Methods and compositions for diagnosis, stratification, and monitoring of Alzheimer's disease and other neurological disorders in body fluids

Abstract

The inventors have discovered a collection of proteinaceous biomarkers (“AD biomarkers) which can be measured in peripheral biological fluid samples to aid in the diagnosis of neurodegenerative disorders, particularly Alzheimer's disease and mild cognitive impairment (MCI). The invention further provides methods of identifying candidate agents for the treatment of Alzheimer's disease by testing prospective agents for activity in modulating AD biomarker levels.

1 . A method of aiding diagnosis of Alzheimer's disease (“AD”), comprising comparing a measured level of at least one AD diagnosis biomarker in a biological fluid sample from an individual to a reference level for the biomarker; wherein the AD diagnosis biomarker is selected from the group consisting of: MCSF, IGF-1, RANTES, GCSF, PARC, Acrp30, Eotaxin-2, BMP-6, ANG, AgRP(ART), FGF-6, TPO, MSP-alpha, betacellulin (BTC), Angiopoetin-2 (ANG-2), IL-12p40, IL-11, Lymphotactin, EGF, MCP-3, IL-3, TRAIL R4, MIP-1delta, IFN-gamma, IGFBP-1, BMP-4, IGFBP-2, TARC, TIMP-1, TIMP-2, ICAM-1, TRAIL R3, uPAR, IGFBP-4, LEPTIN(OB), PDGF-BB, BDNF, NT-3, NAP-2, IL-1ra, SCF, TGF-b3, TNF-b, IL-6 R, sTNF RII, AXL, bFGF, FGF-4, CNTF, MCP-1, MIP-1b, VEGF-B, IL-8, FAS, and EGF-R.  
     
     
         2 . The method of  claim 1 , comprising comparing the measuring level of at least two AD diagnosis biomarkers to a reference level for the biomarkers.  
     
     
         3 . The method of  claim 1 , comprising comparing the measured level of at least three AD diagnosis biomarkers to a reference level for the biomarkers.  
     
     
         4 . The method of  claim 1 , comprising comparing the measured level of at least four AD diagnosis biomarkers to a reference level for the biomarkers.  
     
     
         5 . The method of  claim 1 , comprising comparing the measured level of at least five AD diagnosis biomarkers to a reference level for the biomarkers.  
     
     
         6 . The method of  claim 1 , wherein comparing the measured value to a reference value for each AD diagnosis biomarker measured comprises calculating the fold difference between the measured value and the reference value.  
     
     
         7 . The method of  claim 1 , wherein said biological fluid sample is a peripheral biological fluid sample.  
     
     
         8 . The method of  claim 1 , wherein the at least one AD diagnosis biomarker is selected from the group consisting of: BTC, SDF-1, MCP-2, IFN-gamma, IGFBP-4, IGF-1 SR, IL-8, GM-CSF, and ANG-2.  
     
     
         9 . The method of  claim 1  wherein the at least one AD diagnosis biomarker is selected from the group consisting of biomarkers IFN-gamma and IL-8.  
     
     
         10 . The method of  claim 1  wherein the at least one AD diagnosis biomarker is selected from the group consisting of: TNF RII; MSP-alpha; uPAR; TPO; MIP-1beta; VEGF-beta; FAS; MCP-1; NAP-2; ICAM-1; TRAIL R3; PARC; ANG; IL-3; MIP-1delta; IFN-gamma; IL-8; and FGF-6.  
     
     
         11 . The method of  claim 1  wherein the at least one AD diagnosis biomarker is selected from the group consisting of: lymphotactin and IL-11.  
     
     
         12 . A method for monitoring progression of Alzheimer's disease (AD) in an AD patient, comprising comparing a measured level of at least one AD diagnosis biomarker in a biological sample fluid sample from an individual to a reference level for the biomarker wherein the AD diagnosis biomarker is selected from the group consisting of MCSF, IGF-1, RANTES, GCSF, PARC, Acrp30, Eotaxin-2, BMP-6, ANG, AgRP(ART), FGF-6, TPO, MSP-alpha, betacellulin (BTC), Angiopoetin-2 (ANG-2), IL-12p40, IL-11, Lymphotactin, EGF, MCP-3, IL-3, TRAIL R4, MIP-1delta, IFN-gamma, IGFBP-1, BMP-4, IGFBP-2, TARC, TIMP-1, TIMP-2, ICAM-1, TRAIL R3, uPAR, IGFBP-4, LEPTIN(OB), PDGF-BB, BDNF, NT-3, NAP-2, IL-1ra, SCF, TGF-b3, TNF-b, IL-6 R, sTNF RII, AXL, bFGF, FGF-4, CNTF, MCP-1, MIP-1b, VEGF-B, IL-8, FAS, and EGF-R.  
     
     
         13 . The method of  claim 12 , wherein said reference level is a level obtained from a biological fluid sample from the same AD patient at an earlier point in time.  
     
     
         14 . The method of  claim 12  wherein the biological fluid sample is a peripheral biological fluid sample.  
     
     
         15 . A method for stratifying Alzheimer's disease (AD) in an individual, comprising: 
 comparing a measured level of at least one AD diagnosis biomarker in a biological sample from the individual with a reference level for the at least one biomarker, wherein the at least one biomarker is selected from the group consisting of MCSF, IGF-1, RANTES, GCSF, PARC, Acrp30, Eotaxin-2, BMP-6, ANG, AgRP(ART), FGF-6, TPO, MSP-alpha, betacellulin (BTC), Angiopoetin-2 (ANG-2), IL-12p40, IL-11, Lymphotactin, EGF, MCP-3, IL-3, TRAIL R4, MIP-1delta, IFN-gamma, IGFBP-1, BMP-4, IGFBP-2, TARC, TIMP-1, TIMP-2, ICAM-1, TRAIL R3, uPAR, IGFBP-4, LEPTIN(OB), PDGF-BB, BDNF, NT-3, NAP-2, IL-1ra, SCF, TGF-b3, TNF-b, IL-6 R, sTNF RII, AXL, bFGF, FGF-4, CNTF, MCP-1, MIP-1b, VEGF-B, IL-8, FAS, and EGF-R.    
     
     
         16 . The method of  claim 15  wherein said biological fluid sample is a peripheral fluid sample.