Diagnostic biomarker profiles for the detection and diagnosis of alzheimer's disease

Abstract

The present invention provides methods, compositions and kits for the detection of Alzheimer's disease (AD) diagnostic biomarkers, for the diagnosis of AD, for the identification of a subject at risk for developing AD, and for the generation of patient-specific AD diagnostic biomarker profiles.

What is claimed: 
     
         1 . A method of detecting autoantibodies resulting from Alzheimer's disease in a subject, the method comprising: (a) obtaining an immunoglobulin-containing biological sample from the subject, and (b) performing an assay to determine the presence of greater levels of Alzheimer's disease related autoantibodies in the biological sample compared to healthy controls, wherein the assay comprises: (i) contacting the biological sample with a substrate of up to 50 antigens comprising at least two antigens selected from a first antigen group consisting of cDNA clone MGC:31944 IMAGE:4878869; hematopoietic SH2 domain-containing protein (HSH2D); FERM domain containing 8 (FRMD8); and LIM and senescent cell antigen-like-containing domain protein 1; under conditions that allow immunocomplexes of each of the antigens and a corresponding autoantibody to form; and (ii) detecting the formation of the corresponding immunocomplexes in the biological sample in the reaction mixture, wherein the increased formation of at least two immunocomplexes of the first antigen group indicates the presence of Alzheimer's disease in the subject. 
     
     
         2 . The method of  claim 1 , wherein the biological sample is selected from the group consisting of whole blood, serum, cerebrospinal fluid, saliva, and sputum. 
     
     
         3 . The method of  claim 1 , wherein the antigens are attached to the substrate. 
     
     
         4 . The method of  claim 3 , wherein the antigens are in the form of an array. 
     
     
         5 . The method of  claim 4 , wherein the array is a microarray. 
     
     
         6 . The method of  claim 3 , wherein the substrate is a bead or a nitrocellulose-coated glass slide. 
     
     
         7 . A method of identifying a subject as having, or being at risk for having, a neurodegenerative disease, the method comprising
 (a) obtaining an immunoglobulin-containing biological sample from the subject,   (b) performing an assay to determine the presence or absence of autoantibodies in the biological sample, wherein the assay comprises:
 (i) contacting the biological sample with at least two autoantigens selected from the group consisting of cDNA clone MGC:31944 IMAGE:4878869; cDNA clone MGC:27152 IMAGE:4691630; and hematopoietic SH2 domain-containing protein (HSH2D), under conditions that allow immunocomplexes of each of the at least two autoantigens and a corresponding autoantibody to form; and 
 (ii) detecting the presence or absence of the immunocomplexes in the biological sample, 
   
       wherein, if autoantibodies to the at least two autoantigens are present in the biological sample, the subject is identified as having, or being at risk for having, at least one neurodegenerative disease selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and vascular dementia. 
     
     
         8 . The method of  claim 7 , wherein, if the subject is identified as having, or being at risk for having, the at least one neurodegenerative disease, the subject is further treated for the at least one neurodegenerative disease. 
     
     
         9 . The method of  claim 7 ,
 wherein the assay in (b) further comprises:
 contacting the biological sample with at least one additional autoantigen selected from the group consisting of cDNA clone MGC:32654 IMAGE:4701898 and cleavage and polyadenylation specific factor 3, 73 kDa (CPSF3), under conditions that allow immunocomplexes of each of the at least one additional autoantigen and a corresponding autoantibody to form; and 
 detecting the presence or absence of the corresponding immunocomplexes in the biological sample, and 
   wherein, if the autoantibody/antibodies to the at least one additional autoantigen is/are further present in the biological sample, the subject is identified as having, or being at risk for having, at least one neurodegenerative disease selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and vascular dementia.   
     
     
         10 . The method of  claim 7 , wherein the biological sample is selected from the group consisting of whole blood, serum, cerebrospinal fluid, saliva, and sputum. 
     
     
         11 . The method of  claim 7 , wherein the autoantigens are attached to a substrate. 
     
     
         12 . The method of  claim 7 , wherein the autoantigens are in the form of an array. 
     
     
         13 . The method of  claim 12 , wherein the array is a microarray. 
     
     
         14 . The method of  claim 11 , wherein the substrate is a bead or a nitrocellulose-coated glass slide. 
     
     
         15 . A method of generating a subject-specific, neurodegenerative disease-specific autoantibody profile, the method comprising:
 (a) obtaining an immunoglobulin-containing biological sample from a subject,   (b) performing an assay to determine the presence or absence of autoantibodies in the biological sample, wherein the assay comprises:
 (i) contacting the biological sample with at least two autoantigens selected from the group consisting of cDNA clone MGC:31944 IMAGE:4878869; cDNA clone MGC:27152 IMAGE:4691630; and hematopoietic SH2 domain-containing protein (HSH2D), under conditions that allow immunocomplexes of each of the at least two autoantigens and a corresponding autoantibody to form; and 
 (ii) detecting the presence or absence of the immunocomplexes in the biological sample; and 
   (c) generating a subject-specific neurodegenerative disease-specific autoantibody profile of the disease diagnostic autoantibodies present in the biological sample.   
     
     
         16 . An ordered microarray comprising a substrate and autoantigens immobilized onto the substrate, wherein the only autoantigens in the microarray are the following:
 a first group of autoantigens consisting of Pentatricopeptide repeat domain 2 (PTCD2); FERM domain containing 8 (FRMD8); Chromosome 9 open reading frame 9 (C9orf9); Lectin, galactoside-binding, soluble, 1 (galectin 1) (LGALS1); Proopiomelanocortin (adrenocorticotropin/beta-lipotropin/alpha-melanocyte stimulating hormone/beta-melanocyte stimulating hormone/beta-endorphin) (POMC), transcript variant 2; Mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5), transcript variant 1; Centaurin, alpha 2 (CENTA2); DnaJ homolog subfamily C member 8; Ankyrin repeat and KH domain containing 1 (ANKHD1), transcript variant 3; Mitochondrial ribosomal protein L34 (MRPL34), and nuclear gene encoding mitochondrial protein; and   a second group of two or more autoantigens selected from the group consisting of hematopoietic SH2 domain containing (HSH2D); proteins corresponding to cDNA clone MGC:27152 IMAGE:4691630, complete cds; cDNA clone MGC:31944 IMAGE:4878869, complete cds; and cDNA clone MGC:32654 IMAGE:4701898, complete cds.   
     
     
         17 . The ordered microarray of  claim 16 , wherein two or more autoantigens from the second group are selected from the group consisting of cDNA clone MGC:31944 IMAGE:4878869, complete cds; hematopoietic SH2 domain containing (HSH2D); and cDNA clone MGC:32654 IMAGE:4701898, complete cds. 
     
     
         18 . The ordered microarray of  claim 16 , wherein the substrate is a bead or a nitrocellulose-coated glass slide. 
     
     
         19 . The method of  claim 1 , wherein the substrate antigens consist of antigens that form immunocomplexes with Alzheimer's disease-related autoantibodies.