Methods, Systems & Kits for Prediction, Detection, Monitoring & Treatment of Alzheimer's Disease

A system for detecting salivary biomarkers indicative of Alzheimer's disease (AD) in a saliva sample obtained from a subject to determine whether the subject is afflicted with AD or the severity of AD in the subject, the system comprising:

• (a) binding agents specific to one or more salivary biomarker selected from the group consisting of Insulin-like growth factor binding protein-2 (IGFBP-2), Insulin-like growth factor binding protein-3 (IGFBP-3), Beta-secretase 1 (BACE1), Reduced glutathione (GSH), TNF-related apoptosis-including ligand (TRAIL), Chitinase-3-like protein 1 (YKL-40), Intercellular Adhesion Molecule 1 (ICAM-1), Neurofilament protein L (NfL), Alpha-1 antitrypsin (A1AT), Transthyretin (TTR), Neurogranin, and Human heart fatty acid binding protein (hFABP), and combinations thereof;
• (b) a measurable label associated with the binding agents that indicates a proportional reaction based on the amount of biomarker present in the saliva sample;
• and
• (c) a measurement device operable to utilize the label to provide a qualitative, semi-quantitative, or quantitative measure of the one or more salivary biomarker indicative of whether the subject is afflicted with AD or the severity of AD in the subject.

A kit for detecting salivary biomarkers indicative that a subject is afflicted with Alzheimer's disease (AD) or the severity of AD in the subject, the kit comprising:

• (a) a solid support on which a plurality of binding agents have been affixed, directly or indirectly, capable of binding with one or more biomarker in a saliva sample obtained from the subject selected from the group consisting of;
• Insulin-like growth factor binding protein-2 (IGFBP-2), Insulin-like growth factor binding protein-3 (IGFBP-3), Beta-secretase 1 (BACE1), Reduced glutathione (GSH), TNF-related apoptosis-including ligand (TRAIL), Interleukin 6 (IL-6), Chitinase-3-like protein 1 (YKL-40), Intercellular Adhesion Molecule 1 (ICAM-1), Vascular cell adhesion protein 1 (VCAM-1), Neurofilament protein L (NfL), Alpha-1 antitrypsin (A1AT), Transthyretin (TTR), Neurogranin, and Human heart fatty acid binding protein (hFABP), and combinations thereof;
• (b) a measurable label associated with the binding agents which provides a detectable complex indicative of the amount of the one or more detected biomarker in the saliva sample, wherein IGFBP-2 above about 2500 pg/ml, IGFBP-3 above about 1680 ng/ml, BACE1 above about 700 pg/ml, GSH less than about 1.7 μmol/l, TRAIL above about 3 ng/ml, IL-6 above about 20 pg/ml, YKL-40 above about 30 ng/ml, ICAM-1 above about 200 ng/ml, VCAM-1 above about 450 ng/ml, NfL above about 0.3 pg/ml, A1AT less than about 650 ng/ml, TTR less than about 10 μg/ml, Neurogranin above about 5 pg/ml, and/or hFABP above about 0.80 ng/ml, is indicative that the subject is afflicted with AD.

A method for treatment of a subject afflicted with Alzheimer's disease (AD) comprising the steps of:

• (a) testing a saliva sample from the subject for levels of one or more of a group of biomarkers consisting of Insulin-like growth factor binding protein-2 (IGFBP-2), Insulin-like growth factor binding protein-3 (IGFBP-3), Beta-secretase 1 (BACE1), Reduced glutathione (GSH), TNF-related apoptosis-including ligand (TRAIL), Interleukin 6 (IL-6), Chitinase-3-like protein 1 (YKL-40), Intercellular Adhesion Molecule 1 (ICAM-1), Vascular cell adhesion protein 1 (VCAM-1), Neurofilament protein L (NfL), Alpha-1 antitrypsin (A1AT), Transthyretin (TTR), Neurogranin, and Human heart fatty acid binding protein (hFABP);
• and
• (b) determining that the saliva sample is positive for AD if the levels of the one or more biomarkers of the group meet one or more criteria in a group of test criteria consisting of
• (1) IGFBP-2 above about 2500 pg/ml;
• (2) IGFBP-3 above about 1680 ng/ml;
• (3) BACE1 above about 700 pg/ml;
• (4) GSH less than about 1.7 μmol/l;
• (5) TRAIL above about 3 ng/ml;
• (6) IL-6 above about 20 pg/ml;
• (7) YKL-40 above about 30 ng/ml;
• (8) ICAM-1 above about 200 ng/ml;
• (9) VCAM-1 above about 450 ng/ml;
• (10) NfL above about 0.3 pg/ml;
• (11) A1AT less than about 650 ng/ml;
• (12) TTR less than about 10 μg/ml;
• (13) Neurogranin level above about 5 pg/ml;
• and
• (14) hFABP above about 0.80 ng/ml;
• (c) administering a drug or agent to the subject;
• and
• (d) comparing changes in the test criteria over time responsive to the drug or agent to determine whether the subject has benefited from treatment with said agent or drug.

A method for detecting whether a subject who is asymptomatic of Alzheimer's disease (AD) is actually afflicted with AD comprising the steps of:

• (a) testing a saliva sample from a subject who is asymptomatic of AD for levels of one or more of a group of biomarkers consisting of Insulin-like growth factor binding protein-2 (IGFBP-2), Insulin-like growth factor binding protein-3 (IGFBP-3), Beta-secretase 1 (BACE1), Reduced glutathione (GSH), TNF-related apoptosis-including ligand (TRAIL), Interleukin 6 (IL-6), Chitinase-3-like protein 1 (YKL-40), Intercellular Adhesion Molecule 1 (ICAM-1), Vascular cell adhesion protein 1 (VCAM-1), Neurofilament protein L (NfL), Alpha-1 antitrypsin (A1AT), Transthyretin (TTR), Neurogranin, and Human heart fatty acid binding protein (hFABP);
• and
• (b) determining that the saliva sample is positive for AD if the levels of the one or more biomarkers of the group meet one or more criteria in a group of test criteria consisting of
• (1) IGFBP-2 in the range of about 2600 pg/ml to about 3800 pg/ml;
• (2) IGFBP-3 in the range of about 2100 ng/ml to about 3000 ng/ml;
• (3) BACE1 in the range of about 800 pg/ml to about 1109 pg/ml;
• (4) GSH in the range of about 1 μmol/l to about 1.6 μmol/l;
• (5) TRAIL in the range of about 3 ng/ml to about 5.5 ng/ml;
• (6) IL-6 in the range of about 25 pg/ml to about 36 pg/ml;
• (7) YKL-40 in the range of about 33 ng/ml to about 50 ng/ml;
• (8) ICAM-1 in the range of about 200 ng/ml to about 320 ng/ml;
• (9) VCAM-1 in the range of about 720 ng/ml to about 1065 ng/ml;
• (10) NfL in the range of about 0.5 pg/ml to about 2.5 pg/ml;
• (11) A1AT in the range of about 250 ng/ml to about 500 ng/ml;
• (12) TTR in the range of about less than about 3 μg/ml to about 10 μg/ml;
• (13) Neurogranin in the range of about 4.5 pg/ml to about 7 pg/ml;
• and
• (14) hFABP in the range of about 0.96 ng/ml to about 1.78 ng/ml,
• wherein detection that the biomarker is present in the reference value or amount range is indicative that the subject is afflicted with mild cognitive impairment with probable early AD (MCIAD) equivalent to an MMSE score of about 26.5 to about 26.8.