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(12) Patent Application Publication (10) Pub. No.: US 2014/0304845 A1 Loboda Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0304845 A1 Loboda Et Al US 201403.04845A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0304845 A1 Loboda et al. (43) Pub. Date: Oct. 9, 2014 54) ALZHEMIERS DISEASE SIGNATURE Publicationublication ClassificatiClassification MARKERS AND METHODS OF USE (51) Int. Cl. (71) Applicant: MERCKSHARP & DOHME CORP, CI2O I/68 (2006.01) Rahway, NJ (US) AOIK 67/027 (2006.01) (52) U.S. Cl. (72) Inventors: SIES yet.sS); CPC .......... CI2O I/6883 (2013.01); A0IK 67/0275 Icnaei NepoZnyn, Yeadon, (2013.01) le.East,Italia; David J. Stone, Wyncote, USPC .............. 800/12:536/23.5:536/23.2:506/17 (US); Keith Tanis, Quakertown, PA (US); William J. Ray, Juniper, FL (US) (57) ABSTRACT (21) Appl. No.: 14/354,622 Methods, biomarkers, and expression signatures are dis 1-1. closed for assessing the disease progression of Alzheimer's (22) PCT Filed: Oct. 26, 2012 disease (AD). In one embodiment, BioAge (biological age), NdStress (neurodegenerative stress), Alz (Alzheimer), and (86). PCT No.: PCT/US12A62218 Inflame (inflammation) are used as biomarkers of AD pro S371 (c)(1), gression. In another aspect, the invention comprises a gene (2), (4) Date: Apr. 28, 2014 signature for evaluating disease progression. In still another Related U.S. Application Data abiliticises in (60) Provisional application No. 61/553,400, filed on Oct. used to identify animal models for use in the development and 31, 2011. evaluation of therapeutics for the treatment of AD. Patent Application Publication Oct. 9, 2014 Sheet 1 of 16 US 2014/0304845 A1 Y : : O O O O O O O O D O v v CN On cy Patent Application Publication Oct. 9, 2014 Sheet 2 of 16 US 2014/0304845 A1 900-º,=4,JOE NÈN ?zz NÊN 55 60 65 70 75 80 85 90 95 20 40 60 80 100 Age FIG.2B Patent Application Publication Oct. 9, 2014 Sheet 3 of 16 US 2014/0304845 A1 Correlation of disease-specific genes 1 OO 200 400 1 OO 200 3OO 4OO 5OO 600 Patent Application Publication Oct. 9, 2014 Sheet 4 of 16 US 2014/0304845 A1 Q Lo FIG. 3B Patent Application Publication Oct. 9, 2014 Sheet 5 of 16 US 2014/0304845 A1 0. 3. O S O Age BioAge Lipo Inflame NdStress FIG.4 Patent Application Publication Oct. 9, 2014 Sheet 6 of 16 US 2014/0304845 A1 1 R2 = 0.66, p = 1E-051 0.8 R2 = 0.7, p = 3E-056 0.6 0.4 0.2 O i -0.2 -0.4 -0.5 O -0.6 -0.5 O 0.5 1 -0.5-0.4–0.3-0.2-0.1 0 (0.10.2 0.30.4 0.5 BioAge in PFC1 inflame in PFC 1 FIG. 5A FIG. 5B R2 = 0.94, p = 3E-129 0.3 R2 = 0.16, p = 2E-009 0.25 0.2 0.15 0,1 0.05 O -0.05 -0.1 O -0.15 0.3, -0.1 0 (0.1 0.2 0.3 0.4 0.5 0.6 0.264-03-02-0. 0 0 1 0.2 0.5 O,4 0.5 0.6 NdStreSS in PFC1 AZ in PFC1 FIG.5C FIG.5D Patent Application Publication Oct. 9, 2014 Sheet 7 of 16 US 2014/0304845 A1 PFC2, Alzheimer vs Huntington NdStress FIG.6 Patent Application Publication Oct. 9, 2014 Sheet 8 of 16 US 2014/0304845 A1 Chronological Age (Time) FIG.7A A&Aging A2 S S e NO Lipa N1232Infairne N2NN Aging N5 Aging FIG.7B Patent Application Publication Oct. 9, 2014 Sheet 9 of 16 US 2014/0304845 A1 10 103 is 102 gS 101 100 10-50 10-40 10-50 10-20 10-10 100 p-Value Cutoff FIG. 8A 1 PFC1 PFC1 0.8 ? ge a. 5 S-0.6 L 5 c -- 0.4 O S C 9 0.2 as O O e's - 12345678910 -1 -0.5 O 0.5 1 Principal Components PC1 Correlations in Normal FIG.8B FIG. 8C Patent Application Publication Oct. 9, 2014 Sheet 10 of 16 US 2014/0304845 A1 BTG2 PLK1 CDC25B MAD2L2 RPS27L DDB2 TP53INP1 TPKB TNFRSF10C 09 009 Patent Application Publication Oct. 9, 2014 Sheet 11 of 16 US 2014/0304845 A1 CN C O BACE1 PSEN1 PSEN1 BACE1 S. AKR1A1 AKR1A1 DHRS7B DHRS7B PSEN2 9 (-)NdStress APP MAPT MAPT (-)BioAgeCALB1 S PSMD6 PSMB1 HSPA1B HSPA 1A - S. STP1 (+)NdStress HES1 TGFB2 TGFB2 - S APOE APOE PPAP2B PPAP2B Lipa 2 NOTCH1 (+)BioAgeGFAP IL 10 IL1B s IL 16 CASP1 Inflame TWIST1 WNT6 VIM AZ FN1 FN1 O C O C d O D O r v- CN Patent Application Publication Oct. 9, 2014 Sheet 12 of 16 US 2014/0304845 A1 R2 = 0.36, p = 4E-026 O,6 R2 = 0.28, p = 1E-019 5 o -0.2 0.4 -0.5 O 0.5 1 -0.4 -0.2 0 (0.2 0.4 BioAge in PFC inflone in PFC FIG. 1 1A FIG. 1 1B 0.8 R2 = 0.85, p = 2E-098 R2 = 0.071, p = 2E-005 5 0.6 is 0.4 0.2 O 2 -0.2 -0.4 -0.2 O 0.2 0.4 0.6 -0.4 -0.2 0 (0.2 0.4 NdStress in PFC AIZ in PFC FIG. 1 1 C FIG. 1 1D Patent Application Publication Oct. 9, 2014 Sheet 13 of 16 US 2014/0304845 A1 - 0. 2 FIG. 12C FIG. 1 2D Patent Application Publication Oct. 9, 2014 Sheet 14 of 16 US 2014/0304845 A1 -0.42 -0.44 -0.46 -0.48 -0.5 -0.52 -0.54 -0.56 -0.58 -0.6 Model ZWild-typez Diet ŽNormal%SMethionineSó %SMethionineS WKS 2 5 11 11 11 2 5 11 11 11 2 5 11 11 11 2 5 11 11 11 FIG. 13 Patent Application Publication Oct. 9, 2014 Sheet 15 of 16 US 2014/0304845 A1 1.74 1.72 1.64 1.62 Diet WKS 2 5 11 11 11 2 5 11 11 11 2 5 11 11 11 2 5 11 11 11 FIG. 14 Patent Application Publication Oct. 9, 2014 Sheet 16 of 16 US 2014/0304845 A1 0.2 0.15 0.1 0.05 -0.05 ADEarly AD MS CTRL FIG. 15 US 2014/0304845 A1 Oct. 9, 2014 ALZHEIMER'S DISEASE SIGNATURE tive diseases such as Huntington's disease (HD) and Parkin MARKERS AND METHODS OF USE Son's disease, the formation of toxic insoluble aggregates seems to be a key pathogenic step. It is not known why these FIELD OF THE INVENTION A? and tau aggregates accumulate in AD patients, nor how they contribute to neuronal dysfunction, particularly as to AB 0001) The invention relates generally to the use of gene deposits, which can often be found in the brains of elderly expression marker gene sets that are correlated to Alzhe non-demented subjects (Schmitt, F. A., et al., 2000, Neurol imer's disease progression and methods of using thereof. ogy, 55:370-376). I0004. An important goal of AD research is to identify BACKGROUND OF THE INVENTION interventions that maintain brain function, potentially by 0002. During normal aging the brain undergoes many inhibiting the formation or improving the clearance of neu changes resulting in a gradual but detectable cognitive rotoxic aggregates, or by promoting resistance to or recovery decline that is associated with limited neuronal loss and glial from damage. A number of biological processes have been proliferation in the cortex and gross weight decrease of 2-3% associated with AD including cholesterol metabolism, per decade (Drachman, D. A., 2006, Neurology, 67: 1340 inflammation, and response to misfolded proteins, such as 1352; Yankner, B. A., et al., 2008, Annu. Rev. Pathol. 3:41 increased expression of heat shock proteins. The link with 66). On the molecular level the mechanisms driving aging of lipid metabolism is supported, for example, by the essential the brain are not yet understood, but likely include mitochon role of APOEinlipid transportin the brain (Kleiman, T., et al., drial DNA damage (Lu, T., et al., 2004, Nature 429:883-891) 2006; Stone, D. J., et al., 2010). These processes have not and chronic oxidative stress (Lin, M. T., et al., 2006, Nature been unequivocally ordered into a pathogenic cascade and the 443:787-795). This slow decline in cognitive ability does not molecular mediators and correlates of each are largely interfere with normal function through at least 100 years of unknown. life. In contrast Alzheimer's disease (AD) is a debilitating 0005 Microarray gene expression profiling provides an neurodegenerative disorder associated with a rapid cognitive opportunity to observe processes that are common for normal decline with an average survival of 5-10 years after the diag aging. AD, and other neurodegenerative diseases, as well as to nosis (Blennow, K., et al., 2006, Lancet, 368:387-403): Cum detect the differences between these conditions and disen mings, J. L., 2004, N. Engl. J. Med., 351:56-67: Jakob-Ro tangle their relationships. Towards that end, Applicants pro etne, R. and Jacobsen, H., 2009, Angew. Chem. Int. Ed. Engl., filed post-mortem samples from non-demented and AD sub 48:3030-3059). Age is the main AD risk factor with almost jects and used gene co-expression network analysis to half of the population over age 85 affected. However, AD distinguish several major processes involved in brain aging clearly differs from the normal aging in that it causes dramatic and disease and to define the corresponding signature scores loss of synapses, neurons and brain activity in specific ana quantitatively.
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