2024 Alzheimer's Association Research Fellowship (AARF)
Understanding how parental history of dementia influences offspring AD risk
How does a family history of Alzheimer’s impact an individual’s risk?
Mabel Seto, Ph.D.
Massachusetts General Hospital
Boston, MA - United States
Background
Genes play an important role in Alzheimer’s. For most individuals who have late-onset Alzheimer’s, the genetic mechanisms are complicated. Previous studies have suggested that a family history of Alzheimer’s can increase an individual’s risk of developing Alzheimer’s. More recently, studies have suggested that a maternal history of Alzheimer’s has a greater impact on an individual’s risk for developing Alzheimer’s than a paternal history of Alzheimer’s. The reason for this association is unknown.
Dr. Mabel Seto and colleagues will study the relationship between parental history of Alzheimer’s and how this impacts Alzheimer’s brain changes. In addition, the team will explore whether certain genes passed down from each parent may influence a greater risk of disease.
Research Plan
The research team will look at standardized cognitive tests, measurement of Alzheimer’s biological markers (biomarkers) and brain scans to measure early brain changes associated with Alzheimer’s. Then the researchers will compare the measurements between groups of people with different parental histories of Alzheimer’s to see if they can clarify the sex-specific impact of parental history of Alzheimer’s.
Next, the research team will look at how maternal or paternal history may influence an individual’s risk for developing Alzheimer’s. The genetic makeup of specialized structures inside cells called mitochondria - the powerhouse of energy generation for the cells - is inherited from the Mother. Mitochondrial dysfunction has been associated with Alzheimer’s-like brain changes. Taken together, this makes the DNA of mitochondria an interesting target to investigate for sex-specific differences.
One way in which DNA is modified is by the addition of a chemical methyl group, a process called DNA methylation. Methylation is used to turn genes “on” and “off” during different phases of the body’s development, and it helps regulate proper gene expression (the conversion of genes into proteins). DNA methylation may be involved in many normal brain processes, including learning and memory, and the process may become altered in Alzheimer’s and other dementia. Dr. Seto and colleagues will compare characteristics of mitochondrial DNA between individuals with different parental histories of Alzheimer’s.
Impact
If successful, this study may help inform clinicians on the impact of sex-specific parental history of Alzheimer’s disease on an individual’s risk of developing Alzheimer’s disease.