2024 Alzheimer's Association Research Grant (AARG)
Impact of Sex-Specific Dopamine Alteration in Midlife on AD Pathology
Can midlife changes in the function of stress hormones impact psychiatric symptoms that men and women later experience in Alzheimer’s?
Carole Morel, Ph.D.
Icahn School of Medicine at Mount Sinai
New York, NY - United States
Background
Individuals with Alzheimer’s often experience neuropsychiatric behaviors, such as agitation, depression, and apathy. According to research, these behaviors may occur early in Alzheimer’s, and they may lessen an individual’s quality of life and accelerate dementia-related memory loss and other forms of cognitive decline. Other studies, moreover, indicate that psychological stress, which is linked to neuropsychiatric disorders, may also promote one’s risk for Alzheimer’s. However, relatively little is known about the biological mechanisms that link stress and neuropsychiatric disorders with dementia.
In preliminary studies with genetically engineered Alzheimer’s-like mice, Dr. Carole Morel and colleagues found that exposure to chronic stress aggravates behavioral and cognitive decline in these animals, especially in female mice. They also found that stress can alter the activity of dopamine, a stress hormone, in animals. Taken together, such findings suggest that stress-induced loss of dopamine function in midlife may promote one’s risk for and progression of Alzheimer’s in later life. These effects, moreover, may be more pronounced in women than in men.
Research Plan
Dr. Morel and the team will now conduct a larger study of sex-specific links between midlife stress, dopamine function and later-life Alzheimer’s. For this effort, they will again use genetically engineered Alzheimer’s-like mice. First, they will expose the mice to stress and examine how dopamine activity becomes altered over time in male and female animals. They will also assess how altered dopamine activity impacts dementia-related changes in different sexes – changes such as cognitive loss, altered behavior, and the accumulation of beta-amyloid and tau protein in the brain. Next, the researchers will use a technique called optogenetics (a kind of light-based genetic manipulation) to stimulate the activity of dopamine in mice. They will then examine how this treatment may reduce neuropsychiatric symptoms and dementia-related brain changes in male and female animals.
Impact
Results from Dr. Morel’s study could shed new light on the role of dopamine and other hormones in dementia risk and progression. It could also lead to novel, hormone-related therapies for preventing dementia – therapies that can be targeted specifically for women and men.