Research Enterprise

The steady increase in funding for Alzheimer’s and related dementias research has enabled NIH to redouble investments in key research areas necessary for laying the groundwork for a precision medicine approach to treatment and prevention, from cutting-edge disease mechanisms and genetics research to population studies and innovative drug and biomarker development programs. In addition to these efforts, NIH has launched a number of programs over the past six years to provide researchers with an infrastructure for developing their ideas for medicines and other products, including:

A hallmark of these programs is that they bring together scientists from academia and the pharmaceutical industry who are working in many different disciplines, from epidemiology and genetics to data science and computational biology, molecular and cell biology, and medicinal chemistry and pharmacology. Working in collaboration, the researchers take an open-science/open-source approach to the key steps of the translational process. They are discovering new and better targets for treatment; producing and analyzing extremely large sets of molecular data; and developing high- quality translational research tools, such as animal models, chemical tools, and cellular assays.

Accelerating Medicines Partnership for Alzheimer’s Disease Target Discovery Program

The AMP AD Target Discovery Program was established in 2014 as a partnership among government, nonprofit organizations, and the pharmaceutical industry. This NIA-led program, which is managed by the Foundation for the NIH, is leveraging decades-old public investment in epidemiology research and brain tissue banking by generating high-quality multi-omic data (such as genome, proteome, metabolome, and microbiome data) and deploying cutting-edge computational and experimental methods to deliver deeper understanding of the complex biology of the disease, identify the next generation of therapeutic targets, and make all data, methods, and insights rapidly available to researchers in the U.S. and around the world.

During the first five years of the program, this open science discovery engine delivered an unparalleled amount of high-quality molecular and biological data and enabled many new mechanistic disease insights on the role of the genome, proteome, metabolome, and microbiome. As a result of the open-science research model and team-science approach, seven academic research teams discovered and made publicly available more than 500 unique candidate drug targets along with a wealth of supporting evidence and data. To date, more than 3,000 researchers have accessed the AMP AD data resources through the NIA-supported big data infrastructure: the AD Knowledge Portal and the portal-linked open source platform known as Agora. About 60% of users are from academia, and nearly 40% are from the biotechnology- pharmaceutical industry.

To ensure a seamless transition to the second phase of the partnership, NIH reinvested its support of the program. For this next phase, the NIA-supported data coordinating center and six research teams will collaborate with a new set of pharmaceutical industry and nonprofit sector partners. This expanded partnership will enable a precision medicine approach to the discovery of therapeutic targets and biomarkers. The team will analyze brain tissue, spinal fluid, and blood plasma samples from diverse groups of people, and the team will use new computational methods including machine learning to build predictive models of Alzheimer’s and its subtypes.

Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD)

Launched in 2016, the MODEL-AD consortium is tasked with building better genetically modified mouse models for Alzheimer’s research based on the newly discovered genetic risk factors for late-onset disease and making them available along with all the data and methods used in characterizing the models. In four short years, the MODEL-AD teams have created 28 new genetically modified mouse models and made them available to all researchers for use in basic research or Alzheimer’s therapy development without intellectual property barriers.

A key component of MODEL-AD is the Preclinical Efficacy Testing Core (PTC) responsible for establishing a pipeline for rigorous preclinical testing of promising candidate treatments. In 2020, the PTC launched the Screening the Optimal Pharmaceutical for Alzheimer’s Disease (STOP- AD) portal, which enables drug developers from academia and industry to nominate candidate compounds. Compounds that are selected for preclinical efficacy testing will be paired with a genetically modified mouse model appropriate for the molecular process that is being targeted.

TaRget Enablement to Accelerate Therapy Development for Alzheimer’s Disease (TREAT-AD)

The TREAT-AD consortium is the latest addition to NIH’s translational infrastructure established through the Alzheimer’s Centers for Discovery of New Medicines. This $73 million enterprise has two translational centers with a common mission: to diversify and accelerate therapy development for Alzheimer’s through the development of open source tools, reagents, and methods for robust validation of candidate targets delivered by AMP AD and other target discovery programs and by integrating a set of novel targets into drug discovery campaigns. Each TREAT-AD center brings together world-class expertise in data science, computational biology, disease biology, structural biology, assay development, medicinal chemistry, pharmacology, and clinical research.

TREAT-AD Center at Emory University, Sage Bionetworks, and Structural Genomic Consortium will leverage the data and results from the AMP AD program and develop a series of new therapeutic hypotheses centered around a prioritized set of novel targets. The center will develop a suite of target-enabling tools, including high-quality antibodies and chemical probes, and openly disseminate all data, methods, and reagents to any interested academic or commercial investigator to accelerate validation of novel drug targets and to seed new drug discovery efforts.
TREAT-AD Center at Indiana University School of Medicine and Purdue University will bridge target discovery work done by the AMP AD program with newly discovered molecules that will be studied for disease-modifying potential in Alzheimer’s animal models developed by the MODEL-AD centers. The research team will create a diverse portfolio of Alzheimer’s disease drug targets representing new therapeutic hypotheses with a particular focus on immune pathways and make all data and research tools available to the scientific community.

Over the next five years, these centers will join forces to deliver high-quality target-enabling tools, including crystal structures, antibodies, chemical probes, and cell-based assays, for an array of novel targets; initiate drug discovery for a diverse portfolio of novel targets; and make all data, tools, and methods available to researchers in academia and the biotechnology and pharmaceutical industry for laboratory research and drug discovery.

For a more in-depth look at the research implementation milestones in this area, including progress and accomplishments, visit www.nia.nih.gov/research/milestones/enabling-infrastructure.