Alzheimer's Disease Education and Referral Center

AMP-AD Target Discovery and Preclinical Validation Project

Accelerating Medicines Partnership (AMP) Alzheimer's Disease.

Go to AMP-AD main page

Project Description

The central goal of the Accelerating Medicines Partnership-Alzheimer’s Disease (AMP-AD) Target Discovery and Preclinical Validation Project is to shorten the time between the discovery of potential drug targets and the development of new drugs for Alzheimer’s disease treatment and prevention, by integrating the analyses of large-scale molecular data from human brain samples with network modeling approaches and experimental validation.

The project is a consortium of four multi-institutional, multidisciplinary cooperative agreement grants. The grant awardees are applying cutting-edge systems and network biology approaches to integrate multidimensional human “omic” data (genomic, epigenomic, RNAseq, proteomic) from more than 2,000 human brains at all stages of the disease with clinical and pathological data to:

  • discover novel therapeutic targets for Alzheimer’s disease
  • gain a systems-level understanding of the gene, protein, and metabolic networks within which these novel targets operate
  • evaluate their drugability in multiple model organisms

AMP-AD Knowledge Portal

To achieve this project’s central goal, grant awardees are expected to engage in broad sharing of biological data, analytical methodology, and disease models before publication. Rapid sharing of data and analytical tools is enabled through the AMP-AD Knowledge Portal.

The AMP-AD Knowledge Portal was developed and is maintained by Sage Bionetworks, a nonprofit organization, and is hosted on Synapse, an informatics data platform. This platform is an Institutional Review Board (IRB)-approved environment where data can be stored, accessed, and collaboratively analyzed. The Sage Bionetworks team facilitates data sharing and data integration activities within the AMP-AD Target Discovery Consortium and collaborative analyses between the academic and industry partners.

The AMP-AD Knowledge Portal will host all data generated by the AMP-AD Target Discovery Consortium members. Newly generated data will be deposited into the portal as soon as quality control is completed and made available quarterly to all qualified users.

Access to AMP-AD data is subject to data-use conditions as determined by the informed consent documents for each study guided by the local IRB. No publication embargo will be imposed on the use of data after the data are made available through the AMP-AD Knowledge Portal. However, the data contributors must be acknowledged as specified in the Data Use Terms for each study.

Target Discovery Consortium Grants

The cooperative agreement grants that constitute the consortium were developed in response to the NIA funding opportunity RFA AG13-013: Interdisciplinary Research for the Identification and Validation of Novel Therapeutic Targets for Alzheimer’s Disease.

Pathway Discovery, Validation and Compound Identification for Alzheimer's Disease (U01AG046152)

Principal Investigators:
Philip L. De Jager (Contact PI), Brigham and Women's Hospital and the Broad Institute, Inc.
David A. Bennett, Rush University

Integrative Biology Approach to Complexity of Alzheimer's Disease (U01AG046170)

Principal Investigators:
Eric Schadt (Contact PI), Icahn School of Medicine at Mount Sinai
Bin Zhang, Icahn School of Medicine at Mount Sinai
Jun Zhu, Icahn School of Medicine at Mount Sinai
Sam Gandy, Icahn School of Medicine at Mount Sinai
Michelle Ehrlich, Icahn School of Medicine at Mount Sinai
Vahram Haroutunian, Icahn School of Medicine at Mount Sinai
Koichi Iljima, Thomas Jefferson University
Scott Noggle, New York Stem Cell Foundation

A System Approach to Targeting Innate Immunity in Alzheimer’s Disease (U01AG046139)

Principal Investigators:
Todd Golde (Contact PI), University of Florida
Nathan Price, Institute for Systems Biology
Nilufer Ertekin-Taner, Mayo Clinic Jacksonville
Steven Younkin, Mayo Clinic Jacksonville

Discovery of Novel Proteomic Targets for Treatment of Alzheimer's Disease (U01AG046161)

Principal Investigators:
Allan Levey, Emory University
David Bennett, Rush University
Tom Montine, University of Washington
Juan Troncoso, The Johns Hopkins University
Dan Geschwind, UCLA
Giovanni Coppola, UCLA
John Trojanowski, University of Pennsylvania

Sage Bionetworks facilitates data sharing and data integration activities within the Target Discovery and Preclinical Validation AMP-AD project. The data enablement provided by Sage Bionetworks includes the development and maintenance of the AMP-AD Knowledge Portal and is supported through administrative supplements to the above cooperative agreement grants. Lara Mangravite and Stephen Friend lead the Sage Bionetworks team responsible for the AMP-AD data enablement effort.

Resources

Publications

  • Bennett DA, Yu L, De Jager PL. Building a pipeline to discover and validate novel therapeutic targets and lead compounds for Alzheimer’s disease. Biochemical Pharmacology 2014;88(4):617-630. www.ncbi.nlm.nih.gov/pubmed/24508835
  • Bennett DA, Yu L, Yang J, Srivastava GP, Aubin C, De Jager PL. Epigenomics of Alzheimer’s disease. Translational Research: The Journal of Laboratory and Clinical Medicine 2015;165(1):200-220. www.ncbi.nlm.nih.gov/pubmed/24905038
  • Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, DiNunno N, Rosario AM, Cruz PE, Verbeeck C, Sacino A, Nix S, Janus C, Price ND, Das P, Golde TE. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 2015;85(3):519-533. www.ncbi.nlm.nih.gov/pubmed/25619653
  • De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, Eaton ML, Keenan BT, Ernst J, McCabe C, Tang A, Raj T, Replogle J, Brodeur W, Gabriel S, Chai HS, Younkin C, Younkin SG, Zou F, Szyf M, Epstein CB, Schneider JA, Bernstein BE, Meissner A, Ertekin-Taner N, Chibnik LB, Kellis M, Mill J, Bennett DA. Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nature Neuroscience 2014;17(9):1156-1163. www.ncbi.nlm.nih.gov/pubmed/25129075
  • Hoffman GE, Mezey JG, Schadt EE. lrgpr: interactive linear mixed model analysis of genome-wide association studies with composite hypothesis testing and regression diagnostics in R. Bioinformatics 2014;30(21):3134-3135. www.ncbi.nlm.nih.gov/pubmed/25035399
  • James BD, Leurgans SE, Hebert LE, Scherr PA, Yaffe K, Bennett DA. Contribution of Alzheimer disease to mortality in the United States. Neurology 2014;82(12):1045-1050. www.ncbi.nlm.nih.gov/pubmed/24598707
  • Lim AS, Srivastava GP, Yu L, Chibnik LB2, Xu J, Buchman AS, Schneider JA, Myers AJ, Bennett DA, De Jager PL. 24-hour rhythms of DNA methylation and their relation with rhythms of RNA expression in the human dorsolateral prefrontal cortex. PLoS Genetics 2014;10(11):e1004792. www.ncbi.nlm.nih.gov/pubmed/25375876
  • Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Molecular Neurodegeneration 2014;9:11. www.ncbi.nlm.nih.gov/pubmed/24607147
  • Mukherjee S, Kim S, Ramanan VK, Gibbons LE, Nho K, Glymour MM, Ertekin-Taner N, Montine TJ, Saykin AJ, Crane PK; Alzheimer’s Disease Neuroimaging Initiative. Gene-based GWAS and biological pathway analysis of the resilience of executive functioning. Brain Imaging and Behavior. 2014;8(1):110-118. www.ncbi.nlm.nih.gov/pubmed/24072271
  • Narayanan M, Huynh JL, Wang K, Yang X, Yoo S, McElwee J, Zhang B, Zhang C, Lamb JR, Xie T, Suver C, Molony C, Melquist S, Johnson AD, Fan G, Stone DJ, Schadt EE, Casaccia P, Emilsson V, Zhu J. Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases. Molecular Systems Biology 2014;10:743. www.ncbi.nlm.nih.gov/pubmed/25080494
  • Roussos P, Katsel P, Fam P, Tan W, Purohit DP, Haroutunian V. The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer’s dementia. Alzheimer’s & Dementia 2014;pii: S1552-5260(14)02868-4. www.ncbi.nlm.nih.gov/pubmed/25499537
  • Sproul AA, Jacob S, Pre D, Kim SH, Nestor MW, Navarro-Sobrino M, Santa-Maria I, Zimmer M, Aubry S, Steele JW, Kahler DJ, Dranovsky A, Arancio O, Crary JF, Gandy S, Noggle SA. Characterization and molecular profiling of PSEN1 familial Alzheimer’s disease iPSC-derived neural progenitors. PLoS One 2014;9(1):e84547. www.ncbi.nlm.nih.gov/pubmed/24416243
  • Woodard CM, Campos BA, Kuo SH, Nirenberg MJ, Nestor MW, Zimmer M, Mosharov EV, Sulzer D, Zhou H, Paull D, Clark L, Schadt EE, Sardi SP, Rubin L, Eggan K, Brock M, Lipnick S, Rao M, Chang S, Li A, Noggle SA. iPSC-derived dopamine neurons reveal differences between monozygotic twins discordant for Parkinson’s disease. Cell Reports 2014;9(4):1173-1182. www.ncbi.nlm.nih.gov/pubmed/25456120
  • Yoo S, Huang T, Campbell JD, Lee E, Tu Z, Geraci MW, Powell CA, Schadt EE, Spira A, Zhu J. MODMatcher: multi-omics data matcher for integrative genomic analysis. PLoS Computational Biology 2014;10(8):e1003790. www.ncbi.nlm.nih.gov/pubmed/25122495
  • Yu L, Chibnik LB, Srivastava GP, Pochet N, Yang J, Xu J, Kozubek J, Obholzer N, Leurgans SE, Schneider JA, Meissner A, De Jager PL, Bennett DA. Association of brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease. JAMA Neurology 2015;72(1):15-24. www.ncbi.nlm.nih.gov/pubmed/25365775