Methods for diagnosing alzheimer's disease and other neurological disorders

A method of selecting a subject identified as having or at risk of developing a neurological disorder for treatment with a therapeutic agent, the method comprising:

• (i) contacting a blood sample obtained from the subject with a first affinity ligand specific to a first synaptic protein selected from the group consisting of NPTX2, NPTX1, and NPTXR and a second affinity ligand specific to a second synaptic protein selected from the group consisting of NPTX2, NPTX1, and NPTXR, wherein the first and second synaptic proteins are in a first complex, wherein the contacting produces a second complex comprising the first affinity ligand, the first synaptic protein, the second affinity ligand, and the second synaptic protein, wherein the first and second synaptic proteins are different proteins, and wherein the first affinity ligand is conjugated to an oligonucleotide plus strand and the second affinity ligand is conjugated to an oligonucleotide minus strand;
• (ii) contacting the second complex with a single-stranded connector oligonucleotide and a ligase enzyme, thereby producing a ligated plus-minus oligonucleotide strand (LPMOS), wherein the LPMOS is capable of hybridizing to a forward primer oligonucleotide and a reverse primer oligonucleotide;
• (iii) performing amplification on the LPMOS, wherein the amplification produces a proximity signal when the first synaptic protein is within a proximity distance threshold with respect to the second synaptic protein;
• and
• (iv) detecting the proximity signal in the blood sample, wherein the proximity signal indicates an amount of the first complex in the blood sample;
• wherein the subject is selected for treatment with the therapeutic agent if the amount of the first complex in the blood sample of the subject is increased or decreased as compared to an amount of a first complex in a reference blood sample.

A method of assessing resilience in a subject identified as having or at risk of developing a neurological disorder, the method comprising:

• (i) contacting a blood sample obtained from the subject with a first affinity ligand specific to a first synaptic protein selected from the group consisting of NPTX2, NPTX1, and NPTXR and a second affinity ligand specific to a second synaptic protein selected from the group consisting of NPTX2, NPTX1, and NPTXR, wherein the first and second synaptic proteins are in a first complex, wherein the contacting produces a second complex comprising the first affinity ligand, the first synaptic protein, the second affinity ligand, and the second synaptic protein, wherein the first and second synaptic proteins are different proteins, and wherein the first affinity ligand is conjugated to an oligonucleotide plus strand and the second affinity ligand is conjugated to an oligonucleotide minus strand;
• (ii) contacting the second complex with a single-stranded connector oligonucleotide and a ligase enzyme, thereby producing a ligated plus-minus oligonucleotide strand (LPMOS), wherein the LPMOS is capable of hybridizing to a forward primer oligonucleotide and a reverse primer oligonucleotide;
• (iii) performing amplification on the LPMOS, wherein the amplification produces a proximity signal when the first synaptic protein is within a proximity distance threshold with respect to the second synaptic protein;
• and
• (iv) detecting the proximity signal in the blood sample, wherein the proximity signal indicates an amount of the first complex in the blood sample;
• wherein the subject is determined to not be resilient to the neurological disorder if the amount of the first complex in the blood sample of the subject is increased or decreased as compared to an amount of a first complex in a reference blood sample, wherein the subject is determined to be resilient to the neurological disorder if the amount of the first complex in the blood sample of the subject is unchanged or decreased as compared to an amount of a first complex in the reference blood sample.

A method of determining therapeutic efficacy of an agent in a subject identified as having or at risk of developing a neurological disorder, the method comprising:

• (i) contacting a blood sample obtained from the subject with a first affinity ligand specific to a first synaptic protein selected from the group consisting of NPTX2, NPTX1, and NPTXR and a second affinity ligand specific to a second synaptic protein selected from the group consisting of NPTX2, NPTX1, and NPTXR, wherein the first and second synaptic proteins are in a first complex, wherein the contacting produces a second complex comprising the first affinity ligand, the first synaptic protein, the second affinity ligand, and the second synaptic protein, wherein the first and second synaptic proteins are different proteins, and wherein the first affinity ligand is conjugated to an oligonucleotide plus strand and the second affinity ligand is conjugated to an oligonucleotide minus strand;
• (ii) contacting the second complex with a single-stranded connector oligonucleotide and a ligase enzyme, thereby producing a ligated plus-minus oligonucleotide strand (LPMOS), wherein the LPMOS is capable of hybridizing to a forward primer oligonucleotide and a reverse primer oligonucleotide;
• (iii) performing amplification on the LPMOS, wherein the amplification produces a proximity signal when the first synaptic protein is within a proximity distance threshold with respect to the second synaptic protein;
• and
• (iv) detecting the proximity signal in the blood sample, wherein the proximity signal indicates an amount of the first complex in the blood sample;
• wherein the agent is determined to be therapeutically effective in the subject if the amount of the first complex in the blood sample of the subject is unchanged or decreased as compared to an amount of a first complex in a reference blood sample.

A method of assessing learning and memory in a subject identified as having or at risk of developing a neurological disease or disorder, the method comprising:

• (i) contacting a blood sample obtained from the subject with a first affinity ligand specific to a first synaptic protein selected from the group consisting of NPTX2, NPTX1, and NPTXR and a second affinity ligand specific to a second synaptic protein selected from the group consisting of NPTX2, NPTX1, and NPTXR, wherein the first and second synaptic proteins are in a first complex, wherein the contacting produces a second complex comprising the first affinity ligand, the first synaptic protein, the second affinity ligand, and the second synaptic protein, wherein the first and second synaptic proteins are different proteins, and wherein the first affinity ligand is conjugated to an oligonucleotide plus strand and the second affinity ligand is conjugated to an oligonucleotide minus strand;
• (ii) contacting the second complex with a single-stranded connector oligonucleotide and a ligase enzyme, thereby producing a ligated plus-minus oligonucleotide strand (LPMOS), wherein the LPMOS is capable of hybridizing to a forward primer oligonucleotide and a reverse primer oligonucleotide;
• (iii) performing amplification on the LPMOS, wherein the amplification produces a proximity signal when the first synaptic protein is within a proximity distance threshold with respect to the second synaptic protein;
• and
• (iv) detecting the proximity signal in the blood sample, wherein the proximity signal indicates an amount of the first complex in the blood sample;
• wherein an increase or decrease in the amount of the first complex in the blood sample of the subject as compared to an amount of a first complex in a reference blood sample indicates reduced learning and memory in the subject.