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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation application of U.S. Ser. No. 12 / 148,728, filed Apr. 21, 2008, which claims the benefit of U.S. Provisional Application Ser. No. 60 / 933,583, filed Jun. 6, 2007, and U.S. Provisional Application Ser. No. 60 / 925,638, filed Apr. 20, 2007, all of which are hereby incorporated by reference in their entireties.BACKGROUND[0002]1. Field[0003]The present disclosure relates to genetic markers, compositions for the detection of genetic markers and methods of diagnosing and screening for Alzheimer's disease (AD). Further encompassed are therapeutic methods and agents for decreasing the deterioration of cells associated with AD and methods of screening such agents.[0004]2. Related Art[0005]Disorders of the brain are serious medical conditions causing disability and diminished quality of life. Neurological damage is largely irreversible and thus early diagnosis and close monitoring are critical to the successful treatm...

AI Technical Summary

Benefits of technology

[0014]Another aspect of the disclosure provides for an isolated and / or recombinant nucleic acid encoding the amino acid sequence of GAB2-P2, wherein the amino acid sequence codes for a GAB2 protein that is associated with decreased risk of LOAD in individuals that carry the APOE-ε4 allele. The corresponding nucleotide sequence is provided by GAB2-P1. The nucleic acid can be provided in combination with an expression vector which can be transformed into a host cell such that the host cell expresses the GAB2 protein that is associated with decreased risk of LOAD. This protein has a protective effect and thus, it decreases the likelihood of developing LOAD.

[0017]The disclosure further includes a method of decreasing or preventing neuronal cell deterioration in a subject at risk for LOAD, wherein the method includes administering a compound that modulates PI3K or ERK activity. Such a compound can mimic the function of GAB2 which is encoded by the nucleic acid sequence of SEQ ID NO: 4. The corresponding amino acid sequence is encoded by SEQ ID NO: 5.

[0018]The disclosure also encompasses a method of decreasing or preventing neuronal cell deterioration in a subject at risk for LOAD, wherein the method includes administering an siRNA specific for the haplotype of GAB2 with the SNP haploblock identified by SEQ ID NO: 2. Herein, the subject is heterozygous for the haplotype of GAB2 with the SNP haploblock identified by SEQ ID NO: 2. In a preferred embodiment, the subject is a human or other mammal.

[0019]Yet, another aspect of the disclosure provides a method of treating or preventing neuronal cell deterioration in a subject at risk for LOAD, wherein the method includes isolating stem cells from the subject; contacting the stem cells with a nucleic acid encoding GAB2 or a fragment thereof which is not the haplotype of GAB2 with the SNP haploblock identified by SEQ ID NO: 2, wherein the nucleic acid homologously recombines with at least one genomic copy of GAB2 in the stem cells; and contacting the subject with the stem cells to treat or prevent neuronal cell deterioration. Alternatively, the disclosure provides a method of treating or preventing neuronal cell deterioration in a subject at risk for LOAD, wherein the method includes isolating stem cells from the subject; contacting the stem cells with a nucleic acid encoding GAB2 or a fragment thereof which is the haplotype of GAB2 with the SNP haploblock identified by SEQ ID NO: 1, wherein the nucleic acid homologously recombines with at least one genomic copy of GAB2 in the stem cells; and contacting the subject with the stem cells to treat or prevent neuronal cell deterioration. The subject usually carries an apolipoprotein E allele associated with increased LOAD risk such as the APOE-ε4 allele.

[0020]Still, another aspect of the disclosure provides a method for screening for a therapeutic agent effective to inhibit development of cell deterioration associated with dementia, wherein the method includes incubating neuronal cells in vitro with a mixture of PI3K and an agent to be tested; measuring PI3K activity; comparing the activity to PI3K activity in the absence of the agent to be tested; and identifying the therapeutic agent by indication of PI3K activity in the presence of the agent. The therapeutic agent can inhibit the cell deterioration associated with dementia such as LOAD.

Problems solved by technology

Disorders of the brain are serious medical conditions causing disability and diminished quality of life.

Most of the pathogenic mutations in the APP and presenilin genes are associated with abnormal processing of APP, which leads to the overproduction of toxic Aβ-1-42.

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