Patent Publication Number: US-2023160010-A1

Title: Method for aiding detection of alzheimer&#39; s disease

Description:
TECHNICAL FIELD 
     The present invention relates to a method of assisting the detection of Alzheimer&#39;s disease. 
     BACKGROUND ART 
     Alzheimer&#39;s disease is the most common type of dementia, which accounts for more than half of all dementia cases, and the number of patients with this disease is expected to increase more in future aging societies. In current medicine, drugs and treatments to slow down the progression of Alzheimer&#39;s disease, a progressive disease, are available, though it is impossible to fully cure or prevent the progression of the disease. Thus, it is desirable to detect Alzheimer&#39;s disease as early as possible. Although Alzheimer&#39;s disease is currently diagnosed by means of medical interview, brain MRI scanning, and the like, it is not an easy task to detect early Alzheimer&#39;s disease. 
     Methods in which the abundance of microRNA (hereinafter referred to as “miRNA”) in blood is used as an index to detect Alzheimer&#39;s disease at an early stage have been proposed (Patent Documents 1 to 4, Non-Patent Documents 1 to 3). 
     PRIOR ART DOCUMENTS 
     Patent Documents 
     
         
         Patent Document 1: JP 2014-132863 A 
         Patent Document 2: JP 2014-520529 T 
         Patent Document 3: EP 2733219 A1 
         Patent Document 4: WO 2016/148073 
       
    
     Non-Patent Documents 
     
         
         Non-Patent Document 1: Pavan Kumar et al., PLOS ONE, July 2013, Volume 8, Issue 7, e69807, pp. 1-10. 
         Non-Patent Document 2: Petra Leindinger et al., Genome Biology 2013, 14: R78. 
         Non-Patent Document 3: Wang-Xia Wang et al., The Journal of Neuroscience. Jan. 30, 2008, 28(5): 1213-1223. 
       
    
     SUMMARY OF THE INVENTION 
     Problem to be Solved by the Invention 
     As described above, various miRNAs have been proposed as indexes for the detection of Alzheimer&#39;s disease and, needless to say, it is advantageous if Alzheimer&#39;s disease can be detected with higher accuracy. 
     Thus, an object of the present invention is to provide a method of assisting the detection of Alzheimer&#39;s disease which assists in highly accurate detection of Alzheimer&#39;s disease. 
     Means for Solving the Problem 
     As a result of intensive study, the inventors newly found miRNAs, isoform miRNAs (isomiRs), non-coding RNAs (ncRNAs), transfer RNA fragments (tRFs), LincRNAs, and MiscRNAs which increase or decrease in abundance in Alzheimer&#39;s disease, and discovered that use of these as indexes enables highly accurate detection of Alzheimer&#39;s disease, to thereby complete the present invention. 
     That is, the present invention provides the following: 
     (1) A method of assisting the detection of Alzheimer&#39;s disease, using as an index the abundance of at least one of miRNAs, isomiRs, precursor miRNAs. ncRNAs, transfer RNA fragments, LincRNAs, or MiscRNAs contained in a test sample isolated from a living body, whose nucleotide sequence is represented by any one of SEQ ID NOs: 1, 3, 12, 2, 4 to 11, and 13 to 85, wherein a higher abundance of at least one of the miRNAs, isomiRs, precursor miRNAs, ncRNAs, transfer RNA fragments, LincRNAs, or MiscRNAs whose nucleotide sequence is represented by any one of SEQ ID NOs: 1 to 22 and 66 to 71 than that of healthy subjects or a lower abundance of at least one of the miRNAs, isomiRs, precursor miRNAs, ncRNAs, transfer RNA fragments, LincRNAs, or MiscRNAs whose nucleotide sequence is represented by any one of SEQ ID NOs: 23 to 65 and 72 to 85 than that of healthy subjects indicates a higher likelihood of having Alzheimer&#39;s disease.
 
(2) The method according to (1), wherein the abundance of at least one of miRNAs, isomiRs, precursor miRNAs, ncRNAs, transfer RNA fragments, LincRNAs, or MiscRNAs whose nucleotide sequence is represented by any one of SEQ ID NOs: 1, 3, 12, 2, 4 to 11, and 13 to 65 is used as an index.
 
(3) The method according to (1), wherein the abundance of at least one of miRNAs, isomiRs, precursor miRNAs, transfer RNA fragments, LincRNAs, or MiscRNAs whose nucleotide sequence is represented by any one of SEQ ID NOs: 1, 3, 12, 2, 4 to 11, 46 to 65, 84, and 85 is used as an index.
 
(4) The method according to (3), wherein the abundance of at least one of miRNAs, isomiRs, precursor miRNAs, transfer RNA fragments, or MiscRNAs whose nucleotide sequence is represented by any one of SEQ ID NOs: 1, 3, 12, 2, 4 to 11, and 46 to 65 is used as an index.
 
(5) The method according to (1), wherein the abundance of at least one of miRNAs, isomiRs, or precursor miRNAs whose nucleotide sequence is represented by any one of SEQ ID NOs: 1, 3, 12, and 11 is used as an index.
 
     Effect of the Invention 
     By the method of the present invention, Alzheimer&#39;s disease can be highly accurately and yet conveniently detected. Thus, the method of the present invention will greatly contribute to the detection of Alzheimer&#39;s disease. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     As described above, the abundance of a particular molecule selected from miRNAs, isomiRs, precursor miRNAs, ncRNAs, transfer RNA fragments, LincRNAs, or MiscRNAs (hereinafter sometimes referred to as “miRNAs or the like” for convenience) contained in a test sample isolated from a living body is used as an index in the method of the present invention. These miRNAs or the like (for example, “a miRNA or the like whose nucleotide sequence is represented by SEQ ID NO: 1” is hereinafter sometimes referred to simply as “a miRNA or the like represented by SEQ ID NO: 1” or “one represented by SEQ ID NO: 1” for convenience) themselves are known, and the nucleotide sequences thereof are as shown in Sequence Listing. The list of miRNAs or the like used in the method of the present invention is presented in Table 1. 
     
       
         
           
               
               
               
               
               
               
             
               
                   
               
               
                 SEQ 
                   
                   
                   
                 Length 
                   
               
               
                 ID 
                   
                   
                   
                 (nucleo- 
                   
               
               
                  NO: 
                 Class 
                 Archetype 
                 Type 
                 tides) 
                 Sequence 
               
               
                   
               
             
            
               
                  1 
                 miRNA 
                 mir-340 
                 Mature 3′ 
                 22 
                 uccgucucaguuacuuuauagc 
               
               
                   
               
               
                  2 
                 miRNA 
                 mir-122 
                 Mature 5′ 
                 22 
                 uggagugugacaaugguguuug 
               
               
                   
               
               
                  3 
                 isomiR 
                 mir-181b-1// 
                 Mature 5′ sub 
                 22 
                 acauucauugcugucggugggu 
               
               
                   
                   
                 mir-181b-2 
                   
                   
                   
               
               
                   
               
               
                  4 
                 isomiR 
                 mir-451a 
                 Mature 5′ super 
                 24 
                 aaaccguuaccauuacugaguuua 
               
               
                   
               
               
                  5 
                 isomiR 
                 mir-20a 
                 Mature 5′ sub 
                 22 
                 uaaagugcuuauagugcaggua 
               
               
                   
               
               
                  6 
                 miRNA 
                 mir-20a 
                 Mature 5′ 
                 23 
                 uaaagugcuuauagugcagguag 
               
               
                   
               
               
                  7 
                 isomiR 
                 mir-20a 
                 Mature 5′ sub 
                 21 
                 uaaagugcuuauagugcaggu 
               
               
                   
               
               
                  8 
                 isomiR 
                 mir-451a 
                 Mature 5′ super 
                 23 
                 aaaccguuaccauuacugaguuu 
               
               
                   
               
               
                  9 
                 MiscRNA 
                 ENST00000364600.1// 
                 Exact 
                 26 
                 ggcugguccgaugguaguggguuauc 
               
               
                   
                   
                 ...*1 
                   
                   
                   
               
               
                   
               
               
                 10 
                 miRNA 
                 mir-451a 
                 Mature 5′ 
                 22 
                 aaaccguuaccauuacugaguu 
               
               
                   
               
               
                 11 
                 miRNA 
                 mir-185 
                 Mature 5′ 
                 22 
                 uggagagaaaggcaguuccuga 
               
               
                   
               
               
                 12 
                 precursor 
                 mir-451a 
                 precursor miRNA 
                 16 
                 aaaccguuaccauuac 
               
               
                   
               
               
                 13 
                 isomiR 
                 mir-17 
                 Mature 5′ sub 
                 22 
                 caaagugcuuacagugcaggua 
               
               
                   
               
               
                 14 
                 MiscRNA 
                 ENST00000364600.1// 
                 Exact 
                 27 
                 ggcugguccgaugguaguggguuauca 
               
               
                   
                   
                 ...*1 
                   
                   
                   
               
               
                   
               
               
                 15 
                 precursor 
                 mir-16-1//mir-16-2 
                 precursor miRNA 
                 19 
                 uagcagcacguaaauauug 
               
               
                   
               
               
                 16 
                 isomiR 
                 mir-30d 
                 Mature 5′ super 
                 24 
                 uguaaacauccccgacuggaagcu 
               
               
                   
               
               
                 17 
                 isomiR 
                 mir-185 
                 Mature 5′ sub 
                 21 
                 uggagagaaaggcaguuccug 
               
               
                   
               
               
                 18 
                 isomiR 
                 mir-93 
                 Mature 5′ sub 
                 21 
                 caaagugcuguucgugcaggu 
               
               
                   
               
               
                 19 
                 isomiR 
                 mir-101-1// 
                 Mature 3′ super 
                 22 
                 uacaguacugugauaacugaag 
               
               
                   
                   
                 mir-101-2 
                   
                   
                   
               
               
                   
               
               
                 20 
                 isomiR 
                 mir-30d 
                 Mature 5′ super 
                 23 
                 uguaaacauccecgacuggaagc 
               
               
                   
               
               
                 21 
                 isomiR 
                 mir-30d 
                 Mature 5′ sub 
                 21 
                 uguaaacauccccgacuggaa 
               
               
                   
               
               
                 22 
                 isomiR 
                 mir-145 
                 Mature 5′ sub 
                 22 
                 guccaguuuucccaggaauccc 
               
               
                   
               
               
                 23 
                 precursor 
                 mir-15b 
                 precursor miRNA 
                 19 
                 cgaaucauuauuugcugcu 
               
               
                   
               
               
                 24 
                 precursor 
                 mir-24-1//mir-24-2 
                 precursor miRNA 
                 19 
                 uggcucaguucagcaggaa 
               
               
                   
               
               
                 25 
                 isomiR 
                 mir-484 
                 Mature 5′ sub 
                 21 
                 ucaggcucaguccccucccga 
               
               
                   
               
               
                 26 
                 precursor 
                 mir-191 
                 precursor miRNA 
                 20 
                 caacggaaucccaaaagcag 
               
               
                   
               
               
                 27 
                 precursor 
                 mir-221 
                 precursor miRNA 
                 20 
                 agcuacauugucugcugggu 
               
               
                   
               
               
                 28 
                 isomiR 
                 mir-29c 
                 Mature 3′ sub 
                 20 
                 uagcaccauuugaaaucggu 
               
               
                   
               
               
                 29 
                 miRNA 
                 let-7f-1//let-7f-2 
                 Mature 5′ sub 
                 21 
                 ugagguaguagauuguauagu 
               
               
                   
               
               
                 30 
                 miRNA 
                 mir-484 
                 Mature 5′ 
                 22 
                 ucaggcucaguccccucccgau 
               
               
                   
               
               
                 31 
                 miRNA 
                 mir-130a 
                 Mature 3′ 
                 22 
                 cagugcaauguuaaaagggcau 
               
               
                   
               
               
                 32 
                 isomiR 
                 mir-191 
                 Mature 5′ super 
                 24 
                 caacggaaucccaaaagcagcugu 
               
               
                   
               
               
                 33 
                 isomiR 
                 mir-486-1//mir-486-2 
                 Mature 5′ sub 
                 20 
                 uccuguacugagcugccccg 
               
               
                   
               
               
                 34 
                 isomiR 
                 let-7d 
                 Mature 3′ sub 
                 20 
                 cuauacgaccugcugecuuu 
               
               
                   
               
               
                 35 
                 precursor 
                 mir-15b 
                 precursor miRNA 
                 17 
                 uagcagcacaucauggu 
               
               
                   
               
               
                 36 
                 precursor 
                 mir-142 
                 precursor miRNA 
                 20 
                 cccauaaaguagaaagcacu 
               
               
                   
               
               
                 37 
                 miRNA 
                 let-7a-1//let-7a- 
                 Mature 5′ 
                 22 
                 ugagguaguagguuguauaguu 
               
               
                   
                   
                 2//let-7a-3 
                   
                   
                   
               
               
                   
               
               
                 38 
                 miRNA 
                 mir-151a 
                 Mature 5′ 
                 21 
                 ucgaggagcucacagucuagu 
               
               
                   
               
               
                 39 
                 precursor 
                 mir-103a-2//mir-103a- 
                 precursor miRNA 
                 19 
                 agcagcauuguacagggcu 
               
               
                   
                   
                 1/7mir-107 
                   
                   
                   
               
               
                   
               
               
                 40 
                 miRNA 
                 let-7f-1//let-7f-2 
                 Mature 5′ 
                 22 
                 ugagguaguagauuguauaguu 
               
               
                   
               
               
                 41 
                 miRNA 
                 mir-148a 
                 Mature 3′ 
                 22 
                 ucagugcacuacagaacuuugu 
               
               
                   
               
               
                 42 
                 precursor 
                 mir-142 
                 precursor miRNA 
                 19 
                 cccauaaaguagaaagcac 
               
               
                   
               
               
                 43 
                 isomiR 
                 mir-26b 
                 Mature 5′ super 
                 22 
                 uucaaguaauucaggauagguu 
               
               
                   
               
               
                 44 
                 isomiR 
                 mir-197 
                 Mature 3′ sub 
                 21 
                 uucaccaccuucuccacccag 
               
               
                   
               
               
                 45 
                 precursor 
                 mir-144 
                 precursor miRNA 
                 16 
                 uacaguauagaugaug 
               
               
                   
               
               
                 46 
                 isomiR 
                 mir-191 
                 Mature 5′ sub 
                 22 
                 caacggaaucccaaaagcagcu 
               
               
                   
               
               
                 47 
                 isomiR 
                 mir-27a 
                 Mature 3′ sub 
                 20 
                 uucacaguggcuaaguuccg 
               
               
                   
               
               
                 48 
                 isomiR 
                 mir-3615 
                 Mature 3′ super 
                 22 
                 ucucucggcuccucgeggcucg 
               
               
                   
               
               
                 49 
                 miRNA 
                 mir-423 
                 Mature 3′ 
                 23 
                 agcucggucugaggccccucagu 
               
               
                   
               
               
                 50 
                 isomiR 
                 mir-223 
                 Mature 3′ super 
                 23 
                 ugucaguuugucaaauaccccaa 
               
               
                   
               
               
                 51 
                 isomiR 
                 mir-223 
                 Mature 3′ sub/super 
                 22 
                 gucaguuugucaaauaccccaa 
               
               
                   
               
               
                 52 
                 isomiR 
                 let-7a-1//let-7a- 
                 Mature 5′ sub 
                 21 
                 ugagguaguagguuguauagu 
               
               
                   
                   
                 2//let-7a-3 
                   
                   
                   
               
               
                   
               
               
                 53 
                 isomiR 
                 mir-191 
                 Mature 5′ sub 
                 22 
                 aacggaaucccaaaagcagcug 
               
               
                   
               
               
                 54 
                 miRNA 
                 mir-15b 
                 Mature 5′ 
                 22 
                 uagcagcacaucaugguuuaca 
               
               
                   
               
               
                 55 
                 miRNA 
                 mir-223 
                 Mature 3′ 
                 22 
                 ugucaguuugucaaauacccca 
               
               
                   
               
               
                 56 
                 precursor 
                 mir-223 
                 precursor miRNA 
                 15 
                 ugucaguuugucaaa 
               
               
                   
               
               
                 57 
                 isomiR 
                 mir-223 
                 Mature 3′ sub 
                 21 
                 gucaguuugucaaauacccca 
               
               
                   
               
               
                 58 
                 isomiR 
                 mir-144 
                 Mature 5′ super 
                 23 
                 ggauaucaucauauacuguaagu 
               
               
                   
               
               
                 59 
                 isomiR 
                 mir-223 
                 Mature 3′ sub 
                 21 
                 ugucaguuugucaaauacccc 
               
               
                   
               
               
                 60 
                 miRNA 
                 mir-197 
                 Mature 3′ 
                 22 
                 uucaccaccuucuccacccagc 
               
               
                   
               
               
                 61 
                 miRNA 
                 mir-144 
                 Mature 5′ 
                 22 
                 ggauaucaucauauacuguaag 
               
               
                   
               
               
                 62 
                 isomiR 
                 mir-223 
                 Mature 3′ sub 
                 20 
                 ugucaguuugucaaauaccc 
               
               
                   
               
               
                 63 
                 isomiR 
                 mir-23a 
                 Mature 3′ sub 
                 19 
                 aucacauugccagggauuu 
               
               
                   
               
               
                 64 
                 precursor 
                 mir-223 
                 precursor miRNA 
                 19 
                 ugucaguuugucaaauacc 
               
               
                   
               
               
                 65 
                 isomiR 
                 mir-4286 
                 Mature 5′ super 
                 18 
                 accccacuccugguacca 
               
               
                   
               
               
                 66 
                 miRNA 
                 mir-769 
                 Mature 3′ sub 
                 20 
                 ugggaucuccggggucuugg 
               
               
                   
               
               
                 67 
                 LincRNA 
                 ENST00000517335.1// 
                 Exact 
                 31 
                 ccauguuggucaggcuggucuugaacu 
               
               
                   
                   
                 ...*3 
                   
                   
                 ccug 
               
               
                   
               
               
                 68 
                 ncRNA 
                 ENST00000437898.I 
                 Exact 
                 15 
                 gagggaacgugagcu 
               
               
                   
               
               
                 69 
                 miRNA 
                 let-7g 
                 Mature 5′ 
                 22 
                 ugagguaguaguuuguacaguu 
               
               
                   
               
               
                 70 
                 miRNA 
                 mir-18a 
                 Mature 5′ 
                 23 
                 uaaggugcaucuagugcagauag 
               
               
                   
               
               
                 71 
                 miRNA 
                 mir-106b 
                 Mature 5′ 
                 21 
                 uaaagugcugacagugcagau 
               
               
                   
               
               
                 72 
                 miRNA 
                 mir-19b-1//mir-l9b-2 
                 Mature 3′ 
                 23 
                 ugugcaaauccaugcaaaacuga 
               
               
                   
               
               
                 73 
                 isomiR 
                 mir-876 
                 Mature 5′ 
                 22 
                 uggauuucuuugugaaucacca 
               
               
                   
               
               
                 74 
                 isomiR 
                 mir-223 
                 Mature 3′ sub 
                 17 
                 guuugucaaauacccca 
               
               
                   
               
               
                 75 
                 miRNA 
                 mir-425 
                 Mature 5′ 
                 23 
                 aaugacacgaucacucccguuga 
               
               
                   
               
               
                 76 
                 LincRNA 
                 ENST00000626826.1 
                 Exact 
                 18 
                 aggaggaggaggaggacg 
               
               
                   
               
               
                 77 
                 tRF 
                   Homo _ sapiens _tRNA- 
                 Exact 
                 20 
                 agaguggcgcagcggaagcg 
               
               
                   
                   
                 iMet-CAT-1-1//...*2 
                   
                   
                   
               
               
                   
               
               
                 78 
                 miRNA 
                 mir-2 2 
                 Mature 3′ 
                 22 
                 aagcugccaguugaagaacugu 
               
               
                   
               
               
                 79 
                 MiscRNA 
                 ENST00000410769.1 
                 Exact 
                 15 
                 cacaaccaguuacca 
               
               
                   
               
               
                 80 
                 ncRNA 
                 ENST00000635274.1// 
                 Exact 
                 17 
                 ggcuguagugcgcuaug 
               
               
                   
                   
                 ...*5 
                   
                   
                   
               
               
                   
               
               
                 81 
                 LincRNA 
                 ENST00000567317.5 
                 Exact 
                 35 
                 gccugaggucuacugcugccuuaucca 
               
               
                   
                   
                   
                   
                   
                 gagcugcc 
               
               
                   
               
               
                 82 
                 isomiR 
                 mir-361 
                 Mature 3′ sub 
                 20 
                 ucceccaggugugauucuga 
               
               
                   
               
               
                 83 
                 LincRNA 
                 ENST00000556266.1// 
                 Exact 
                 16 
                 cuuaugcaggaggacc 
               
               
                   
                   
                 ...*4 
                   
                   
                   
               
               
                   
               
               
                 84 
                 isomiR 
                 mir-320a 
                 Mature 3′ 
                 22 
                 aaaagcuggguugagagggcga 
               
               
                   
               
               
                 85 
                 LincRNA 
                 ENST00000607746.1 
                 Exact 
                 15 
                 agagcagaagggaag 
               
               
                   
               
               
                 *1: ENST00000364600.1//ENST00000577883.2//ENST00000577984.2//ENST00000516678.1//ENST00000516507.1//ENST000004810413// 
               
               
                 ENST00000579625.2//ENST00000365571.2//ENST00000578877.2//ENST00000364908.18 
               
               
                 *2:  Homo _ sapiens _tRNA-iMet-CAT-1-1// Homo _ sapiens _tRNA-iMet-CAT-1-2// Homo _ sapiens _tRNA-iMet-CAT-1-3// Homo _ sapiens _tRNA- 
               
               
                 iMet-CAT-1-4// Homo _ sapiens _tRNA-iMet-CAT-1-5// Homo _ sapiens _tRNA-iMet-CAT-1-6// Homo _ sapiens _tRNA-iMet-CAT-1-7// 
               
               
                   Homo _ sapiens _tRNA-iMet-CAT-1-8// Homo _ sapiens _tRNA-iMet-CAT-2-1 
               
               
                 *3: ENST00000517335.1//ENST00000499583.1//ENST00000455531.1//ENST00000398461.5//ENST00000612531.1//ENST00000425800.1// 
               
               
                 ENST00000455253.6//ENST00000454128.2//ENST00000602737.5//ENST00000414209.5//ENST00000452320.3//ENST00000640355.1// 
               
               
                 ENST00000638174.1//ENST00000581398.1 
               
               
                 *4: ENST00000556266.1//ENST0000055444l.5//ENST00000557532.5//ENST00000554694.1 
               
               
                 *5: ENST00000635274.1//ENST00000461926.3//ENST00000582522.2//ENST00000469617.3//ENST00000476501.3//ENST00000581392.2// 
               
               
                 ENST00000487309.3//ENST00000481857.3//ENST00000486780.3//ENST00000463926.3//ENST00000478498.3//ENST00000577207.2// 
               
               
                 ENST00000463397.3//ENST00000619303.1//ENST00000470786.3//ENST00000493013.3//ENST00000618786.1//ENST00000581458.2// 
               
               
                 ENST00000491451.3//ENST00000467883.3//ENST00000479428.3//ENST00000496780.3//ENST00000585237.2//ENST00000610674.1// 
               
               
                 ENST00000490232.3//ENST00000584058.2 
               
            
           
         
       
     
     Most of those miRNAs or the like show the logarithm of the ratio of the abundance in serum from patients with Alzheimer&#39;s disease to the abundance in serum from healthy subjects (represented by “log FC,” which means the logarithm of FC (fold change) to base 2) is more than 1.0 in absolute value (that is, a ratio of not less than 2 or not more than ½) as indicated in Table 2 below, which is statistically significant (t-test; p&lt;0.05). 
     The abundance of miRNAs or the like represented by SEQ ID NOs: 1 to 22 and 66 to 71 is higher in patients with Alzheimer&#39;s disease than in healthy subjects. while the abundance of miRNAs or the like represented by SEQ ID NOs: 23 to 65 and 72 to 85 is lower in patients with Alzheimer&#39;s disease than in healthy subjects. 
     Among those, the miRNAs or the like represented by SEQ ID NOs: 1, 3, 11, 12, 2, 4 to 10, 46 to 65, 84, and 85 have a log FC value of not less than 1.5 in absolute value and thus function as indexes with especially high sensitivity, and are preferable. 
     The accuracy of each biomarker is indicated using the area under the ROC curve (AUC: Area Under Curve) as an index, and biomarkers with an AUC value of 0.7 or higher are generally considered effective. AUC values of 0.90 or higher, 0.97 or higher, 0.98 or higher, and 1.00 correspond to biomarkers with high accuracy, very high accuracy, even higher accuracy, and complete accuracy (with no false-positive and false-negative events), respectively. Thus, the AUC value of each biomarker is likewise preferably 0.90, more preferably not less than 0.97, still more preferably not less than 0.98, and most preferably 0.99 in the present invention. The miRNAs or the like represented by SEQ ID NOs: 1, 3, 11, and 12 are preferable because of an AUC value of 0.97 or higher; among those, the miRNAs or the like represented by SEQ ID NOs: 1 and 3 are more preferable because of an AUC value of 0.98 or higher; the miRNA represented by SEQ ID NO: 1 is most preferable because of an AUC value of 1.00. 
     The test sample is not specifically limited, provided that the test sample is a body fluid containing miRNAs; typically, it is preferable to use a blood sample (including plasma, serum, and whole blood). It is simple and preferable to use serum or plasma as a test sample. 
     The abundance of each miRNA or the like is preferably measured (quantified) using a next-generation sequencer. Any instrument may be used and is not limited to a specific type of instrument, provided that the instrument determines sequences, similarly to next-generation sequencers. In the method of the present invention, as specifically described in Examples below, use of a next-generation sequencer is preferred over quantitative reverse-transcription PCR (qRT-PCR) which is widely used for quantification of miRNAs, to perform measurements from the viewpoint of accuracy because miRNAs or the like to be quantified include, for example, isomiRs, in which only one or more nucleotides are deleted from or added to the 5′ and/or 3′ ends of the original mature miRNAs thereof, and which should be distinguished from the original miRNAs when measured. Briefly, though details will be described specifically in Examples below, the quantification method can be performed, for example, as follows. When the RNA content in serum or plasma is constant, among reads measured in a next-generation sequencing analysis of the RNA content, the number of reads for each isomiR or mature miRNA per million reads is considered as the measurement value, where the total counts of reads with human-derived sequences are normalized to one million reads. When the RNA content in serum or plasma is variable in comparison with healthy subjects due to a disease, miRNAs showing little abundance variation in serum and plasma may be used. In cases where the abundance of miRNAs or the like in serum or plasma is measured, at least one miRNA selected from the group consisting of let-7g-5p, miR-425-3p, and miR-425-5p is preferably used as an internal control, which are miRNAs showing little abundance variation in serum and plasma. 
     The cut-off value for the abundance of each miRNA or the like for use in evaluation is preferably determined based on the presence or absence of a statistically significant difference (t-test; p&lt;0.05, preferably p&lt;0.01, more preferably p&lt;0.001) from healthy subjects with regard to the abundance of the miRNA or the like. Specifically, the value of log 2  read counts (the cut-off value) can be preferably determined for each miRNA or the like, for example, at which the false-positive rate is optimal (the lowest); for example, the cut-off values (the values of log 2 read counts) for several miRNAs or the like are as indicated in Table 2. The cut-off values indicated in Table 2 are only examples, and other values may be employed as cut-off values as long as those values are appropriate to determine statistically significant difference. Additionally, the optimal cut-off values vary among different populations of patients and healthy subjects from which data is collected. However, a cut-off value may be set such that the cut-off value is within the range of, usually ±20%, particularly ±10%, from the cut-off value indicated in Table 2. 
     Additionally, the abundance of a miRNA and that of each isomiR thereof are different between patients and healthy subjects, even among miRNAs or the like derived from the same archetype. Thus, the measurement of a certain miRNA and an isomiR thereof in one patient, which are derived from the same archetype, can assist in Alzheimer&#39;s disease detection based on the abundance ratio thereof. Because small differences in nucleotide sequence should be accurately distinguished, when the abundance of a certain miRNA and that of an isomiR thereof are measured, use of a next-generation sequencer is preferred over quantitative reverse-transcription PCR (qRT-PCR) which is typically used in miRNA measurement, to perform measurements. 
     Each of the above miRNAs or the like is statistically significantly different in abundance between patients with Alzheimer&#39;s disease and healthy subjects, and may thus be used alone as an index. However, a combination of multiple miRNAs or the like may also be used as an index, which can assist in more accurate detection of Alzheimer&#39;s disease. 
     Moreover, a method of detecting the abundance of miRNAs or the like in a test sample from an individual suspected of having or affected with Alzheimer&#39;s disease is also provided. 
     That is, a method of detecting the abundance of at least one of miRNAs, isomiRs, precursor miRNAs, ncRNAs, transfer RNA fragments, LincRNAs, or MiscRNAs whose nucleotide sequence is represented by any one of SEQ ID NOs: 1, 3, 11, 12, 2, 4 to 10, and 13 to 85 in a test sample from an individual suspected of having or affected with Alzheimer&#39;s disease is also provided, wherein the method includes the steps of: 
     collecting a blood sample from the individual; and 
     measuring the abundance of the miRNA(s), isomiR(s), precursor miRNA(s), ncRNA(s), transfer RNA fragment(s), LincRNA(s), or MiscRNA(s) in the blood sample by means of a next-generation sequencer or qRT-PCR; 
     wherein the abundance of at least one of the miRNAs, isomiRs, precursor miRNAs, ncRNAs, transfer RNA fragments, LincRNAs, or MiscRNAs whose nucleotide sequence is represented by any one of SEQ ID NOs: 1 to 22 and 66 to 71 is higher in patients than in healthy subjects, or the abundance of at least one of the miRNAs, isomiRs, precursor miRNAs, ncRNAs, transfer RNA fragments, LincRNAs, or MiscRNAs whose nucleotide sequence is represented by any one of SEQ ID NOs: 23 to 65 and 72 to 85 is lower in patients than in healthy subjects. 
     Additionally, in cases where the detection of Alzheimer&#39;s disease is successfully achieved by the above-described method of the present invention, an effective amount of an Alzheimer&#39;s disease drug can be administered to patients in whom Alzheimer&#39;s disease is detected, to treat the Alzheimer&#39;s disease. Examples of the Alzheimer&#39;s disease drug can include donepezil, rivastigmine, galantamine, and memantine. 
     The present invention will be specifically described below by way of examples and comparative examples. However, the present invention is not limited to the examples below. 
     Examples 1 to 85 
     1. Materials and Methods 
     (1) Clinical Samples 
     Plasma samples from 43 patients with Alzheimer&#39;s disease and from 32 healthy subjects were used. 
     (2) Extraction of RNA in Serum 
     Extraction of RNA in serum was performed using the miRNeasy Mini kit (QIAGEN). 
     1) Each frozen serum sample was thawed and centrifuged at 10,000 rpm for 5 minutes at room temperature to precipitate aggregated proteins and blood cell components.
 
2) To a new 1.5-mL tube, 200 μL of the supernatant was transferred.
 
3) To the tube, 1000 μL of the QIAzol Lysis Reagent was added and mixed thoroughly to denature protein components.
 
4) To the tube, 10 μL of 0.05 nM cel-miR-39 was added as a control RNA for RNA extraction, mixed by pipetting, and then left to stand at room temperature for 5 minutes.
 
5) To promote separation of the aqueous and organic solvent layers, 200 μL of chloroform was added to the tube, mixed thoroughly, and left to stand at room temperature for 3 minutes.
 
6) The tube was centrifuged at 12,000×g for 15 minutes at 4° C. and 650 μL of the upper aqueous layer was transferred to a new 2-mL tube.
 
7) For the separation of RNA, 975 μL of 100% ethanol was added to the tube and mixed by pipetting.
 
8) To a miRNeasy Mini spin column (hereinafter referred to as “column”), 650 μL of the mixture in the step 7 was transferred, left to stand at room temperature for 1 minute, and then centrifuged at 8000×g for 15 seconds at room temperature to allow RNA to be adsorbed on the filter of the column. The flow-through solution from the column was discarded.
 
9) The step 8 was repeated until the total volume of the solution of the step 7 was filtered through the column to allow all the RNA to be adsorbed on the filter.
 
10) To remove impurities attached on the filter, 650 μL of Buffer RWT was added to the column and centrifuged at 8000×g for 15 seconds at room temperature. The flow-through solution from the column was discarded.
 
11) To clean the RNA adsorbed on the filter, 500 μL of Buffer RPE was added to the column and centrifuged at 8000×g for 15 seconds at room temperature. The flow-through solution from the column was discarded.
 
12) To clean the RNA adsorbed on the filter, 500 μL of Buffer RPE was added to the column and centrifuged at 8000×g for 2 minutes at room temperature. The flow-through solution from the column was discarded.
 
13) To completely remove any solution attached on the filter, the column was placed in a new 2-mL collection tube and centrifuged at 10,000×g for 1 minute at room temperature.
 
14) The column was placed into a 1.5-mL tube and 50 μL of RNase-free water was added thereto and left to stand at room temperature for 1 minute.
 
15) Centrifugation was performed at 8000×g for 1 minute at room temperature to elute the RNA adsorbed on the filter. The eluted RNA was used in the following experiment without further purification and the remaining portion of the eluted RNA was stored at −80° C.
 
(4) Quantification of miRNAs or the Like
 
     The quantification of miRNAs or the like was performed as follows. In cases where miRNAs or the like from, for example, two groups were quantified, extracellular vesicles (including exosomes) isolated by the same method were used to extract RNAs through the same method, from which cDNA libraries were prepared and then analyzed by next-generation sequencing. The next-generation sequencing analysis is not limited by a particular instrument, provided that the instrument determines sequences. 
     2. Results 
     The results are presented in Table 2. 
     
       
         
           
               
               
               
               
               
               
               
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                   
                   
                   
                 Length 
                 Average 
                 Average 
                   
                   
                 Cut- 
               
               
                   
                 SEQ 
                   
                   
                   
                 (nucleo- 
                 in healthy 
                 in AD 
                 log 
                   
                 off 
               
               
                 Example 
                 ID NO: 
                 Class 
                 Archetype 
                 Type 
                 tides) 
                 subjects 
                 patients* 
                 FC 
                 AUC 
                 value 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Example 1 
                 1 
                 miRNA 
                 mir-340 
                 Mature 3′ 
                 22 
                 1 
                 2984 
                 11.1 
                 1.000 
                 8.90 
               
               
                 Example 2 
                 2 
                 miRNA 
                 mir-122 
                 Mature 5′ 
                 22 
                 216 
                 1611 
                 2.9 
                 0.852 
                 8.98 
               
               
                 Example 3 
                 3 
                 isomiR 
                 mir-181b-1//mir-181b-2 
                 Mature 5′ sub 
                 22 
                 96 
                 695 
                 2.9 
                 0.993 
                 7.60 
               
               
                 Example 4 
                 4 
                 isomiR 
                 mir-451a 
                 Mature 5′ super 
                 24 
                 568 
                 3471 
                 2.6 
                 0.919 
                 9.77 
               
               
                 Example 5 
                 5 
                 isomiR 
                 mir-20a 
                 Mature 5′ sub 
                 22 
                 173 
                 798 
                 2.2 
                 0.83 
                 8.36 
               
               
                 Example 6 
                 6 
                 miRNA 
                 mir-20a 
                 Mature 5′ 
                 23 
                 744 
                 3149 
                 2.1 
                 0.881 
                 10.63 
               
               
                 Example 7 
                 7 
                 isomiR 
                 mir-20a 
                 Mature 5′ sub 
                 21 
                 519 
                 1822 
                 1.8 
                 0.652 
                 10.70 
               
               
                 Example 8 
                 8 
                 isomiR 
                 mir-451a 
                 Mature 5′ super 
                 23 
                 20679 
                 72278 
                 1.8 
                 0.926 
                 14.48 
               
               
                 Example 9 
                 9 
                 MiscRNA 
                 ENST00000364600.1// . . . *1 
                 Exact 
                 26 
                 1870 
                 5975 
                 1.7 
                 0.941 
                 11.81 
               
               
                 Example 10 
                 10 
                 miRNA 
                 mir-451a 
                 Mature 5′ 
                 22 
                 49304 
                 148434 
                 1.6 
                 0.852 
                 16.84 
               
               
                 Example 11 
                 11 
                 miRNA 
                 mir-185 
                 Mature 5′ 
                 22 
                 2520 
                 7180 
                 1.5 
                 0.97 
                 11.94 
               
               
                 Example 12 
                 12 
                 precursor 
                 mir-451a 
                 precursor miRNA 
                 16 
                 252 
                 645 
                 1.4 
                 0.97 
                 9.14 
               
               
                 Example 13 
                 13 
                 isomiR 
                 mir-17 
                 Mature 5′ sub 
                 22 
                 284 
                 726 
                 1.4 
                 0.859 
                 9.10 
               
               
                 Example 14 
                 14 
                 MiscRNA 
                 ENST00000364600.1// . . . *1 
                 Exact 
                 27 
                 206 
                 492 
                 1.3 
                 0.822 
                 8.46 
               
               
                 Example 15 
                 15 
                 precursor 
                 mir-16-1//mir-16-2 
                 precursor miRNA 
                 19 
                 278 
                 616 
                 1.1 
                 0.844 
                 8.64 
               
               
                 Example 16 
                 16 
                 isomiR 
                 mir-30d 
                 Mature 5′ super 
                 24 
                 444 
                 941 
                 1.1 
                 0.837 
                 9.10 
               
               
                 Example 17 
                 17 
                 isomiR 
                 mir-185 
                 Mature 5′ sub 
                 21 
                 2331 
                 4824 
                 1 
                 0.919 
                 11.78 
               
               
                 Example 18 
                 18 
                 isomiR 
                 mir-93 
                 Mature 5′ sub 
                 21 
                 433 
                 891 
                 1 
                 0.815 
                 10.00 
               
               
                 Example 19 
                 19 
                 isomiR 
                 mir-101-1//mir-101-2 
                 Mature 3′ super 
                 22 
                 941 
                 1915 
                 1 
                 0.667 
                 11.04 
               
               
                 Example 20 
                 20 
                 isomiR 
                 mir-30d 
                 Mature 5′ super 
                 23 
                 182 
                 367 
                 1 
                 0.785 
                 8.00 
               
               
                 Example 21 
                 21 
                 isomiR 
                 mir-30d 
                 Mature 5′ sub 
                 21 
                 661 
                 1310 
                 1 
                 0.726 
                 9.89 
               
               
                 Example 22 
                 22 
                 isomiR 
                 mir-145 
                 Mature 5′ sub 
                 22 
                 381 
                 745 
                 1 
                 0.756 
                 9.53 
               
               
                 Example 23 
                 23 
                 precursor 
                 mir-15b 
                 precursor miRNA 
                 19 
                 444 
                 230 
                 −1 
                 0.844 
                 7.40 
               
               
                 Example 24 
                 24 
                 precursor 
                 mir-24-1//mir-24-2 
                 precursor miRNA 
                 19 
                 607 
                 306 
                 −1 
                 0.748 
                 8.06 
               
               
                 Example 25 
                 25 
                 isomiR 
                 mir-484 
                 Mature 5′ sub 
                 21 
                 6274 
                 3127 
                 −1 
                 0.933 
                 12.30 
               
               
                 Example 26 
                 26 
                 precursor 
                 mir-191 
                 precursor miRNA 
                 20 
                 3638 
                 1794 
                 −1 
                 0.852 
                 11.37 
               
               
                 Example 27 
                 27 
                 precursor 
                 mir-221 
                 precursor miRNA 
                 20 
                 561 
                 274 
                 −1 
                 0.741 
                 8.44 
               
               
                 Example 28 
                 28 
                 isomiR 
                 mir-29c 
                 Mature 3′ sub 
                 20 
                 351 
                 170 
                 −1 
                 0.926 
                 7.53 
               
               
                 Example 29 
                 29 
                 miRNA 
                 let-7f-1//let-7f-2 
                 Mature 5′ sub 
                 21 
                 866 
                 414 
                 −1.1 
                 0.83 
                 9.10 
               
               
                 Example 30 
                 30 
                 miRNA 
                 mir-484 
                 Mature 5′ 
                 22 
                 2241 
                 1055 
                 −1.1 
                 0.941 
                 10.60 
               
               
                 Example 31 
                 31 
                 miRNA 
                 mir-130a 
                 Mature 3′ 
                 22 
                 473 
                 221 
                 −1.1 
                 0.844 
                 8.39 
               
               
                 Example 32 
                 32 
                 isomiR 
                 mir-191 
                 Mature 5′ super 
                 24 
                 475 
                 217 
                 −1.1 
                 0.711 
                 7.54 
               
               
                 Example 33 
                 33 
                 isomiR 
                 mir-486-1//mir-486-2 
                 Mature 5′ sub 
                 20 
                 6476 
                 2942 
                 −1.1 
                 0.948 
                 12.18 
               
               
                 Example 34 
                 34 
                 isomiR 
                 lct-7d 
                 Mature 3′ sub 
                 20 
                 168 
                 76 
                 −1.1 
                 0.859 
                 7.14 
               
               
                 Example 35 
                 35 
                 precursor 
                 mir-15b 
                 precursor miRNA 
                 17 
                 187 
                 81 
                 −1.2 
                 0.696 
                 6.15 
               
               
                 Example 36 
                 36 
                 precursor 
                 mir-142 
                 precursor miRNA 
                 20 
                 2105 
                 906 
                 −1.2 
                 0.956 
                 10.29 
               
               
                 Example 37 
                 37 
                 miRNA 
                 let-7a-1//let-7a-2//let-7a-3 
                 Mature 5′ 
                 22 
                 1853 
                 795 
                 −1.2 
                 0.807 
                 9.63 
               
               
                 Example 38 
                 38 
                 miRNA 
                 mir-151a 
                 Mature 5′ 
                 21 
                 564 
                 233 
                 −1.3 
                 0.859 
                 8.42 
               
               
                 Example 39 
                 39 
                 precursor 
                 mir-103a-2//mir-103a-1//mir-107 
                 precursor miRNA 
                 19 
                 3502 
                 1437 
                 −1.3 
                 0.867 
                 11.03 
               
               
                 Example 40 
                 40 
                 miRNA 
                 let-7f-1//let-7f-2 
                 Mature 5′ 
                 22 
                 481 
                 196 
                 −1.3 
                 0.844 
                 7.71 
               
               
                 Example 41 
                 41 
                 miRNA 
                 mir-148a 
                 Mature 3′ 
                 22 
                 346 
                 135 
                 −1.4 
                 0.793 
                 7.99 
               
               
                 Example 42 
                 42 
                 precursor 
                 mir-142 
                 precursor miRNA 
                 19 
                 294 
                 114 
                 −1.4 
                 0.889 
                 6.77 
               
               
                 Example 43 
                 43 
                 isomiR 
                 mir-26b 
                 Mature 5′ super 
                 22 
                 177 
                 68 
                 −1.4 
                 0.815 
                 5.20 
               
               
                 Example 44 
                 44 
                 isomiR 
                 mir-197 
                 Mature 3′ sub 
                 21 
                 398 
                 147 
                 −1.4 
                 0.919 
                 7.54 
               
               
                 Example 45 
                 45 
                 precursor 
                 mir-144 
                 precursor miRNA 
                 16 
                 333 
                 122 
                 −1.4 
                 0.748 
                 6.14 
               
               
                 Example 46 
                 46 
                 isomiR 
                 mir-191 
                 Mature 5′ sub 
                 22 
                 1956 
                 700 
                 −1.5 
                 0.933 
                 10.36 
               
               
                 Example 47 
                 47 
                 isomiR 
                 mir-27a 
                 Mature 3′ sub 
                 20 
                 3273 
                 1150 
                 −1.5 
                 0.859 
                 11.30 
               
               
                 Example 48 
                 48 
                 isomiR 
                 mir-3615 
                 Mature 3′ super 
                 22 
                 128 
                 45 
                 −1.5 
                 0.793 
                 5.46 
               
               
                 Example 49 
                 49 
                 miRNA 
                 mir-423 
                 Mature 3′ 
                 23 
                 295 
                 101 
                 −1.6 
                 0.904 
                 7.36 
               
               
                 Example 50 
                 50 
                 isomiR 
                 mir-223 
                 Mature 3′ super 
                 23 
                 42236 
                 13998 
                 −1.6 
                 0.83 
                 14.44 
               
               
                 Example 51 
                 51 
                 isomiR 
                 mir-223 
                 Mature 3′ sub/super 
                 22 
                 12615 
                 4139 
                 −1.6 
                 0.859 
                 13.47 
               
               
                 Example 52 
                 52 
                 isomiR 
                 let-7a-1//let-7a-2//let-7a-3 
                 Mature 5′ sub 
                 21 
                 2213 
                 675 
                 −1.7 
                 0.904 
                 10.30 
               
               
                 Example 53 
                 53 
                 isomiR 
                 mir-191 
                 Mature 5′ sub 
                 22 
                 713 
                 208 
                 −1.8 
                 0.948 
                 8.57 
               
               
                 Example 54 
                 54 
                 miRNA 
                 mir-15b 
                 Mature 5′ 
                 22 
                 747 
                 213 
                 −1.8 
                 0.896 
                 8.86 
               
               
                 Example 55 
                 55 
                 miRNA 
                 mir-223 
                 Mature 3′ 
                 22 
                 39732 
                 10170 
                 −2 
                 0.837 
                 13.45 
               
               
                 Example 56 
                 56 
                 precursor 
                 mir-223 
                 precursor miRNA 
                 15 
                 108 
                 27 
                 −2 
                 0.822 
                 5.83 
               
               
                 Example 57 
                 57 
                 isomiR 
                 mir-223 
                 Mature 3′ sub 
                 21 
                 7627 
                 1711 
                 −2.2 
                 0.844 
                 12.22 
               
               
                 Example 58 
                 58 
                 isomiR 
                 mir-144 
                 Mature 5′ super 
                 23 
                 309 
                 66 
                 −2.2 
                 0.867 
                 7.00 
               
               
                 Example 59 
                 59 
                 isomiR 
                 mir-223 
                 Mature 3′ sub 
                 21 
                 5364 
                 985 
                 −2.4 
                 0.889 
                 10.15 
               
               
                 Example 60 
                 60 
                 miRNA 
                 mir-197 
                 Mature 3′ 
                 22 
                 877 
                 147 
                 −2.6 
                 0.963 
                 8.54 
               
               
                 Example 61 
                 61 
                 miRNA 
                 mir-144 
                 Mature 5′ 
                 22 
                 243 
                 36 
                 −2.7 
                 0.911 
                 6.67 
               
               
                 Example 62 
                 62 
                 isomiR 
                 mir-223 
                 Mature 3′ sub 
                 20 
                 3274 
                 430 
                 −2.9 
                 0.867 
                 8.88 
               
               
                 Example 63 
                 63 
                 isomiR 
                 mir-23a 
                 Mature 3′ sub 
                 19 
                 496 
                 57 
                 −3.1 
                 0.896 
                 6.64 
               
               
                 Example 64 
                 64 
                 precursor 
                 mir-223 
                 precursor miRNA 
                 19 
                 1849 
                 209 
                 −3.1 
                 0.904 
                 8.86 
               
               
                 Example 65 
                 65 
                 isomiR 
                 mir-4286 
                 Mature 5′ super 
                 18 
                 515 
                 42 
                 −3.6 
                 0.896 
                 6.98 
               
               
                 Example 66 
                 66 
                 isomiR 
                 mir-769 
                 Mature 3′ sub 
                 20 
                 3789 
                 9843 
                 1.38 
                 0.81 
                 12.5 
               
               
                 Example 67 
                 67 
                 LincRNA 
                 ENST00000517335.1// . . . *3 
                 Exact 
                 31 
                 1589 
                 3580 
                 1.17 
                 0.759 
                 11.2 
               
               
                 Example 68 
                 68 
                 ncRNA 
                 ENST00000437898.1 
                 Exact 
                 15 
                 25718 
                 57524 
                 1.16 
                 0.783 
                 15.13 
               
               
                 Example 69 
                 69 
                 miRNA 
                 let-7g 
                 Mature 5′ 
                 22 
                 4370 
                 7081 
                 0.70 
                 0.684 
                 12.09 
               
               
                 Example 70 
                 70 
                 miRNA 
                 mir-18a 
                 Mature 5′ 
                 23 
                 1811 
                 2713 
                 0.58 
                 0.619 
                 11.37 
               
               
                 Example 71 
                 71 
                 miRNA 
                 mir-106b 
                 Mature 5′ 
                 21 
                 2501 
                 3470 
                 0.47 
                 0.587 
                 11.53 
               
               
                 Example 72 
                 72 
                 miRNA 
                 mir-19b-1//mir-19b-2 
                 Mature 3′ 
                 23 
                 97040 
                 73555 
                 −0.40 
                 0.695 
                 16.69 
               
               
                 Example 73 
                 73 
                 miRNA 
                 mir-876 
                 Mature 5′ 
                 22 
                 5753 
                 3772 
                 −0.61 
                 0.762 
                 12.24 
               
               
                 Example 74 
                 74 
                 isomiR 
                 mir-223 
                 Mature 3′ sub 
                 17 
                 2889 
                 1880 
                 −0.62 
                 0.672 
                 11.76 
               
               
                 Example 75 
                 75 
                 miRNA 
                 mir-425 
                 Mature 5′ 
                 23 
                 6399 
                 4114 
                 −0.64 
                 0.689 
                 12.46 
               
               
                 Example 76 
                 76 
                 LincRNA 
                 ENST00000626826.1 
                 Exact 
                 18 
                 3513 
                 2080 
                 −0.76 
                 0.738 
                 11.3 
               
               
                 Example 77 
                 77 
                 tRF 
                 Homo_sapiens_tRNA-iMet- 
                 Exact 
                 20 
                 1446 
                 768 
                 −0.91 
                 0.779 
                 10.4 
               
               
                   
                   
                   
                 CAT-1-1// . . . *2 
               
               
                 Example 78 
                 78 
                 miRNA 
                 mir-22 
                 Mature 3′ 
                 22 
                 6348 
                 3301 
                 −0.94 
                 0.677 
                 12.22 
               
               
                 Example 79 
                 79 
                 MiscRNA 
                 ENST00000410769.1 
                 Exact 
                 15 
                 3136 
                 1488 
                 −1.08 
                 0.83 
                 10.9 
               
               
                 Example 80 
                 80 
                 ncRNA 
                 ENST00000635274.1// . . . *5 
                 Exact 
                 17 
                 1674 
                 739 
                 −1.18 
                 0.799 
                 9.81 
               
               
                 Example 81 
                 81 
                 LincRNA 
                 ENST00000567317.5 
                 Exact 
                 35 
                 1386 
                 593 
                 −1.22 
                 0.803 
                 9.96 
               
               
                 Example 82 
                 82 
                 isomiR 
                 mir-361 
                 Mature 3′ sub 
                 20 
                 1714 
                 677 
                 −1.34 
                 0.84 
                 9.92 
               
               
                 Example 83 
                 83 
                 LincRNA 
                 ENST00000556266.1// . . . *4 
                 Exact 
                 16 
                 1237 
                 481 
                 −1.36 
                 0.893 
                 9.29 
               
               
                 Example 84 
                 84 
                 miRNA 
                 mir-320a 
                 Mature 3′ 
                 22 
                 24669 
                 7832 
                 −1.66 
                 0.78 
                 13.76 
               
               
                 Example 85 
                 85 
                 LincRNA 
                 ENST00000607746.1 
                 Exact 
                 15 
                 1115 
                 258 
                 −2.11 
                 0.92 
                 8.99 
               
               
                   
               
               
                 *AD: Alzheimer&#39;s disease 
               
               
                 *1 to *5 in this table represent the same molecules represented by *1 to *5 in Table 1. 
               
            
           
         
       
     
     As seen in these results, among those sequences, the abundance of the miRNAs or the like represented by SEQ ID NOs: 1 to 22 and 66 to 71 was significantly higher in the patients with Alzheimer&#39;s disease than in the healthy subjects, and the abundance of the miRNAs or the like represented by SEQ ID NOs: 23 to 65 and 72 to 85 was significantly lower in the patients with Alzheimer&#39;s disease than in the healthy subjects. Moreover, all the p-values determined by t-test in Examples 1 to 85 were less than 0.05, indicating the effectiveness in detection of Alzheimer&#39;s disease.