Methods of diagnosing alzheimer's disease and markers identified by set association

Abstract

The present disclosure relates to genetic markers and methods of diagnosing and screening for late-onset Alzheimer's disease (LOAD). As such, the disclosure encompasses a whole-genome association analysis of single nucleotide polymorphisms (SNPs) of which a number are located within the GRB2-associated binding protein 2 (GAB2) gene as well as other markers associated with other genes. The disclosure identifies two novel haplotypes within the GAB2 gene, i.e., a LOAD risk-enhancing and a LOAD risk-decreasing haplotype. These haplotypes modify LOAD risk differentially in combination with APOE alleles. Further encompassed are therapeutic methods and agents of decreasing the deterioration of cells associated with LOAD.

1 . A method of assigning a subject to a late onset Alzheimer's disease (LOAD) risk group, the method comprising:
 a.) providing a biological sample from the subject;   c.) detecting, directly or indirectly, a marker in the biological sample selected from a group comprising: a marker associated with a haplotype of GAB2 associated with LOAD and a marker in Table 7; and   d.) assigning the subject to the late onset Alzheimer's disease (LOAD) risk group based upon the presence or absence of the haplotype.   
     
     
         2 . The method of  claim 1 , wherein the marker is associated with increased risk of LOAD and the subject is assigned to a high LOAD risk group if the subject has the marker. 
     
     
         3 . The method of  claim 2 , wherein the marker is associated with the haplotype of GAB2 and is selected from the SNP haploblock identified by SEQ ID NO: 2. 
     
     
         4 . The method of  claim 3 , wherein said assigning is further based upon the presence or absence in the subject of an apolipoprotein E allele associated with increased LOAD risk. 
     
     
         5 . The method of  claim 4 , wherein said apolipoprotein E allele is APOE-ε4. 
     
     
         6 . The method of  claim 3 , wherein said assigning is further based upon the presence or absence in the subject of an apolipoprotein C allele associated with increased LOAD risk. 
     
     
         7 . The method of  claim 6 , wherein said apolipoprotein C allele is APOC-1a as identified by SNP rs4420638. 
     
     
         8 . The method of  claim 1 , wherein the haplotype of GAB2 is associated with decreased risk of LOAD and the subject is assigned to a low LOAD risk group if the subject has the haplotype of GAB2. 
     
     
         9 . The method of  claim 8 , wherein the marker is associated with the haplotype of GAB2 and is selected from the SNP haploblock identified by SEQ ID NO: 1. 
     
     
         10 . The method of  claim 9 , wherein said assigning is further based upon the presence or absence in the subject of an apolipoprotein E allele associated with increased LOAD risk. 
     
     
         11 . The method of  claim 10 , wherein said apolipoprotein E allele is APOE-ε4. 
     
     
         12 . The method of  claim 1 , wherein the marker is detected by a method selected from the group consisting of nucleic acid hybridization, GAB2 antibody binding, and GAB2 activity assay. 
     
     
         13 . The method of  claim 12 , wherein the marker is detected by nucleic acid hybridization using at least one hybridization probe specific to a SNP specific to the SNP haploblock identified by SEQ ID NO:1 or SEQ ID NO:2. 
     
     
         14 . The method of  claim 1 , wherein the marker is detected by polymerase chain reaction (PCR). 
     
     
         15 . The method of  claim 1 , wherein the marker is detected through a S1 nuclease assay. 
     
     
         16 . The method of  claim 1 , wherein the marker is detected by a gene chip. 
     
     
         17 . A set of molecular probes for diagnosis or monitoring a late onset Alzheimer's disease (LOAD) comprising at least two probes capable of detecting directly or indirectly at least two markers selected from a group comprising: a marker associated with a haplotype of GAB2 associated with LOAD, a marker in Table 7, wherein said molecular probes are not associated with a microarray of greater than 1000 elements. 
     
     
         18 . A non-human transgenic animal with a genome comprising the human GAB2 gene of the haplotype identified by the SNP haploblock of SEQ ID NO: 1 or SEQ ID NO: 2. 
     
     
         19 . A method for screening for a therapeutic agent effective to inhibit development of cell deterioration associated with dementia, said method comprising:
 a.) providing the transgenic animal of  claim 18 ;   b.) administering to the transgenic animal an agent to be tested for its effectiveness in treating or preventing said cell deterioration associated with dementia; and   c.) assessing the effectiveness of the agent.   
     
     
         20 . The method of  claim 19 , wherein said dementia is LOAD.