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MODEL-AD: Next-generation mouse models of Alzheimer’s disease

Lorenzo Refolo
Lorenzo REFOLO,
Chief, Translational Research Branch,
Division of Neuroscience (DN)
Jaya Viswanathan
Editor’s Note: The author is grateful for Health Scientist Specialist Jaya Viswanathan’s contributions to this post.

Many drug candidates that are promising in preclinical studies don’t meet their primary endpoints in clinical trials. This attrition is particularly high in Alzheimer’s, due to the complexity of the disease and a lack of models that accurately represent key features of Alzheimer’s in humans, among other reasons. NIA established the Model Organism Development & Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) consortium in 2016 to bridge this gap in Alzheimer’s drug development by generating animal models that more closely resemble human characteristics of the disease. MODEL-AD has made considerable progress since then and was recently renewed for another five years. Here we highlight the consortium’s successes and how scientists can use its models, resources, and tools in their own research.

Some key challenges

Of the many factors that could contribute to an Alzheimer’s drug not meeting its primary goals in a clinical trial, the poor validity of existing genetically modified models has consistently been at the top of the list. Reasons for this include:

  • A narrow genetic and mechanistic understanding that has limited these models to early-onset Alzheimer’s, which represents a small fraction of total clinical cases.
  • Lack of long-term characterization of these models and biomarkers consistent with human disease progression.
  • Legal restrictions that limit reproducibility of studies that use proprietary models.

One solution

The MODEL-AD consortium comprises multiple research sites using complementary approaches to comprehensively address these challenges. MODEL-AD teams have used genetic, molecular, clinical, and imaging studies to generate and deeply characterize more than 50 mouse models of late-onset Alzheimer’s, the most common form of the disease. Researchers leverage these models to screen candidate therapeutics through the consortium’s Preclinical Testing Center using rigorous methodology.

Use MODEL-AD resources in your research

MODEL-AD investigators are committed to open science principles, transparent reporting, and rapid dissemination of its models to all qualified researchers. All consortium data and experimental resources are available without restrictions.

We encourage you to use these deeply characterized models in your own preclinical and mechanistic Alzheimer’s studies. Check out the MODEL-AD Explorer, an interactive platform that enables you to explore gene expression and pathology data from the available mouse models and see the extent to which they mimic human Alzheimer’s. You can then choose the most appropriate model to address the biological process you are investigating. Have a candidate therapeutic ready for preclinical testing in an animal model? Submit the compound to be tested.

MODEL-AD consortium researchers will continue developing novel models and translational tools using systems biology approaches, so stay tuned to the MODEL-AD website for updates, publications, and model releases. If you have questions about how to get started, email me or leave a comment below.

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