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2024 Alzheimer's Association Research Fellowship (AARF)

Proteomic signatures of cognitive resilience in excitatory cortical neurons

What factors contribute to “cognitive resilience” in specific nerve cells?

Lauren Fish, Ph.D.
The Regents of the University of Michigan
Ann Arbor, MI - United States


Alzheimer’s disease is associated with specific brain changes including the accumulation of the proteins beta-amyloid and tau into abnormal plaques and tangles, respectively. Interestingly, some individuals can have significant amounts of plaques and tangles in their brain while maintaining normal thinking, memory, and behavior. These individuals are referred to as “cognitively resilient.” The specific qualities that make these individuals so resilient despite Alzheimer’s related brain changes are an important area of study.

Nerve cells are a special type of brain cell that focus on communication and are the building blocks for thinking, memory, and behavior. Studying how nerve cells differ in individuals who are “cognitively resilient” may shed light on certain qualities that can protect the brain from Alzheimer’s-related brain changes.

Research Plan

Dr. Lauren Fish and colleagues have developed a genetically engineered mouse that mirrors both the Alzheimer’s-like brain changes and the cognitive resilience seen in humans. The research team will use these mice to study differences in the nerve cells of mice that show cognitive resilience and mice that do not. 

First, the researchers will look at differences in the amount of specific proteins in nerve cells from cognitively resilient mice using an advanced computational technique called proteomics. Dr. Fish and colleagues will use this information to identify the proteins that are the most likely responsible for cognitive resilience in nerve cells. 

Using these candidate proteins identified in the previous experiment, the researchers will further explore whether they are responsible for cognitive resilience. To do this, the researchers will evaluate existing drugs that completely block the activity and a drug that increases the activity of each candidate protein. If there is not a good drug candidate for a certain protein, Dr. Fish and colleagues will create a drug specific to this protein.  Using these drugs - to increase or block protein signaling -the study team will observe how these candidate proteins impact the function of nerve cells to promote cognitive resilience.


The results from this study may shed light on important targets that are responsible for protecting thinking, memory, and behavior in the presence of Alzheimer’s-related brain changes.

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