-7g-5p 0.0353 0.0050 0.0022 hsa-let-7i-5p 0.1291 0.0200 0.0182 hsa-miR-103a-3p 0.0569 0.0996 0.0389 hsa-miR-106a-5p 0.0253 0.0638 0.0442 hsa-miR-106b-3p 0.0249 0.1644 0.0124 hsa-miR-107 0.0271 0.0612 0.0202 hsa-miR-10a-5p 0.0132 0.8914 0.0043 hsa-miR-12136 0.0293 0.0546 0.0027 hsa-miR-1226-3p 1.0000 0.0625 0.0402 hsa-miR-1229-3p 0.2678 0.0089 0.0023 hsa-miR-1260b 0.5473 0.0032 0.0061 hsa-miR-126-3p 0.0138 0.1310 0.0252 hsa-miR-127-5p 0.0515 0.5308 0.0048 hsa-miR-1277-3p 0.2355 0.0102 0.0000 hsa-miR-1277-5p 0.3944 0.0035 0.0049 hsa-miR-128-3p 0.0132 0.9706 0.0203 hsa-miR-1292-5p 0.2136 0.0981 0.0148 hsa-miR-130a-3p 0.0138 0.0776 0.0027 hsa-miR-133b 0.0582 0.8756 0.0489 hsa-miR-1343-3p 0.0889 0.0062 0.0000 hsa-miR-139-3p 0.1329 0.1030 0.0024 hsa-miR-140-3p 0.0373 0.3488 0.0278 hsa-miR-142-5p 0.1462 0.8622 0.0011 hsa-miR-143-5p 0.1051 0.0897 0.0021 hsa-miR-144-5p 0.0289 0.0448 0.0000 hsa-miR-145-3p 0.0902 0.0590 0.0185 hsa-miR-145-5p 0.0334 0.1713 0.0036 hsa-miR-146a-3p 0.0341 0.7181 0.0108 hsa-miR-154-3p 0.0721 0.3604 0.0488 hsa-miR-155-5p 0.0344 0.7080 0.0036 hsa-miR-15b-3p 0.1251 0.0195 0.0006 hsa-miR-181a-2-3p 0.0229 0.0769 0.0479 hsa-miR-181a-5p 0.0222 0.1749 0.0064 hsa-miR-18a-5p 0.0387 0.3895 0.0058 hsa-miR-1908-5p 0.0976 0.5411 0.0089 hsa-miR-1914-3p 0.0124 0.3943 0.0122 hsa-miR-192-3p 0.0292 0.0142 0.0040 hsa-miR-192-5p 0.0990 0.1433 0.0001 hsa-miR-194-5p 0.0171 0.3383 0.0121 hsa-miR-195-5p 0.0166 0.5803 0.0167 hsa-miR-199a-3p 0.0211 0.0108 0.0286 hsa-miR-199b-3p 0.0213 0.0109 0.0283 hsa-miR-19a-3p 0.5732 0.3449 0.0007 hsa-miR-19b-3p 0.1984 0.5702 0.0010 hsa-miR-200a-3p 0.0102 0.8884 0.0266 hsa-miR-210-3p 0.0377 0.0058 0.0005 hsa-miR-219a-5p 0.1436 0.7819 0.0430 hsa-miR-221-5p 0.0896 0.9409 0.0273 hsa-miR-22-3p 0.1060 0.3777 0.0034 hsa-miR-224-5p 0.0627 0.4880 0.0117 hsa-miR-23a-5p 0.2489 0.4824 0.0187 hsa-miR-23b-3p 0.3934 0.2265 0.0228 hsa-miR-23c 0.1094 0.3178 0.0098 hsa-miR-24-1-5p 0.0422 0.0030 0.0022 hsa-miR-24-2-5p 0.0287 0.0113 0.0008 hsa-miR-24-3p 0.0650 0.0415 0.0193 hsa-miR-26a-1-3p 0.0317 0.5114 0.0206 hsa-miR-26a-2-3p 0.0797 0.1858 0.0001 hsa-miR-29b-1-5p 0.0190 0.1353 0.0146 hsa-miR-301a-3p 0.6969 0.9697 0.0020 hsa-miR-301b-3p 0.0992 0.3054 0.0010 hsa-miR-30d-3p 0.0350 0.0198 0.0047 hsa-miR-30e-5p 0.0164 0.9245 0.0006 hsa-miR-3136-5p 0.1589 0.1012 0.0472 hsa-miR-3138 0.1089 0.7797 0.0136 hsa-miR-3143 0.0478 0.0998 0.0402 hsa-miR-3154 0.0352 1.0000 0.0167 hsa-miR-3173-5p 0.2582 0.0115 0.0038 hsa-miR-3179 0.0279 0.5076 0.0088 hsa-miR-320a-3p 0.1434 0.5590 0.0139 hsa-miR-320b 0.0983 0.1920 0.0008 hsa-miR-320c 0.0951 0.2782 0.0001 hsa-miR-320d 0.0495 0.2374 0.0002 hsa-miR-320e 0.3136 0.3171 0.0026 hsa-miR-330-3p 0.0142 0.0059 0.0002 hsa-miR-331-3p 0.0548 0.5807 0.0287 hsa-miR-338-3p 0.0322 0.0097 0.0001 hsa-miR-33a-3p 0.0215 0.0112 0.0000 hsa-miR-370-3p 0.0624 0.3003 0.0287 hsa-miR-374b-3p 0.0470 0.4245 0.0007 hsa-miR-374c-5p 0.0498 0.8384 0.0221 hsa-miR-376a-2-5p 0.0350 0.7913 0.0278 hsa-miR-376a-3p 0.0202 0.2628 0.0024 hsa-miR-376b-3p 0.6547 0.0097 0.0204 hsa-miR-377-3p 0.0674 0.7006 0.0008 hsa-miR-382-3p 0.0135 0.6032 0.0075 hsa-miR-411-3p 0.0303 0.1359 0.0144 hsa-miR-411-5p 0.0298 0.2016 0.0039 hsa-miR-423-5p 0.0116 0.0197 0.0000 hsa-miR-425-3p 0.0214 0.0859 0.0027 hsa-miR-429 0.0105 0.0043 0.0068 hsa-miR-4306 0.4303 0.0527 0.0283 hsa-miR-432-5p 0.3890 0.4549 0.0208 hsa-miR-4446-3p 0.3152 0.2042 0.0052 hsa-miR-4485-5p 0.2748 0.0054 0.0000 hsa-miR-4498 0.0668 0.6063 0.0327 hsa-miR-451a 0.2702 0.1145 0.0000 hsa-miR-4524a-3p 0.0455 0.0372 0.0225 hsa-miR-4533 0.1061 0.0015 0.0124 hsa-miR-4659b-3p 0.0136 0.0502 0.0026 hsa-miR-4662a-5p 0.0321 0.3356 0.0157 hsa-miR-4665-5p 0.0175 0.0021 0.0000 hsa-miR-4685-3p 0.2018 0.0117 0.0150 hsa-miR-4748 0.2602 0.2131 0.0163 hsa-miR-484 0.5068 0.0020 0.0030 hsa-miR-486-3p 0.3036 0.0024 0.0020 hsa-miR-493-5p 0.0268 0.2520 0.0312 hsa-miR-495-3p 0.0372 0.1928 0.0113 hsa-miR-5010-5p 0.0218 0.7782 0.0181 hsa-miR-501-5p 0.3221 0.5266 0.0187 hsa-miR-502-3p 0.0398 0.0152 0.0214 hsa-miR-532-5p 0.0573 0.0337 0.0062 hsa-miR-539-3p 0.0941 0.0139 0.0056 hsa-miR-545-3p 0.1091 0.0155 0.0005 hsa-miR-548aa 0.0735 0.1758 0.0318 hsa-miR-548ad-5p 0.0275 0.9918 0.0188 hsa-miR-548ae-5p 0.0277 0.9918 0.0187 hsa-miR-548ap-3p 0.1409 0.0672 0.0394 hsa-miR-548ay-5p 0.0648 0.1649 0.0298 hsa-miR-548d-3p 0.0147 1.0000 0.0017 hsa-miR-548d-5p 0.0650 0.1647 0.0300 hsa-miR-548f-3p 0.0401 0.2080 0.0010 hsa-miR-548h-3p 0.0167 0.1026 0.0013 hsa-miR-548t-3p 0.0734 0.1755 0.0318 hsa-miR-548z 0.0166 0.1029 0.0013 hsa-miR-576-5p 0.0158 0.0128 0.0009 hsa-miR-598-5p 0.6808 0.2624 0.0387 hsa-miR-616-3p 0.0346 0.1442 0.0003 hsa-miR-625-5p 0.0159 0.0054 0.0008 hsa-miR-628-5p 0.1729 0.0522 0.0161 hsa-miR-641 0.0185 0.5297 0.0182 hsa-miR-6511b-3p 0.5033 0.0160 0.0004 hsa-miR-6515-5p 0.2563 0.3126 0.0142 hsa-miR-6516-5p 0.0286 0.3478 0.0368 hsa-miR-654-5p 0.7810 0.1278 0.0431 hsa-miR-6735-5p 0.1026 0.0367 0.0085 hsa-miR-6754-5p 0.2282 0.0018 0.0122 hsa-miR-6763-5p 0.5121 0.1924 0.0046 hsa-miR-6767-5p 0.0520 0.0152 0.0040 hsa-miR-6779-5p 0.0126 0.2932 0.0313 hsa-miR-6783-5p 0.1544 0.0142 0.0159 hsa-miR-6802-5p 0.0271 0.3495 0.0017 hsa-miR-6809-5p 0.0984 0.0963 0.0235 hsa-miR-6810-3p 0.0305 0.0579 0.0000 hsa-miR-6837-5p 0.4464 0.0404 0.0272 hsa-miR-6873-5p 0.1607 0.1156 0.0341 hsa-miR-6875-5p 0.0408 0.2778 0.0176 hsa-miR-6876-5p 0.0754 0.0371 0.0472 hsa-miR-6877-5p 0.0215 0.5275 0.0004 hsa-miR-7109-3p 0.6530 0.0111 0.0246 hsa-miR-7-1-3p 0.0110 0.8785 0.0043 hsa-miR-7151-3p 0.3853 0.2563 0.0352 hsa-miR-760 0.2336 0.5016 0.0067 hsa-miR-874-3p 0.1419 0.0018 0.0035 hsa-miR-877-3p 0.0160 0.1019 0.0032 hsa-miR-92a-1-5p 0.0437 1.0000 0.0429 hsa-miR-92b-3p 0.2423 0.0268 0.0039 hsa-miR-92b-5p 0.0896 1.0000 0.0011 hsa-miR-99b-5p 0.0103 0.3052 0.0442 Mature-1121 0.1255 0.0324 0.0077 Mature-1390 0.0513 0.2484 0.0016 Mature-154 0.1410 0.2534 0.0112 Mature-173 0.0948 0.0356 0.0335 Mature-184 0.0176 0.1741 0.0001 Mature-191 0.1984 0.2986 0.0103 Mature-208 0.0267 0.0404 0.0033 Mature-289 0.2222 0.0964 0.0009 Mature-298 0.2192 0.0086 0.0037 Mature-322 0.8699 0.0136 0.0113 Mature-330 0.2195 0.1289 0.0186 Mature-392 0.0959 0.0516 0.0017 Mature-394 0.0272 0.0945 0.0208 Mature-452 0.3022 0.0216 0.0031 Mature-611 0.7970 0.0408 0.0105 Mature-627 0.0263 0.0273 0.0033 Mature-667 0.1227 0.0982 0.0099 Mature-808 0.0431 0.2922 0.0396 Mature-847 0.1899 0.2697 0.0116 Mature-896 0.1227 0.0982 0.0099

[0109] C+E+F G3-G5, p G2-G7, p G5-G7,p hsa-let-7a-3p 0.0001 0.2688 0.0000 hsa-let-7g-3p 0.0002 0.0002 0.0000 hsa-let-7i-3p 0.0003 0.0012 0.0000 hsa-miR-101-3p 0.0041 0.0017 0.0000 hsa-miR-101-5p 0.0007 0.0811 0.0002 hsa-miR-10399-5p 0.0025 0.0143 0.0003 hsa-miR-103a-1-5p 0.0064 0.0964 0.0002 hsa-miR-106b-5p 0.0014 0.0004 0.0000 hsa-miR-11400 0.0003 0.0000 0.0000 hsa-miR-1228-5p 0.0035 0.8364 0.0000 hsa-miR-126-5p 0.0053 0.0201 0.0000 hsa-miR-1271-5p 0.0028 0.5427 0.0023 hsa-miR-1287-5p 0.0080 0.0348 0.0021 hsa-miR-1306-5p 0.0031 0.0000 0.0000 hsa-miR-1307-5p 0.0003 0.6731 0.0006 hsa-miR-136-3p 0.0024 0.1724 0.0001 hsa-miR-140-5p 0.0024 0.0793 0.0001 hsa-miR-141-3p 0.0026 0.0002 0.0000 hsa-miR-143-3p 0.0003 0.0271 0.0000 hsa-miR-144-3p 0.0010 0.2741 0.0000 hsa-miR-146b-3p 0.0006 0.4334 0.0002 hsa-miR-148a-3p 0.0049 0.0998 0.0007 hsa-miR-148b-3p 0.0014 0.0167 0.0005 hsa-miR-148b-5p 0.0000 0.0021 0.0000 hsa-miR-150-3p 0.0043 0.3847 0.0004 hsa-miR-1537-5p 0.0009 0.0002 0.0000 hsa-miR-154-5p 0.0002 0.1299 0.0003 hsa-miR-15a-3p 0.0000 0.0036 0.0000 hsa-miR-15a-5p 0.0100 0.0125 0.0000 hsa-miR-15b-5p 0.0001 0.0036 0.0000 hsa-miR-16-1-3p 0.0012 0.0169 0.0002 hsa-miR-16-5p 0.0082 0.0434 0.0004 hsa-miR-17-3p 0.0000 0.0000 0.0000 hsa-miR-181a-3p 0.0042 0.2007 0.0001 hsa-miR-181c-5p 0.0009 0.0313 0.0000 hsa-miR-188-5p 0.0002 0.0005 0.0000 hsa-miR-1908-3p 0.0008 0.0312 0.0000 hsa-miR-197-3p 0.0000 0.0000 0.0000 hsa-miR-199a-5p 0.0000 0.0002 0.0000 hsa-miR-199b-5p 0.0001 0.0033 0.0000 hsa-miR-19b-1-5p 0.0004 0.0166 0.0001 hsa-miR-20a-3p 0.0001 0.0004 0.0000 hsa-miR-20a-5p 0.0022 0.0003 0.0018 hsa-miR-2110 0.0050 0.4125 0.0025 hsa-miR-21-3p 0.0000 0.0098 0.0000 hsa-miR-22-5p 0.0058 0.0149 0.0024 hsa-miR-2355-3p 0.0001 0.0024 0.0001 hsa-miR-2355-5p 0.0011 0.1004 0.0001 hsa-miR-26b-3p 0.0052 0.2810 0.0002 hsa-miR-27a-3p 0.0000 0.0024 0.0000 hsa-miR-27b-3p 0.0002 0.0126 0.0000 hsa-miR-29a-3p 0.0000 0.0001 0.0000 hsa-miR-29b-3p 0.0000 0.0001 0.0000 hsa-miR-29c-3p 0.0000 0.0000 0.0000 hsa-miR-29c-5p 0.0011 0.0703 0.0001 hsa-miR-301b-5p 0.0060 0.0390 0.0036 hsa-miR-30e-3p 0.0039 0.0298 0.0001 hsa-miR-32-3p 0.0000 0.0091 0.0000 hsa-miR-32-5p 0.0000 0.0000 0.0000 hsa-miR-337-3p 0.0003 0.0968 0.0000 hsa-miR-337-5p 0.0000 0.0058 0.0000 hsa-miR-33a-5p 0.0000 0.0000 0.0000 hsa-miR-33b-5p 0.0000 0.0000 0.0000 hsa-miR-340-3p 0.0014 0.1559 0.0000 hsa-miR-340-5p 0.0000 0.0334 0.0000 hsa-miR-3613-5p 0.0000 0.0000 0.0000 hsa-miR-363-3p 0.0036 0.0000 0.0001 hsa-miR-369-3p 0.0002 0.0131 0.0002 hsa-miR-369-5p 0.0001 0.0832 0.0004 hsa-miR-370-5p 0.0044 0.4161 0.0136 hsa-miR-374a-3p 0.0000 0.0000 0.0000 hsa-miR-374a-5p 0.0021 0.4192 0.0000 hsa-miR-374b-5p 0.0005 0.0206 0.0000 hsa-miR-376c-3p 0.0077 0.5514 0.0012 hsa-miR-378a-5p 0.0088 0.1212 0.0119 hsa-miR-380-3p 0.0031 0.0175 0.0011 hsa-miR-381-3p 0.0060 0.0051 0.0001 hsa-miR-4286 0.0005 0.8044 0.0154 hsa-miR-4463 0.0000 0.0457 0.0067 hsa-miR-4473 0.0075 0.2583 0.0034 hsa-miR-452-5p 0.0091 0.1159 0.0014 hsa-miR-454-5p 0.0005 0.6561 0.0001 hsa-miR-4644 0.0001 0.2231 0.0468 hsa-miR-4654 0.0050 0.2575 0.0002 hsa-miR-4687-5p 0.0011 0.0008 0.0000 hsa-miR-4732-5p 0.0010 0.5777 0.0097 hsa-miR-4799-5p 0.0093 0.2332 0.0094 hsa-miR-483-3p 0.0023 0.2935 0.0123 hsa-miR-487a-3p 0.0008 0.4026 0.0126 hsa-miR-487b-3p 0.0020 0.0490 0.0032 hsa-miR-496 0.0001 0.0001 0.0001 hsa-miR-497-5p 0.0010 0.0066 0.0000 hsa-miR-542-3p 0.0032 0.0330 0.0000 hsa-miR-548ap-5p 0.0010 0.2415 0.0002 hsa-miR-548av-3p 0.0018 0.2356 0.0034 hsa-miR-548j-5p 0.0010 0.2415 0.0002 hsa-miR-548o-3p 0.0047 0.4100 0.0025 hsa-miR-551b-3p 0.0028 0.0459 0.0129 hsa-miR-556-3p 0.0006 0.0503 0.0000 hsa-miR-556-5p 0.0014 0.0015 0.0000 hsa-miR-5698 0.0029 0.1257 0.0024 hsa-miR-579-5p 0.0025 0.0009 0.0015 hsa-miR-590-5p 0.0001 0.0284 0.0000 hsa-miR-598-3p 0.0000 0.0016 0.0000 hsa-miR-642a-3p 0.0000 0.2822 0.0001 hsa-miR-642b-3p 0.0001 0.2354 0.0004 hsa-miR-654-3p 0.0028 0.0599 0.0029 hsa-miR-656-3p 0.0041 1.0000 0.0213 hsa-miR-660-5p 0.0008 0.0044 0.0000 hsa-miR-671-5p 0.0000 0.0039 0.0000 hsa-miR-6885-5p 0.0012 0.0072 0.0000 hsa-miR-744-3p 0.0049 0.5697 0.0128 hsa-miR-8485 0.0000 0.0032 0.0000 hsa-miR-939-5p 0.0005 0.0579 0.0001 hsa-miR-98-3p 0.0009 0.4773 0.0005 hsa-miR-99a-3p 0.0031 0.0229 0.0097 Mature-1251 0.0001 0.2253 0.0002 Mature-1259 0.0002 0.0000 0.0000 Mature-1322 0.0000 0.0000 0.0000 Mature-1331 0.0038 0.9925 0.0073 Mature-168 0.0035 0.0064 0.0000 Mature-169 0.0035 0.0064 0.0000 Mature-176 0.0035 0.0064 0.0000 Mature-181 0.0035 0.0064 0.0000 Mature-240 0.0002 0.0001 0.0030 Mature-326 0.0000 0.1849 0.0166 Mature-509 0.0001 0.1455 0.0000 Mature-565 0.0000 0.0141 0.0004 Mature-567 0.0078 0.1856 0.0338 Mature-626 0.0003 0.0003 0.0000 Mature-639 0.0000 0.0000 0.0000 Mature-655 0.0000 0.0000 0.0000 Mature-893 0.0017 0.5675 0.0039 hsa-miR-1255a 0.0065 0.7336 0.1826 hsa-miR-134-3p 0.0074 0.1763 0.0636 hsa-miR-214-3p 0.0069 0.3638 0.2004 hsa-miR-2392 0.0000 0.3882 0.1447 hsa-miR-4271 0.0000 0.1985 0.1050 hsa-miR-431-3p 0.0059 0.5724 0.1254 hsa-miR-99a-5p 0.0086 1.0000 0.1705 Mature-1363 0.0013 0.8297 0.0671 hsa-let-7g-3p 0.0002 0.0002 0.0000 hsa-miR-106b-5p 0.0014 0.0004 0.0000 hsa-miR-11400 0.0003 0.0000 0.0000 hsa-miR-1306-5p 0.0031 0.0000 0.0000 hsa-miR-141-3p 0.0026 0.0002 0.0000 hsa-miR-1537-5p 0.0009 0.0002 0.0000 hsa-miR-17-3p 0.0000 0.0000 0.0000 hsa-miR-188-5p 0.0002 0.0005 0.0000 hsa-miR-197-3p 0.0000 0.0000 0.0000 hsa-miR-199a-5p 0.0000 0.0002 0.0000 hsa-miR-20a-3p 0.0001 0.0004 0.0000 hsa-miR-20a-5p 0.0022 0.0003 0.0018 hsa-miR-29a-3p 0.0000 0.0001 0.0000 hsa-miR-29b-3p 0.0000 0.0001 0.0000 hsa-miR-29c-3p 0.0000 0.0000 0.0000 hsa-miR-32-5p 0.0000 0.0000 0.0000 hsa-miR-33a-5p 0.0000 0.0000 0.0000 hsa-miR-33b-5p 0.0000 0.0000 0.0000 hsa-miR-3613-5p 0.0000 0.0000 0.0000 hsa-miR-363-3p 0.0036 0.0000 0.0001 hsa-miR-374a-3p 0.0000 0.0000 0.0000 hsa-miR-4687-5p 0.0011 0.0008 0.0000 hsa-miR-496 0.0001 0.0001 0.0001 hsa-miR-579-5p 0.0025 0.0009 0.0015 Mature-1259 0.0002 0.0000 0.0000 Mature-1322 0.0000 0.0000 0.0000 Mature-240 0.0002 0.0001 0.0030 Mature-626 0.0003 0.0003 0.0000 Mature-639 0.0000 0.0000 0.0000 Mature-655 0.0000 0.0000 0.0000

[0111] Additional analyses were performed on Group 2 and Group 7, Group 5 and Group 7, and Group 3 and Group 5 using the acquired biomarkers. The heatmaps of two-way hierarchical clustering using Z-scores are shown in Figures 4 to 6. Additionally, the Volcano plots for comparisons between groups are shown in Figures 7 to 9.

[0113] The present invention has been described above with reference to its preferred embodiments. Those skilled in the art will understand that the present invention may be embodied in modified forms without departing from the essential characteristics of the invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the invention is defined by the claims, not by the foregoing description, and all variations within the scope of the claims should be interpreted as being included in the invention.

Claims

Claim 1 A composition for the early diagnosis of Alzheimer's disease comprising a preparation for measuring the expression levels of miRNAs hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, Mature-1322, Mature-639, and Mature-655, wherein Mature-1322 is represented by SEQ ID NO. 1, Mature-639 is represented by SEQ ID NO. 2, and Mature-655 A composition represented by SEQ ID NO.

3. Claim 2 The composition for the early diagnosis of Alzheimer's disease according to claim 1, wherein the composition further comprises a preparation for measuring the expression level of one or more miRNAs selected from the group consisting of hsa-let-7g-3p, hsa-miR-188-5p, Mature-1259, Mature-240, hsa-miR-11400, Mature-626, and hsa-miR-1537-5p, wherein Mature-1259 is represented by SEQ ID NO. 4, Mature-240 is represented by SEQ ID NO. 5, and Mature-626 is represented by SEQ ID NO.

6. Claim 3 A composition for the early diagnosis of Alzheimer's disease according to claim 2, wherein the composition further comprises a preparation for measuring the expression level of one or more miRNAs selected from the group consisting of hsa-miR-4687-5p, hsa-miR-106b-5p, hsa-miR-20a-5p, hsa-miR-579-5p, hsa-miR-141-3p, hsa-miR-1306-5p and hsa-miR-363-3p. Claim 4 HSA-LET-7A-3P, HSA-LET-7I-3P, HSA-MIR-101-3P, HSA-MIR-101-5P, HSA-MIR-10399-5P, hsa-miR-103a-1-5p, hsa-miR-1228-5p, hsa-miR-126-5p, hsa-miR-1271-5p, hsa-miR-1287-5p, hsa-miR-1307-5p, hsa-miR-136-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-146b-3p, hsa-miR-148a-3p, hsa-miR-148b-3p, hsa-miR-148b-5p, hsa-miR-150-3p, hsa-miR-154-5p, hsa-miR-15a-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1-3p, hsa-miR-16-5p, hsa-miR-181a-3p, hsa-miR-181c-5p, hsa-miR-1908-3p, hsa-miR-199b-5p, hsa-miR-19b-1-5p, hsa-miR-2110 hsa-miR-21-3p, hsa-miR-22-5p, hsa-miR-2355-3p, hsa-miR-2355-5p, hsa-miR-26b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29c-5p, hsa-miR-301b-5p, hsa-miR-30e-3p, hsa-miR-32-3p, hsa-miR-337-3p, hsa-miR-337-5p, hsa-miR-340-3p, hsa-miR-340-5p, hsa-miR-369-3p, hsa-miR-369-5p, hsa-miR-370-5p hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-376c-3p, hsa-miR-378a-5p, hsa-miR-380-3p, hsa-miR-381-3p, hsa-miR-4286, hsa-miR-4463, hsa-miR-4473, hsa-miR-452-5p,hsa-miR-454-5p, hsa-miR-4644, hsa-miR-4654, hsa-miR-4732-5p, hsa-miR-4799-5p, hsa-miR-483-3p, hsa-miR-487a-3p, hsa-miR-487b-3p, hsa-miR-497-5p, hsa-miR-542-3p, hsa-miR-548ap-5p, hsa-miR-548av-3p, hsa-miR-548j-5p, hsa-miR-548o-3p, hsa-miR-551b-3p, hsa-miR-556-3p, hsa-miR-556-5p, hsa-miR-5698, hsa-miR-590-5p, hsa-miR-598-3p, hsa-miR-642a-3p, hsa-miR-642b-3p, hsa-miR-654-3p, hsa-miR-656-3p, hsa-miR-660-5p, hsa-miR-671-5p, hsa-miR-6885-5p, hsa-miR-744-3p, hsa-miR-8485, hsa-miR-939-5p, hsa-miR-98-3p, hsa-miR-99a-3p, Mature-1251, Mature-1331, Mature-168, Mature-169, Mature-176, Mature-181, Mature-326, Mature-509, Mature-565, Mature-567, and A composition for the early diagnosis of Alzheimer's disease further comprising a preparation for measuring the expression level of one or more miRNAs selected from the group consisting of Mature-893, wherein Mature-1251 is represented by SEQ ID NO. 7, Mature-1331 is represented by SEQ ID NO. 8, Mature-168 is represented by SEQ ID NO. 9, Mature-169 is represented by SEQ ID NO. 10, Mature-176 is represented by SEQ ID NO. 11, Mature-181 is represented by SEQ ID NO. 12, Mature-326 is represented by SEQ ID NO. 13, and Mature-509 is represented by SEQ ID NO. 14.A composition wherein the Mature-565 is represented by SEQ ID NO. 15, the Mature-567 is represented by SEQ ID NO. 16, and the Mature-893 is represented by SEQ ID NO.

17. Claim 5 The composition for the early diagnosis of Alzheimer's disease according to claim 1, wherein the composition further comprises a preparation for measuring the expression level of one or more miRNAs selected from the group consisting of hsa-miR-1255a, hsa-miR-134-3p, hsa-miR-214-3p, hsa-miR-2392, hsa-miR-4271, hsa-miR-431-3p, hsa-miR-99a-5p, and Mature-1363, wherein Mature-1363 is represented by SEQ ID NO.

18. Claim 6 In claim 1, the composition comprises hsa-miR-142-3p, hsa-miR-184, hsa-miR-21-5p, hsa-miR-3200-3p, hsa-miR-328-3p, hsa-miR-376a-5p, hsa-miR-424-5p, hsa-miR-4433b-5p, hsa-miR-450a-5p, hsa-miR-5100, hsa-miR-548am-5p, hsa-miR-548au-5p, hsa-miR-548c-5p, hsa-miR-548o-5p, hsa-miR-590-3p, hsa-miR-6511a-3p, hsa-miR-6793-3p, A composition for the early diagnosis of Alzheimer's disease further comprising a preparation for measuring the expression level of one or more miRNAs selected from the group consisting of hsa-miR-6858-3p, hsa-miR-766-3p, hsa-miR-8072, Mature-600, Mature-65, and Mature-759, wherein the Mature-600 is represented by SEQ ID NO. 19, the Mature-65 is represented by SEQ ID NO. 20, and the Mature-759 is represented by SEQ ID NO.

21. Claim 7 HSA-LET-7F-1-3P, HSA-LET-7F-2-3P, HSA-LET-7G-5P, HSA-LET-7I-5P, HSA-MIR-103A-3P, hsa-miR-106a-5p, hsa-miR-106b-3p, hsa-miR-107, hsa-miR-10a-5p, hsa-miR-12136, hsa-miR-1226-3p, hsa-miR-1229-3p, hsa-miR-1260b, hsa-miR-126-3p, hsa-miR-127-5p, hsa-miR-1277-3p, hsa-miR-1277-5p, hsa-miR-128-3p, hsa-miR-1292-5p, hsa-miR-130a-3p, hsa-miR-133b, hsa-miR-1343-3p, hsa-miR-139-3p, hsa-miR-140-3p, hsa-miR-142-5p, hsa-miR-143-5p, hsa-miR-144-5p, hsa-miR-145-3p, hsa-miR-145-5p, hsa-miR-146a-3p, hsa-miR-154-3p, hsa-miR-155-5p, hsa-miR-15b-3p hsa-miR-181a-2-3p, hsa-miR-181a-5p, hsa-miR-18a-5p, hsa-miR-1908-5p, hsa-miR-1914-3p, hsa-miR-192-3p, hsa-miR-192-5p, hsa-miR-194-5p, hsa-miR-195-5p, hsa-miR-199a-3p, hsa-miR-199b-3p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-200a-3p, hsa-miR-210-3p, hsa-miR-219a-5p, hsa-miR-221-5p, hsa-miR-22-3p hsa-miR-224-5p, hsa-miR-23a-5p, hsa-miR-23b-3p, hsa-miR-23c, hsa-miR-24-1-5p, hsa-miR-24-2-5p, hsa-miR-24-3p, hsa-miR-26a-1-3p, hsa-miR-26a-2-3p,hsa-miR-29b-1-5p, hsa-miR-301a-3p, hsa-miR-301b-3p, hsa-miR-30d-3p, hsa-miR-30e-5p, hsa-miR-3136-5p, hsa-miR-3138, hsa-miR-3143, hsa-miR-3154, hsa-miR-3173-5p, hsa-miR-3179, hsa-miR-320a-3p, hsa-miR-320b, hsa-miR-320c, hsa-miR-320d, hsa-miR-320e, hsa-miR-330-3p, hsa-miR-331-3p, hsa-miR-338-3p hsa-miR-33a-3p, hsa-miR-370-3p, hsa-miR-374b-3p, hsa-miR-374c-5p, hsa-miR-376a-2-5p, hsa-miR-376a-3p, hsa-miR-376b-3p, hsa-miR-377-3p, hsa-miR-382-3p, hsa-miR-411-3p, hsa-miR-411-5p, hsa-miR-423-5p, hsa-miR-425-3p, hsa-miR-429, hsa-miR-4306, hsa-miR-432-5p, hsa-miR-4446-3p, hsa-miR-4485-5p hsa-miR-4498, hsa-miR-451a, hsa-miR-4524a-3p, hsa-miR-4533, hsa-miR-4659b-3p, hsa-miR-4662a-5p, hsa-miR-4665-5p, hsa-miR-4685-3p, hsa-miR-4748, hsa-miR-484, hsa-miR-486-3p, hsa-miR-493-5p, hsa-miR-495-3p, hsa-miR-5010-5p, hsa-miR-501-5p, hsa-miR-502-3p, hsa-miR-532-5p, hsa-miR-539-3p, hsa-miR-545-3p hsa-miR-548aa, hsa-miR-548ad-5p, hsa-miR-548ae-5p, hsa-miR-548ap-3p, hsa-miR-548ay-5p, hsa-miR-548d-3p,hsa-miR-548d-5p, hsa-miR-548f-3p, hsa-miR-548h-3p, hsa-miR-548t-3p, hsa-miR-548z, hsa-miR-576-5p, hsa-miR-598-5p, hsa-miR-616-3p, hsa-miR-625-5p, hsa-miR-628-5p, hsa-miR-641, hsa-miR-6511b-3p, hsa-miR-6515-5p, hsa-miR-6516-5p, hsa-miR-654-5p, hsa-miR-6735-5p, hsa-miR-6754-5p, hsa-miR-6763-5p, hsa-miR-6767-5p, hsa-miR-6779-5p, hsa-miR-6783-5p, hsa-miR-6802-5p, hsa-miR-6809-5p, hsa-miR-6810-3p, hsa-miR-6837-5p, hsa-miR-6873-5p, hsa-miR-6875-5p, hsa-miR-6876-5p, hsa-miR-6877-5p, hsa-miR-7109-3p, hsa-miR-7-1-3p, hsa-miR-7151-3p, hsa-miR-760, hsa-miR-874-3p, hsa-miR-877-3p, hsa-miR-92a-1-5p, A composition for the early diagnosis of Alzheimer's disease further comprising a preparation for measuring the expression level of one or more miRNAs selected from the group consisting of hsa-miR-92b-3p, hsa-miR-92b-5p, hsa-miR-99b-5p, Mature-1121, Mature-1390, Mature-154, Mature-173, Mature-184, Mature-191, Mature-208, Mature-289, Mature-298, Mature-322, Mature-330, Mature-392, Mature-394, Mature-452, Mature-611, Mature-627, Mature-667, Mature-808, Mature-847, and Mature-896, wherein Mature-1121 is represented by SEQ ID NO. 22.The above Mature-1390 is indicated by SEQ ID NO. 23, the above Mature-154 is indicated by SEQ ID NO. 24, the above Mature-173 is indicated by SEQ ID NO. 25, the above Mature-184 is indicated by SEQ ID NO. 26, the above Mature-191 is indicated by SEQ ID NO. 27, the above Mature-208 is indicated by SEQ ID NO. 28, the above Mature-289 is indicated by SEQ ID NO. 29, the above Mature-298 is indicated by SEQ ID NO. 30, the above Mature-322 is indicated by SEQ ID NO. 31, the above Mature-330 is indicated by SEQ ID NO. 32, the above Mature-392 is indicated by SEQ ID NO. 33, the above Mature-394 is indicated by SEQ ID NO. 34, the above Mature-452 is indicated by SEQ ID NO. 35, the above Mature-611 is indicated by SEQ ID NO. 36, the above Mature-627 is indicated by SEQ ID NO. 37, and the above A composition wherein Mature-667 is represented by SEQ ID NO. 38, the Mature-808 is represented by SEQ ID NO. 39, the Mature-847 is represented by SEQ ID NO. 40, and the Mature-896 is represented by SEQ ID NO.

41. Claim 8 The composition for the early diagnosis of Alzheimer's disease according to claim 1, wherein the composition further comprises a preparation for measuring the expression level of one or more miRNAs selected from the group consisting of hsa-miR-3620-3p, hsa-miR-4701-5p, hsa-miR-490-3p, and hsa-miR-95-5p. Claim 9 A kit for early diagnosis of Alzheimer's disease comprising the composition of any one of claims 1 to 8. Claim 10 In claim 9, the kit further comprises a reagent for nucleic acid amplification. Claim 11 a) a step of preparing a biological sample of an isolated subject; b) a step of measuring the expression levels of miRNAs hsa-miR-33b-5p, hsa-miR-33a-5p, hsa-miR-32-5p, hsa-miR-29a-3p, hsa-miR-29c-3p, hsa-miR-17-3p, hsa-miR-29b-3p, hsa-miR-3613-5p, hsa-miR-199a-5p, hsa-miR-374a-3p, hsa-miR-197-3p, hsa-miR-496, hsa-miR-20a-3p, Mature-1322, Mature-639, and Mature-655 in the prepared biological sample; and c) a step of comparing the measured miRNA expression level with a control group; a method for providing information for early diagnosis or detailed diagnosis of Alzheimer's disease, wherein the Mature-1322 is represented by SEQ ID NO. 1, the Mature-639 is represented by SEQ ID NO. 2, and the Mature-655 is represented by SEQ ID NO.

3. Claim 12 A method according to claim 11, wherein the biological sample in step a) is one or more selected from the group consisting of blood, plasma, serum, lymph fluid, saliva, urine, and tissue. Claim 13 A method according to claim 11, wherein the miRNA expression level of step b) is measured by one or more methods selected from the group consisting of polymerase chain reaction (PCR), reverse transcription polymerase chain reaction (RT-PCR), competitive RT-PCR, real-time RT-PCR, nuclease protection assay, in situ hybridization, microarray, and Northern blot. Claim 14 In claim 11, the step b) comprises, in the biological sample, miRNAs hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-1306-5p, hsa-miR-141-3p, hsa-miR-1537-5p, hsa-miR-188-5p, hsa-miR-20a-5p, hsa-miR-363-3p, hsa-miR-4687-5p, hsa-miR-579-5p, Mature-1259, Mature-240, Mature-626, hsa-miR-142-3p, hsa-miR-184, hsa-miR-21-5p, hsa-miR-3200-3p, hsa-miR-328-3p, hsa-miR-376a-5p, hsa-miR-424-5p, hsa-miR-4433b-5p, hsa-miR-450a-5p, hsa-miR-5100, hsa-miR-548am-5p, hsa-miR-548au-5p, hsa-miR-548c-5p, hsa-miR-548o-5p, hsa-miR-590-3p, hsa-miR-6511a-3p, hsa-miR-6793-3p, hsa-miR-6858-3p, hsa-miR-766-3p, hsa-miR-8072, Mature-600, Mature-65, Mature-759, hsa-miR-3620-3p, hsa-miR-4701-5p, hsa-miR-490-3p A method for further measuring the expression level of one or more selected from the group consisting of and hsa-miR-95-5p, wherein Mature-1259 is represented by SEQ ID NO. 4, Mature-240 is represented by SEQ ID NO. 5, Mature-626 is represented by SEQ ID NO. 6, Mature-600 is represented by SEQ ID NO. 19, Mature-65 is represented by SEQ ID NO. 20, and Mature-759 is represented by SEQ ID NO.

21. Claim 15 b) 단계는 상기 생물학적 시료에서 miRNA인 hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-1306-5p, hsa-miR-141-3p, hsa-miR-1537-5p, hsa-miR-188-5p, hsa-miR-20a-5p, hsa-miR-363-3p, hsa-miR-4687-5p, hsa-miR-579-5p, Mature-1259, Mature-240, Mature-626, hsa-let-7a-3p, hsa-let-7i-3p, hsa-miR-101-3p, hsa-miR-101-5p, hsa-miR-10399-5p, hsa-miR-103a-1-5p, hsa-miR-1228-5p, hsa-miR-126-5p, hsa-miR-1271-5p, hsa-miR-1287-5p, hsa-miR-1307-5p, hsa-miR-136-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-146b-3p, hsa-miR-148a-3p, hsa-miR-148b-3p hsa-miR-148b-5p, hsa-miR-150-3p, hsa-miR-154-5p, hsa-miR-15a-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1-3p, hsa-miR-16-5p, hsa-miR-181a-3p, hsa-miR-181c-5p, hsa-miR-1908-3p, hsa-miR-199b-5p, hsa-miR-19b-1-5p, hsa-miR-2110, hsa-miR-21-3p, hsa-miR-22-5p, hsa-miR-2355-3p, hsa-miR-2355-5p hsa-miR-26b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29c-5p, hsa-miR-301b-5p, hsa-miR-30e-3p, hsa-miR-32-3p, hsa-miR-337-3p, hsa-miR-337-5p, hsa-miR-340-3p,hsa-miR-340-5p, hsa-miR-369-3p, hsa-miR-369-5p, hsa-miR-370-5p, hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-376c-3p, hsa-miR-378a-5p, hsa-miR-380-3p, hsa-miR-381-3p, hsa-miR-4286, hsa-miR-4463, hsa-miR-4473, hsa-miR-452-5p, hsa-miR-454-5p, hsa-miR-4644, hsa-miR-4654, hsa-miR-4732-5p, hsa-miR-4799-5p, hsa-miR-483-3p, hsa-miR-487a-3p, hsa-miR-487b-3p, hsa-miR-497-5p, hsa-miR-542-3p, hsa-miR-548ap-5p, hsa-miR-548av-3p, hsa-miR-548j-5p, hsa-miR-548o-3p, hsa-miR-551b-3p, hsa-miR-556-3p, hsa-miR-556-5p, hsa-miR-5698, hsa-miR-590-5p, hsa-miR-598-3p, hsa-miR-642a-3p, hsa-miR-642b-3p, hsa-miR-654-3p, hsa-miR-656-3p, hsa-miR-660-5p, hsa-miR-671-5p, hsa-miR-6885-5p, hsa-miR-744-3p, hsa-miR-8485, hsa-miR-939-5p, hsa-miR-98-3p, hsa-miR-99a-3p, Mature-1251, Mature-1331, Mature-168, Mature-169, Mature-176, Mature-181, Mature-326, Mature-509, Mature-565, Mature-567, Mature-893, hsa-miR-142-3p, hsa-miR-184, hsa-miR-21-5p, hsa-miR-3200-3p, hsa-miR-328-3p, hsa-miR-376a-5p, hsa-miR-424-5p, hsa-miR-4433b-5p,hsa-miR-450a-5p, hsa-miR-5100, hsa-miR-548am-5p, hsa-miR-548au-5p, hsa-miR-548c-5p, hsa-miR-548o-5p, hsa-miR-590-3p, hsa-miR-6511a-3p, hsa-miR-6793-3p, hsa-miR-6858-3p, hsa-miR-766-3p, hsa-miR-8072, Mature-600, Mature-65, Mature-759, hsa-let-7f-1-3p, hsa-let-7f-2-3p, hsa-let-7g-5p, hsa-let-7i-5p, hsa-miR-103a-3p, hsa-miR-106a-5p, hsa-miR-106b-3p, hsa-miR-107, hsa-miR-10a-5p, hsa-miR-12136, hsa-miR-1226-3p, hsa-miR-1229-3p, hsa-miR-1260b, hsa-miR-126-3p, hsa-miR-127-5p, hsa-miR-1277-3p, hsa-miR-1277-5p, hsa-miR-128-3p, hsa-miR-1292-5p, hsa-miR-130a-3p, hsa-miR-133b, hsa-miR-1343-3p, hsa-miR-139-3p hsa-miR-140-3p, hsa-miR-142-5p, hsa-miR-143-5p, hsa-miR-144-5p, hsa-miR-145-3p, hsa-miR-145-5p, hsa-miR-146a-3p, hsa-miR-154-3p, hsa-miR-155-5p, hsa-miR-15b-3p, hsa-miR-181a-2-3p, hsa-miR-181a-5p, hsa-miR-18a-5p, hsa-miR-1908-5p, hsa-miR-1914-3p, hsa-miR-192-3p, hsa-miR-192-5p, hsa-miR-194-5p hsa-miR-195-5p, hsa-miR-199a-3p, hsa-miR-199b-3p, hsa-miR-19a-3p, hsa-miR-19b-3p, hsa-miR-200a-3p,hsa-miR-210-3p, hsa-miR-219a-5p, hsa-miR-221-5p, hsa-miR-22-3p, hsa-miR-224-5p, hsa-miR-23a-5p, hsa-miR-23b-3p, hsa-miR-23c, hsa-miR-24-1-5p, hsa-miR-24-2-5p, hsa-miR-24-3p, hsa-miR-26a-1-3p, hsa-miR-26a-2-3p, hsa-miR-29b-1-5p, hsa-miR-301a-3p, hsa-miR-301b-3p, hsa-miR-30d-3p, hsa-miR-30e-5p hsa-miR-3136-5p, hsa-miR-3138, hsa-miR-3143, hsa-miR-3154, hsa-miR-3173-5p, hsa-miR-3179, hsa-miR-320a-3p, hsa-miR-320b, hsa-miR-320c, hsa-miR-320d, hsa-miR-320e, hsa-miR-330-3p, hsa-miR-331-3p, hsa-miR-338-3p, hsa-miR-33a-3p, hsa-miR-370-3p, hsa-miR-374b-3p, hsa-miR-374c-5p, hsa-miR-376a-2-5p, hsa-miR-376a-3p, hsa-miR-376b-3p, hsa-miR-377-3p, hsa-miR-382-3p, hsa-miR-411-3p, hsa-miR-411-5p, hsa-miR-423-5p, hsa-miR-425-3p, hsa-miR-429, hsa-miR-4306, hsa-miR-432-5p, hsa-miR-4446-3p, hsa-miR-4485-5p, hsa-miR-4498, hsa-miR-451a, hsa-miR-4524a-3p, hsa-miR-4533, hsa-miR-4659b-3p, hsa-miR-4662a-5p hsa-miR-4665-5p, hsa-miR-4685-3p, hsa-miR-4748, hsa-miR-484, hsa-miR-486-3p, hsa-miR-493-5p,hsa-miR-495-3p, hsa-miR-5010-5p, hsa-miR-501-5p, hsa-miR-502-3p, hsa-miR-532-5p, hsa-miR-539-3p, hsa-miR-545-3p, hsa-miR-548aa, hsa-miR-548ad-5p, hsa-miR-548ae-5p, hsa-miR-548ap-3p, hsa-miR-548ay-5p, hsa-miR-548d-3p, hsa-miR-548d-5p, hsa-miR-548f-3p, hsa-miR-548h-3p, hsa-miR-548t-3p, hsa-miR-548z, hsa-miR-576-5p, hsa-miR-598-5p, hsa-miR-616-3p, hsa-miR-625-5p, hsa-miR-628-5p, hsa-miR-641, hsa-miR-6511b-3p, hsa-miR-6515-5p, hsa-miR-6516-5p, hsa-miR-654-5p, hsa-miR-6735-5p, hsa-miR-6754-5p, hsa-miR-6763-5p, hsa-miR-6767-5p, hsa-miR-6779-5p, hsa-miR-6783-5p, hsa-miR-6802-5p, hsa-miR-6809-5p, hsa-miR-6810-3p, hsa-miR-6837-5p, hsa-miR-6873-5p, hsa-miR-6875-5p, hsa-miR-6876-5p, hsa-miR-6877-5p, hsa-miR-7109-3p, hsa-miR-7-1-3p, hsa-miR-7151-3p, hsa-miR-760, hsa-miR-874-3p, hsa-miR-877-3p, hsa-miR-92a-1-5p, hsa-miR-92b-3p, hsa-miR-92b-5p, hsa-miR-99b-5p, Mature-1121, Mature-1390, Mature-154, Mature-173, Mature-184, Mature-191, Mature-208, Mature-289, Mature-298, Mature-322, Mature-330,A method comprising further measuring the expression level of one or more selected from the group consisting of Mature-392, Mature-394, Mature-452, Mature-611, Mature-627, Mature-667, Mature-808, Mature-847, and Mature-896, wherein Mature-1259 is represented by SEQ ID NO. 4, Mature-240 is represented by SEQ ID NO. 5, Mature-626 is represented by SEQ ID NO. 6, Mature-1251 is represented by SEQ ID NO. 7, Mature-1331 is represented by SEQ ID NO. 8, Mature-168 is represented by SEQ ID NO. 9, Mature-169 is represented by SEQ ID NO. 10, Mature-176 is represented by SEQ ID NO. 11, Mature-181 is represented by SEQ ID NO. 12, Mature-326 is represented by SEQ ID NO. 13, Mature-509 is represented by SEQ ID NO. 14, and Mature-565 is indicated by sequence number 15, the above Mature-567 is indicated by sequence number 16, the above Mature-893 is indicated by sequence number 17, the above Mature-600 is indicated by sequence number 19, the above Mature-65 is indicated by sequence number 20, the above Mature-759 is indicated by sequence number 21, the above Mature-1121 is indicated by sequence number 22, the above Mature-1390 is indicated by sequence number 23, the above Mature-154 is indicated by sequence number 24, the above Mature-173 is indicated by sequence number 25, the above Mature-184 is indicated by sequence number 26, the above Mature-191 is indicated by sequence number 27, and the above Mature-208 is indicated by sequence number 28.A method wherein the above Mature-289 is represented by SEQ ID NO. 29, the above Mature-298 is represented by SEQ ID NO. 30, the above Mature-322 is represented by SEQ ID NO. 31, the above Mature-330 is represented by SEQ ID NO. 32, the above Mature-392 is represented by SEQ ID NO. 33, the above Mature-394 is represented by SEQ ID NO. 34, the above Mature-452 is represented by SEQ ID NO. 35, the above Mature-611 is represented by SEQ ID NO. 36, the above Mature-627 is represented by SEQ ID NO. 37, the above Mature-667 is represented by SEQ ID NO. 38, the above Mature-808 is represented by SEQ ID NO. 39, the above Mature-847 is represented by SEQ ID NO. 40, and the above Mature-896 is represented by SEQ ID NO.

41. Claim 16 b) 단계는 상기 생물학적 시료에서 miRNA인 hsa-miR-106b-5p, hsa-miR-11400, hsa-miR-1306-5p, hsa-miR-141-3p, hsa-miR-1537-5p, hsa-miR-188-5p, hsa-miR-20a-5p, hsa-miR-363-3p, hsa-miR-4687-5p, hsa-miR-579-5p, Mature-1259, Mature-240, Mature-626, hsa-let-7a-3p, hsa-let-7i-3p, hsa-miR-101-3p, hsa-miR-101-5p, hsa-miR-10399-5p, hsa-miR-103a-1-5p, hsa-miR-1228-5p, hsa-miR-126-5p, hsa-miR-1271-5p, hsa-miR-1287-5p, hsa-miR-1307-5p, hsa-miR-136-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-144-3p, hsa-miR-146b-3p, hsa-miR-148a-3p, hsa-miR-148b-3p hsa-miR-148b-5p, hsa-miR-150-3p, hsa-miR-154-5p, hsa-miR-15a-3p, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-16-1-3p, hsa-miR-16-5p, hsa-miR-181a-3p, hsa-miR-181c-5p, hsa-miR-1908-3p, hsa-miR-199b-5p, hsa-miR-19b-1-5p, hsa-miR-2110, hsa-miR-21-3p, hsa-miR-22-5p, hsa-miR-2355-3p, hsa-miR-2355-5p hsa-miR-26b-3p, hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-29c-5p, hsa-miR-301b-5p, hsa-miR-30e-3p, hsa-miR-32-3p, hsa-miR-337-3p, hsa-miR-337-5p, hsa-miR-340-3p,hsa-miR-340-5p, hsa-miR-369-3p, hsa-miR-369-5p, hsa-miR-370-5p, hsa-miR-374a-5p, hsa-miR-374b-5p, hsa-miR-376c-3p, hsa-miR-378a-5p, hsa-miR-380-3p, hsa-miR-381-3p, hsa-miR-4286, hsa-miR-4463, hsa-miR-4473, hsa-miR-452-5p, hsa-miR-454-5p, hsa-miR-4644, hsa-miR-4654, hsa-miR-4732-5p, hsa-miR-4799-5p, hsa-miR-483-3p, hsa-miR-487a-3p, hsa-miR-487b-3p, hsa-miR-497-5p, hsa-miR-542-3p, hsa-miR-548ap-5p, hsa-miR-548av-3p, hsa-miR-548j-5p, hsa-miR-548o-3p, hsa-miR-551b-3p, hsa-miR-556-3p, hsa-miR-556-5p, hsa-miR-5698, hsa-miR-590-5p, hsa-miR-598-3p, hsa-miR-642a-3p, hsa-miR-642b-3p, hsa-miR-654-3p, hsa-miR-656-3p, hsa-miR-660-5p, hsa-miR-671-5p, hsa-miR-6885-5p, hsa-miR-744-3p, hsa-miR-8485, hsa-miR-939-5p, hsa-miR-98-3p, hsa-miR-99a-3p, Mature-1251, Mature-1331, Mature-168, Mature-169, Mature-176, Mature-181, Mature-326, Mature-509, Mature-565, Mature-567, Mature-893, hsa-miR-1255a, hsa-miR-134-3p, hsa-miR-214-3p, hsa-miR-2392, hsa-miR-4271, hsa-miR-431-3p,A method comprising further measuring the expression level of one or more selected from the group consisting of hsa-miR-99a-5p and Mature-1363, wherein Mature-1259 is represented by SEQ ID NO. 4, Mature-240 is represented by SEQ ID NO. 5, Mature-626 is represented by SEQ ID NO. 6, Mature-1251 is represented by SEQ ID NO. 7, Mature-1331 is represented by SEQ ID NO. 8, Mature-168 is represented by SEQ ID NO. 9, Mature-169 is represented by SEQ ID NO. 10, Mature-176 is represented by SEQ ID NO. 11, Mature-181 is represented by SEQ ID NO. 12, Mature-326 is represented by SEQ ID NO. 13, Mature-509 is represented by SEQ ID NO. 14, Mature-565 is represented by SEQ ID NO. 15, Mature-567 is represented by SEQ ID NO. 16, and A method in which Mature-893 is represented by sequence number 17, and the above Mature-1363 is represented by sequence number 18.

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