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2017 Grants - Yang
Pathophysiologic Link between TDP-43 Pathology and Alzheimer’s Disease
Hyun-Sik Yang, M.D.
The Brigham and Women’s Hospital, Inc.
2017 Alzheimer’s Association Clinical Fellowship (AACF)
Does abnormal build-up of the TDP-43 protein in the brain impact the progression of Alzheimer’s disease?
Abnormal accumulation of the protein TAR DNA-binding protein 43 (TDP-43) in the brain is a hallmark of amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) and frontotemporal dementia (FTD). About half of individuals with Alzheimer’s disease also have clumps of TDP-43 in the brain in addition to amyloid plaques and tau tangles. Recent studies have shown that TDP-43 accumulation may be associated with brain shrinkage and cognitive decline in people with Alzheimer’s disease, but the mechanisms by which TDP-43 may influence disease progression are not yet known.
Hyan-Sik Yang, M.D., and colleagues have proposed a series of studies to better understand how the abnormal accumulation of TDP-43 affects brain structure and function in older people with and without Alzheimer’s disease. They will use large datasets of genetic, brain imaging and cognitive testing measurements collected over several years from participants in the Religious Orders Study (ROS), the Rush Memory and Aging Project (MAP) and the Harvard Aging Brain Study (HABS). They will determine if TDP-43 alone contributes to cognitive decline and changes in the size of the hippocampus, a brain region important for learning and memory. They will also determine if TDP-43 “accelerates” the build-up of plaques and tangles and promotes cognitive decline in people with Alzheimer’s disease. The researchers are also interested to see how a genetic variation associated with increased Alzheimer’s risk (APOE-ε4) may impact the level of abnormal TDP-43 accumulation in the brain.
The results of this study could shed new light on how TDP-43 accumulation can affect the progression of Alzheimer’s or other dementias. In addition, this work could help determine if TDP-43 could be targeted for the development of new diagnostic and therapeutic strategies for Alzheimer’s and other neurodegenerative diseases.