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2024 Alzheimer's Association Clinician Scientist Fellowship (AACSF)

Short Tandem Repeats as a Novel Genetic Driver of Alzheimer's Disease

Do short, repeated sequences of genetic code contribute to brain cell changes seen in Alzheimer’s?

Michael Guo, M.D., Ph.D.
The Trustees of the University of Pennsylvania
Philadelphia, PA - United States


Studies have shown that variations in certain genes can affect a person’s risk of developing neurodegenerative diseases. One type of these variations is called tandem repeats. Tandem repeats consist of short sequences of the genetic material (DNA) that repeat a number of times and are a source of genetic variations. This is partly due to the fact that tandem repeats can destabilize DNA inside cells, leading to further variations.

When found in brain cells, tandem repeats are associated with accelerated neurodegeneration and early onset of some brain diseases. However, the role of this kind of genetic variation in Alzheimer’s is unclear. More research is required to understand how tandem repeats occur in Alzheimer’s, and how they might influence disease progression.

Research Plan

Using genetic data available through the Alzheimer’s Disease Sequencing Project, Dr. Michael Guo and colleagues will study tandem repeats in people who had Alzheimer’s. Their first goal is to test whether the presence of these variations inside cells is associated with the onset or progression of Alzheimer’s. The researchers will use advanced statistical methods to study hundreds of thousands of tandem repeats in more than 11,000 individuals with Alzheimer’s. They will look for associations between the level of tandem repeats and the age of disease onset, as well as the rate of symptom progression.

As a second goal, Dr. Guo’s team will test whether tandem repeats inside brain cells might make the cells more vulnerable to tau protein, which forms tangles, a hallmark protein of Alzheimer’s. The researchers will study brain tissue samples donated by 10 people who had Alzheimer’s. They will measure amounts of tandem repeats inside the samples. Then, they will compare these amounts between samples with and without tau protein. This will help Dr. Guo determine any associations between tandem repeats and tau protein burden in the brain during Alzheimer’s.


This study could identify tandem repeats as a risk factor for brain changes associated with Alzheimer’s. It provides an important step toward understanding how genetic instability inside brain cells might contribute to neurodegenerative disease progression.

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