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2024 Alzheimer's Association Clinician Scientist Fellowship (AACSF)

Mechanisms of White Matter Injury in Alzheimer's Disease and Mixed Dementia

How do cells and genes in certain brain regions differ, and how might they change during Alzheimer’s?

Andrew Kraft, M.D., Ph.D.
Broad Institute (Eli and Edythe L. Broad Institute of MIT and Harvard )
Cambridge, MA - United States



Background

White matter is a type of brain tissue that is found throughout the brain. It is located in different brain regions and can be readily viewed by specialized brain scans. White matter is primarily responsible for supporting nerve cell communication.

In some types of dementia, including Alzheimer’s, injury to white matter can occur, which researchers believe may contribute to cognitive symptoms. There are several different types of injury that can occur. Research by Dr. Andrew Kraft and others suggests white matter injuries that occur in dementia are specific to different brain regions. For example, cerebral arteriolosclerosis (CASC) injuries are typically found in the frontal lobe, while cerebral amyloid angiopathy (CAA) injuries are seen throughout the brains of people who had Alzheimer’s.

Research Plan

In the current study, Dr. Kraft’s team will determine the kinds of cells that are found in different white matter regions, and why these cells are vulnerable to different types of injury. To do this, the researchers will use a technique developed by Dr. Kraft and colleagues, which allows them to measure gene levels inside individual cells and display where the gene activity is located inside brain tissue samples. 

First, the researchers will analyze the cells found in white matter samples donated by healthy people who were ages 25 to 70 years old. This will help Dr. Kraft understand the different cell populations that comprise different white matter brain regions. Then, Dr. Kraft’s team will use their technique to measure gene levels inside the cells. By comparing results between study participants, the researchers will study how healthy aging changes the cells and genes found in the cells. This will allow Dr. Kraft to more deeply understand the cells that are found in different white matter regions.

Next, the researchers will analyze cells found in brain tissue samples from people who did and did not have Alzheimer’s, and who had different kinds of white matter injuries, including CASC and CAA injuries. The researchers will determine how different types of injury might change the cells found in white matter. The researchers will also compare gene activity between the injured and healthy tissue samples. Together, these experiments may allow Dr. Kraft to detect disease-specific changes that may occur in white matter.

Impact

This study will provide a wealth of data related to the kinds of cells found in different brain regions that are important for Alzheimer’s. It also helps define how gene activity changes in the brain during cognitive disease. Results could inform future research related to the molecular mechanisms that underlie white matter brain injuries seen in Alzheimer’s and other dementias.

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