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2020 Alzheimer's Association Research Grant (AARG)

Calcium dysregulation and hypothalamic dysfunction in Alzheimer's disease

How do calcium levels in the brain impact weight in individuals with Alzheimer’s?

Makoto Ishii, M.D., Ph.D.
Joan & Sanford I. Weill Medical College of Cornell University
New York, NY - United States


Brain changes observed in Alzheimer’s (such as accumulation of beta-amyloid into plaques) begin decades before the emergence of memory loss and other clinical symptoms. Researchers are trying to uncover biological changes that occur in early stages of disease in order to potentially stop or slow dementia onset. Recent studies suggest that some people may experience significant weight loss prior to the onset of Alzheimer’s. 

Dr. Makato Ishii and colleagues found that brain regions responsible for controlling a person’s weight, specifically the hypothalamus, was impaired in individuals with Alzheimer’s. Preliminary results from Dr. Ishii’s team show that genetically engineered Alzheimer’s like mice have abnormally high calcium levels in this brain region as well. However, more research is needed to understand whether abnormal calcium levels in the brain might contribute to weight loss in Alzheimer’s.

Research Plan

Dr. Ishii’s team will now explore how brain changes associated with Alzheimer’s, such as the buildup of beta-amyloid, may affect calcium levels in the hypothalamus.  He will aim to understand how these levels are associated with weight loss in individuals with Alzheimer’s. Using brain cells growing in laboratory dishes, the researchers will study how beta-amyloid may impact small channels on the surfaces of brain cells that are responsible for transporting calcium in and out of the cells. 

In another set of experiments, the researchers will determine whether blocking the calcium channels with chemical compounds in genetically engineered Alzheimer’s-like mice, makes them less vulnerable to the impact of beta-amyloid. To evaluate this, the researchers will study the effectiveness of these compounds by studying how mouse weight, cognition and disease progression are impacted. 

Through this study, Dr. Ishii aims to understand how beta-amyloid may impact calcium levels in the hypothalamus and in turn how this may be associated with weight loss that may precede Alzheimer’s. 


If successful, this study could provide insights into the biological mechanisms that may underlie weight loss associated with early stages of Alzheimer’s. Families facing Alzheimer’s now and in the future will benefit greatly from early detection, allowing for important care and planning. Furthermore, when we have new therapies, we will be in a better position to know who needs treatment at the earliest time point.

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