Biomarkers for alzheimer's disease

Abstract

The present invention provides protein-based biomarkers and biomarker combinations that are useful in qualifying Alzheimer's disease status in a patient. In particular, the biomarkers of this invention are useful to classify a subject sample as Alzheimer's or non-Alzheimer's dementia or normal. The biomarkers can be detected by SELDI mass spectrometry. In addition, the invention provides appropriate treatment interventions and methods for measuring response to treatment. Certain biomarkers of the invention may also be suitable for employment as radio-labeled ligands in non-invasive imaging techniques such as Positron Emission Tomography (PET).

1 . A method for qualifying Alzheimer's disease status in a subject comprising:
 a. measuring at least one biomarker in a biological sample from the subject, wherein the at least one biomarker is selected from the group consisting of M60464.7 (Hemopexin), M3513.9 (7B2 CT fragment), M8291.0 (Ubiquitin-3aa from CT), M9802.4 (EA-92 (ChrA peptide)), M16207.4 (Pancreatic ribonuclease), M14092.7 (Transthyretin S-glutathionylated), M13904.7 (Transthyretin S-Cys/S-CysGly), M12545.9 (Cystatin-C-8aa from NT), M8183.6 (Ubiquitin-4aa from CT), M5227.4, M3687.0 (Secretoneurin (ChrC/SGII peptide)), M3906.4 Vasostatin II (ChrA peptide), M14565.1 (Pancreatic ribonuclease), M6509.6 (Chromogranin B peptide), M4320.6 (A-beta 1-40), M7258.2 (Chromogranin B peptide), M17349.3 (Apolipoprotein A-II dimer), M8938.5 (C3a des-Arg), M23477.4 (Prostaglandin-D synthase), M4357.0 (Alpha-l-antichymotrypsin CT fragment), M7653.2 (Osteopontin CT fragment), M4812.5 (VGF(NCBI) peptide), M4989.4 (Thymosin beta-4-acetylated), and M7718.8 (Osteopontin CT fragment phosphorylated); and   b. correlating the measurement with Alzheimer's disease status.   
     
     
         2 . The method of  claim 1 , further comprising measuring at least one additional biomarker in a biological sample from said subject, wherein said at least one additional biomarker is selected from the group consisting of M11725.7 (Beta-2-Microglobulin), M78936.5 (transferrin), M13349.5 (Cystatin C), M66479.2 (Albumin) and M8585.9 (Ubiquitin). 
     
     
         3 . A method for qualifying Alzheimer's disease status in a subject comprising:
 a. measuring at least one biomarker in a biological sample from the subject, wherein the at least one biomarker is selected from the group consisting of M60464.7(Hemopexin), M3513.9 (7B2 CT fragment), M8291.0 (Ubiquitin-3aa from CT), M5044.2, M10379.8 (10.3 kDa), M9984.6 (related to 10.3 kDa), M10265.6 (related to 10.3 kDa), M9802.4 (EA-92 (ChrA peptide)), 9757.0 (related to 10.3 kDa), M16207.4 (Pancreatic ribonuclease), M14092.7 (Transthyretin S-glutathionylated), M13904.7 (Transthyretin S-Cys/S-CysGly), M12545.9 (Cystatin-C-8aa from NT), M8183.6 (Ubiquitin-4aa from CT), M5227.4, M3687.0 (Secretoneurin (ChrC/SGII peptide)), M3906.4 Vasostatin II (ChrA peptide), M3806.2, M8955.1, M5263.9, M14565.1 (Pancreatic ribonuclease), M20839.2, M6509.6 (Chromogranin B peptide), M4320.6 (A-beta 1-40), M7258.2 (Chromogranin B peptide), M17349.3 (Apolipoprotein A-II dimer), M58845.4, M8938.5 (C3a des-Arg), M6608.9, M5838.3, M23477.4 (Prostaglandin-D synthase), M4357.0 (Alpha-1-antichymotrypsin CT fragment), M7653.2 (Osteopontin CT fragment), M16716.9, M4812.5 (VGF(NCBI) peptide), M4989.4 (Thymosin beta-4-acetylated), M7878.7, M92082.4, M66479.2 (Albumin), M3967.6, M7718.8 (Osteopontin CT fragment phosphor), M89707.1, M11579.2, and M4455.4; and   b. correlating the measurement with Alzheimer's disease status.   
     
     
         4 . The method of  claim 3 , further comprising measuring at least one additional biomarker in a biological sample from said subject, wherein said at least one additional biomarker is selected from the group consisting of M11725.7 (Beta-2-Microglobulin), M78936.5 (transferrin), M13349.5 (Cystatin C), M66479.2 (Albumin) and M8585.9 (Ubiquitin). 
     
     
         5 . The method of  claim 1 , wherein said at least one biomarker comprises M60464.7 (Hemopexin). 
     
     
         6 . The method of  claim 3 , wherein said at least one biomarker comprises M10379.8 (10.3 kDa). 
     
     
         7 . The method of  claim 1 , wherein said at least one biomarker comprises M17349.3 (Apolipoprotein A-II dimer). 
     
     
         8 . The method of  claim 3 , further comprising measuring each of the following biomarkers: M17349.3 (Apolipoprotein A-II dimer), M60464.7 (Hemopexin), M10379.8 (10.3 kDa) and M11725.7 (Beta-2-Microglobulin). 
     
     
         9 . The method of  claim 1 , further comprising measuring each of the following biomarkers: M17349.3 (Apolipoprotein A-II dimer) and M60464.7 (Hemopexin). 
     
     
         10 . The method of  claim 1 , further comprising measuring each of the following biomarkers: M17349.3 (Apolipoprotein A-II dimer), M60464.7 (Hemopexin) and M3513.9 (7B2 CT fragment). 
     
     
         11 . The method of  claim 1 , wherein the at least one biomarker is measured by capturing the biomarker on an adsorbent surface of a SELDI probe and detecting the captured biomarkers by laser desorption-ionization mass spectrometry. 
     
     
         12 . The method of  claim 1 , wherein the at least one biomarker is measured by immunoassay 
     
     
         13 . The method of  claim 1 , wherein the sample is CSF or serum. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the correlating is performed by a software classification algorithm. 
     
     
         16 . The method of  claim 1 , wherein Alzheimer's disease status is selected from Alzheimer's disease and non-dementia. 
     
     
         17 . The method of  claim 1 , further comprising (c) managing subject treatment based on the status. 
     
     
         18 - 27 . (canceled) 
     
     
         28 . A kit comprising:
 (a) a solid support comprising at least one capture reagent attached thereto, wherein the capture reagent binds at least one biomarker selected from a first group consisting of M60464.7 (Hemopexin), M3513.9 (7B2 CT fragment), M8291.0 (Ubiquitin-3aa from CT), M5044.2, M10379.8 (10.3 kDa), M9984.6 (related to 10.3 kDa), M10265.6 (related to 10.3 kDa), M9802.4 (EA-92 (ChrA peptide)), 9757.0 (related to 10.3 kDa), M16207.4 (Pancreatic ribonuclease), M14092.7 (Transthyretin S-glutathionylated), M13904.7 (Transthyretin S-Cys/S-CysGly), M12545.9 (Cystatin-C-8aa from NT), M8183.6 (Ubiquitin-4aa from CT), M5227.4, M3687.0 (Secretoneurin (ChrC/SGII peptide)), M3906.4 Vasostatin II (ChrA peptide), M3806.2, M8955.1, M5263.9, M14565.1 (Pancreatic ribonuclease), M20839.2, M6509.6 (Chromogranin B peptide), M4320.6 (A-beta 1-40), M7258.2 (Chromogranin B peptide), M17349.3 (Apolipoprotein A-II dimer), M58845.4, M8938.5 (C3a des-Arg), M6608.9, M5838.3, M23477.4 (Prostaglandin-D synthase), M4357.0 (Alpha-l-antichymotrypsin CT fragment), M7653.2 (Osteopontin CT fragment), M16716.9, M4812.5 (VGF(NCBI) peptide), M4989.4 (Thymosin beta-4-acetylated), M7878.7, M92082.4, M66479.2 (Albumin), M3967.6, M7718.8 (Osteopontin CT fragment phosphor), M89707.1, M11579.2, and M4455.4; and   (b) instructions for using the solid support to detect a biomarker of Table II, Table IV-A or Table IV-B.   
     
     
         29 - 41 . (canceled) 
     
     
         42 . A software product comprising:
 a. code that accesses data attributed to a sample, the data comprising measurement of at least one biomarker in the sample, the biomarker selected from the group consisting of M60464.7 (Hemopexin), M3513.9 (7B2 CT fragment), M8291.0 (Ubiquitin-3aa from CT), M5044.2, M10379.8 (10.3 kDa), M9984.6 (related to 10.3 kDa), M10265.6 (related to 10.3 kDa), M9802.4 (EA-92 (ChrA peptide)), 9757.0 (related to 10.3 kDa), M16207.4 (Pancreatic ribonuclease), M14092.7 (Transthyretin S-glutathionylated), M13904.7 (Transthyretin S-Cys/S-CysGly), M12545.9 (Cystatin-C-8aa from NT), M8183.6 (Ubiquitin-4aa from CT), M5227.4, M3687.0 (Secretoneurin (ChrC/SGII peptide)), M3906.4 Vasostatin II (ChrA peptide), M3806.2, M8955.1, M5263.9, M14565.1 (Pancreatic ribonuclease), M20839.2, M6509.6 (Chromogranin B peptide), M4320.6 (A-beta 1-40), M7258.2 (Chromogranin B peptide), M17349.3 (Apolipoprotein A-II dimer), M58845.4, M8938.5 (C3a des-Arg), M6608.9, M5838.3, M23477.4 (Prostaglandin-D synthase), M4357.0 (Alpha-l-antichymotrypsin CT fragment), M7653.2 (Osteopontin CT fragment), M16716.9, M4812.5 (VGF(NCBI) peptide), M4989.4 (Thymosin beta-4-acetylated), M7878.7, M92082.4, M66479.2 (Albumin), M3967.6, M7718.8 (Osteopontin CT fragment phosphor), M89707.1, M11579.2, and M4455.4; and   b. code that executes a classification algorithm that classifies the Alzheimer's disease status of the sample as a function of the measurement.   
     
     
         43 - 63 . (canceled) 
     
     
         64 . A method for modulating the concentration of Cystatin C in a cell, wherein said method comprises: contacting said cell with a protease inhibitor, wherein said protease inhibitor prevents cleavage of cystatin C between Arg8 and Leu9. 
     
     
         65 - 69 . (canceled)