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How can genetic variations of a specific gene impact the development and progression of Alzheimer’s?
Stephanie Schultz, Ph.D.
Massachusetts General Hospital
Boston, MA - United States
Background
The Dominantly Inherited Alzheimer’s Network (DIAN) is an international consortium that collects data from families with Dominantly Inherited Alzheimer’s Disease worldwide. There are deterministic genes that directly cause a disease in any individual who inherits them. This is referred to as familial or dominantly inherited Alzheimer’s. Studies show that the dominantly inherited Alzheimer’s is characterized by a genetic variation in one of the three genes (presenilin 1 (PS1), presenilin 2 (PS2) and amyloid precursor protein (APP)).
Individuals with a genetic variation in the PS1 gene develop early-onset Alzheimer’s and may have brain changes observed in Alzheimer’s (such as accumulation of beta-amyloid into plaques, one of the hallmark brain changes in Alzheimer’s) that could impact memory in middle-age. Studies show that there may be over 200 genetic variations in PS1 that may be associated with the development of Alzheimer’s. Studies also suggest that the different PS1 genetic variations may be associated with variability in individual brain changes, age of symptom onset such as memory loss and cognitive decline.
Research Plan
Dr. Stephanie Schultz and colleagues will use cells in the laboratory dish to study how different genetic variations of PS1 may impact the levels of beta-amyloid plaques. Additionally, the researchers will leverage the DIAN trial; they will use a specialized type of stem cell collected from adult human tissue (from DIAN participants) called iPSCs or induced Pluripotent Stem Cells. iPSCs can be programmed to grow into any type of cell in the body. Dr. Schultz’s team will use iPSCs to grow nerve cells in a laboratory dish and study how genetic variations of PS1 may impact the levels of plaques.
Furthermore, the research team will study whether the impact of different PS1 genetic variations on the levels of plaques may be associated with biomarkers of Alzheimer’s. To do so, the researchers will leverage datasets of DIAN participants - with genetic variation in PS1 - that includes cerebrospinal fluid samples (the biological fluid surrounding brain and spinal cord) as well as MRI (Magnetic Resonance Imaging) brain scans. Using these datasets, the researchers will study biomarkers of Alzheimer’s including levels of plaques and tau tangles, which is formed by the accumulation of tau tangles, another hallmark brain change observed in Alzheimer’s and other brain diseases.
Finally, Dr. Schultz and her research team will analyze the data using sophisticated statistical techniques to study whether their findings may be able to predict cognitive decline in these DIAN participants during long-term follow up studies.
Impact
The study results may improve our understanding of how genetics could be associated with the progression of Alzheimer’s. If successful, these findings could be used to develop potentially personalized therapeutic interventions to tackle the development and progression of Alzheimer’s.
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