Methods for treating, diagnosing and monitoring alzheimer's disease
AssigneeF. Hoffman-La Roche AG
InventorsTimothy W. Behrens, Robert R. Graham, Tushar Bhangale
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Abstract
The invention provides methods of diagnosis and prognosis of Alzheimer' disease (AD) in a subject comprising detecting the presence or absence of one or more genetic variations in a sample from the subject, wherein the presence of the genetic variation indicates that the subject is afflicted with, or at risk of developing, AD. Methods of predicting the response of a subject to therapeutic agents for the treatment of AD are also provided.
Claims98
A method for detecting the presence or absence of a genetic variation indicative of Alzheimer's disease (AD) in a subject, comprising:
- (a) contacting a sample from the subject with a reagent capable of detecting the presence or absence of a genetic variation in a gene selected from the genes encoding IL6R, NTF4 and UNC5C, or a gene product thereof;
- and
- (b) determining the presence or absence of the genetic variation, wherein the presence of the genetic variation indicates that the subject is afflicted with, or at risk of developing, AD.
A method for detecting a genetic variation indicative of Alzheimer's disease (AD) in a subject, comprising:
- determining the presence or absence of a genetic variation in a gene selected from the genes encoding IL6R, NTF4 and UNC5C, or a gene product thereof, in a biological sample from a subject, wherein the presence of the genetic variation indicates that the subject is afflicted with, or at risk of developing, AD.
A method for diagnosing or prognosing AD in a subject, comprising:
- (a) contacting a sample from the subject with a reagent capable of detecting the presence or absence of a genetic variation in a gene selected from the genes encoding IL6R, NTF4 and UNC5C, or a gene product thereof;
- and
- (b) determining the presence or absence of the genetic variation, wherein the presence of the genetic variation indicates that the subject is afflicted with, or at risk of developing, AD.
A method of diagnosing or prognosing AD in a subject, comprising:
- determining the presence or absence of a genetic variation in a gene selected from the genes encoding IL6R, NTF4 and UNC5C, or a gene product thereof, in a biological sample from a subject, wherein the presence of the genetic variation indicates that the subject is afflicted with, or at risk of developing, AD.
A method of identifying a subject having an increased risk of earlier age of diagnosis of AD, comprising:
- determining the presence or absence of a genetic variation in a gene selected from the genes encoding IL6R, NTF4 and UNC5C, or a gene product thereof, in a biological sample from a subject,
- determining the presence or absence of at least one APOE-ε4 allele,
- wherein the presence of the genetic variation and at least one APOE-ε4 allele indicates that the subject has an increased risk of earlier age of diagnosis of AD as compared to a subject lacking the presence of the genetic variation and at least one APOE-ε4 allele.
A method of aiding prognosis of a subphenotype of AD in a subject, the method comprising detecting in a biological sample derived from the subject the presence of a SNP that results in the amino acid substitution D358A in the amino acid sequence of IL6R (SEQ ID NO:1), wherein the subphenotype of AD is characterized at least in part by increased levels of soluble IL6R in a biological sample derived from the subject as compared to one or more control subjects.
A method of predicting the response of a subject to an AD therapeutic agent that targets IL6R, comprising detecting in a biological sample obtained from the subject a SNP that results in the amino acid substitution D358A in the amino acid sequence of IL6R (SEQ ID NO:1), wherein the presence of the SNP is indicative of a response to a therapeutic agent that targets IL6R.
A method of aiding prognosis of a subphenotype of AD in a subject, the method comprising detecting in a biological sample derived from the subject the presence of a SNP that results in the amino acid substitution R206W in the amino acid sequence of NTF4 (SEQ ID NO:2), wherein the subphenotype of AD is characterized at least in part by decreased activation of TrkB in a biological sample derived from the subject as compared to one or more control subjects.
A method of predicting the response of a subject to an AD therapeutic agent that targets TrkB, comprising detecting in a biological sample obtained from the subject a SNP that results in the amino acid substitution R206W in the amino acid sequence of NTF4 (SEQ ID NO:2), wherein the presence of the SNP is indicative of a response to a therapeutic agent that targets TrkB.
A method of aiding prognosis of a subphenotype of AD in a subject, the method comprising detecting in a biological sample derived from the subject the presence of a SNP that results in the amino acid substitution T835M in the amino acid sequence of UNC5C (SEQ ID NO:3), wherein the subphenotype of AD is characterized at least in part by increased apoptotic activity of UNC5C in a biological sample derived from the subject as compared to one or more control subjects.
A method of predicting the response of a subject to an AD therapeutic agent that targets UNC5C, comprising detecting in a biological sample obtained from the subject a SNP that results in the amino acid substitution T835M in the amino acid sequence of UNC5C (SEQ ID NO:3), wherein the presence of the SNP is indicative of a response to a therapeutic agent that targets UNC5C.
A method of diagnosing or prognosing Alzheimer's Disease (AD) in a subject, comprising:
- (a) contacting a sample from the subject with a reagent capable of detecting the presence or absence of one or more SNPs selected from the group consisting of a SNP that results in the amino acid substitution D358A in the amino acid sequence of IL6R (SEQ ID NO:1), a SNP that results in the amino acid substitution R206W in the amino acid sequence of NTF4, and a SNP that results in the amino acid substitution T835M in the amino acid sequence of UNC5C (SEQ ID NO:3), and
- (b) analyzing the sample to detect the presence of said one or more SNPs, wherein the presence of the one or more SNPs in the sample indicates that the subject is afflicted with, or at risk of developing, AD.
The method of claim 85, further comprising detecting one or more SNPs selected from the SNPs listed in Table 3.
A method of diagnosing or prognosing Alzheimer's Disease (AD) in a subject, comprising:
- (a) contacting a sample from the subject with a reagent capable of detecting the presence or absence of one or more amino acid substitutions selected from the group consisting of the amino acid substitution D358A in the amino acid sequence of IL6R (SEQ ID NO:1), the amino acid substitution R206W in the amino acid sequence of NTF4, and the amino acid substitution T835M in the amino acid sequence of UNC5C (SEQ ID NO:3), and
- (b) analyzing the sample to detect the presence of said one or more amino acid substitutions, wherein the presence of the one or more amino acid substitutions in the sample indicates that the subject is afflicted with, or at risk of developing, AD.
A therapeutic target for the treatment of AD, wherein the therapeutic target is one or a combination of proteins encoded by the genes selected from IL6R, NTF4 and UNC5C.
A set of molecular probes for diagnosis or prognosing AD comprising at least two probes capable of detecting directly or indirectly at least two markers selected from the group comprising:
- a SNP that results in the amino acid substitution D358A in the amino acid sequence of IL6R (SEQ ID NO:1), a SNP that results in the amino acid substitution R206W in the amino acid sequence of NTF4, and a SNP that results in the amino acid substitution T835M in the amino acid sequence of UNC5C (SEQ ID NO:3), wherein said molecular probes are not associated with a microarray of greater than 1000 elements.
A method of screening for genetic variants having a detrimental or beneficial effect on the development of AD in subjects having at least one APOE-ε4 allele, the method comprising identifying a genetic variant that is present at increased or decreased frequency in subjects under 65 years of age, having AD, and having at least one APOE-ε4 allele, as compared to control subjects over 75 years of age, without AD, and having at least one APOE-ε4 allele, wherein increased frequency in subjects having AD as compared to control subjects indicates that the genetic variation is associated with a detrimental effect in subjects having at least one APOE-ε4 allele, and decreased frequency in subjects having AD as compared to control subjects indicates that the genetic variation is associated with a beneficial effect in subjects having at least one APOE-ε4 allele.
A method of screening for genetic variants having a detrimental or beneficial effect on the development of AD in subjects having at least one APOE-ε4 allele, the method comprising
- (a) determining the genotype at one or more genetic locus of a plurality of subjects under 65 years of age, having AD, and having at least one APOE-ε4 allele;
- (b) determining the genotype at one or more genetic locus of a plurality of control subjects over 75 years of age, without AD, and having at least one APOE-ε4 allele;
- and
- (c) identifying a genetic variant that is present at increased or decreased frequency in subjects having AD as compared to control subjects, wherein increased frequency in subjects having AD as compared to control subjects indicates that the genetic variation is associated with a detrimental effect in subjects having at least one APOE-ε4 allele, and decreased frequency in subjects having AD as compared to control subjects indicates that the genetic variation is associated with a beneficial effect in subjects having at least one APOE-ε4 allele.
Dependencies are inferred from the claim text.