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2023 Alzheimer's Association Research Grant (AARG)

Interrogating Metabolic Dysregulation in Neurodegeneration Using Organoids

How does the brain’s metabolism change during Alzheimer’s?

Madeline Andrews, Ph.D.
Arizona Board of Regents for and on behalf of Arizona State University
Tempe, AZ - United States


Metabolism is the process of the body breaking down foods into energy. During metabolism, the body produces different compounds called metabolites that are transported throughout the body to cells to carry out vital functions. For example, a healthy metabolism helps grow and maintain brain cells and supports healthy brain function. It’s unclear how changes in an individual's metabolism might influence the progression of brain diseases, like Alzheimer’s.

Since it is such a dynamic process, it can be a challenge for researchers to study metabolism using only biological samples collected at a single point in time. Recently, researchers have developed a three-dimensional brain-like structure (known as a brain organoid) that can be grown in a laboratory dish to more closely resemble human brain tissue. Organoids are grown from a specialized type of stem cell collected from adult human tissue called induced pluripotent stem cells (iPSCs). These are adult human skin cells that can be “reprogrammed” into any type of cell in the human body. These models offer an opportunity to study multiple kinds of brain cells growing together over time.

Research Plan

Dr. Madeline Andrews and colleagues will study how metabolism might change during Alzheimer’s by directly comparing metabolism gene levels in a variety of laboratory models. These models will include organoids created using cells that were donated by individuals with and without Alzheimer’s. The researchers will create metabolism gene “signatures” that correspond to specific kinds of brain cells in the models and look for differences that occur in Alzheimer’s. The researchers will verify their genetic findings using a national database of biological samples from individuals with Alzheimer’s.

To contextualize the genetic findings, Dr. Andrews’ team will also study active metabolism in the organoids. The researchers will measure sugar, oxygen, and energy used by the organoids, and metabolites produced by the organoids. They will also measure hallmark changes in the organoids similar to those that occur in the brain during Alzheimer’s, such as increased cell death or accumulation of beta-amyloid or tau proteins (two hallmark brain changes in Alzheimer’s). Finally, the researchers will study how certain stressors affect organoid metabolism. They will test whether preventing stress might help delay or prevent brain cell death in the models.


This study could identify specific features in living brain cells that occur during Alzheimer’s. By using different kinds of laboratory models, this study also provides a comprehensive analysis of how changes in metabolism, such as those that occur in Alzheimer’s, might impact overall brain health.

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