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2022 Alzheimer's Association Research Grant (AARG)

Developing risk and resiliency models of neuropsychiatric symptoms in AD

Can high levels of a specific protein in the brain promote depression and other psychiatric risk factors of Alzheimer’s disease?

Laura Blair, Ph.D.
University of South Florida
Tampa, FL - United States


Studies show that depression and other neuropsychiatric symptoms in older adults may increase their risk for Alzheimer’s. Other studies have found that depression may lead to faster rates of cognitive decline in individuals with Alzheimer’s. Scientists, however, do not yet understand exactly how neuropsychiatric symptoms and dementia are linked. 

In initial research, Dr. Laura Blair and colleagues studied Alzheimer’s-like mice engineered to lack tau, a protein that accumulates into tangles, one of the hallmark brain changes in Alzheimer’s and other brain diseases. They found that these animals had less depression-like behavior than did similar mice with tau. They also found that a protein linked to depression in individuals with Alzheimer’s, known as FKBP51, helps to promote high levels of tau in the brains of Alzheimer’s-like mice. The protein prevents FKBP51 from being cleared from the brain. Dr. Blair’s team then engineered mice without FKBP51 and found that the animals did not develop neuropsychiatric symptoms, as well as disease-related changes in nerve cell communication and cognition. 

Research Plan

Dr. Blair and team will now conduct a larger study to verify and expand on their earlier findings. First, they will engineer Alzheimer’s-like mice with a variation of the FKBP51 gene – resulting in higher brain levels of FKBP51 protein. They will then examine how high FKBP51 protein levels impact such factors such as depression, tau accumulation, brain inflammation, and loss of nerve cell function. They will evaluate these questions in both male and female mice. Finally, they will study a second group of mice engineered to have high levels of tau but lack FKBP51. The investigators will determine how the loss of FKBP51 links tau and FKBP51 in the male and female mice. 


Results from this study will shed light on potential factors that underlie both the neuropsychiatric and molecular aspects of dementia and understand these factors in males and females. They could also lead to novel therapies that target the disease-related FKBP51 gene variation. 

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