As undergraduates, Will McLean and Sydney Ragsdale both watched beloved family members lose parts of themselves to dementia, a hallmark of many neurodegenerative disorders, including Alzheimer’s disease. Both knew they wanted to better understand – and help develop new treatments for Alzheimer’s and other dementia-related diseases.

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Today, they’re both graduate students in Roberta Brinton’s lab in the University of Arizona Center for Innovation in Brain Science, which Brinton also directs. The center’s research spans the discovery of the causes of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis to translating those discoveries into treatments. 

“Discovery is exciting, and translating those discoveries into impactful therapies for Alzheimer’s, which doesn’t have a cure, is discovery with purpose,” Brinton said. “We’re preparing the next generation of translational scientists to make a difference.” 

Brinton is the principal investigator of a five-year, $1.8 million grant, now in its second iteration, from the National Institute on Aging, or NIA, a division of the National Institutes of Health. The funding supports the University of Arizona Training Program to Advance Translational Research in Alzheimer's Disease and Related Dementias, or AZ-TRADD, which is aimed at creating a new generation of cross-disciplinary, translational scientists. Such scientists will be part of a workforce trained with the knowledge and skills to discover and develop new drugs for Alzheimer’s and other neurodegenerative diseases. AZ-TRADD fellows come from multiple graduate degree programs, including Medical Pharmacology, Neuroscience, Biomedical Engineering, Clinical Translational Sciences and the U of A College of Medicine MD/PhD Medical Scientist Training Program. 

“The National Institute on Aging created the training program in therapeutic development to address the need for translational research knowledge in graduate programs in the Alzheimer’s field,” Brinton said. “Through the NIA program, AZ-TRADD fellows learn the skills and knowledge required to successfully navigate the entire translational research process, from discovering a potential drug target on a cell to clinical trials to biotech start-up.” 

Aging and the brain

McLean is a sixth-year doctoral student in neuroscience and is set to graduate this summer. Originally from Birmingham, he majored in neuroscience at the University of Alabama at Birmingham as an undergraduate.

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“Through coursework and personal experience, I realized that not only was it fascinating to learn how the brain works, but also to understand when and why the brain isn’t working properly, and specifically how it changes with aging and in dementia,” he said. “That guided my graduate school choice, which led me to the U of A and this program. When I found Dr. Brinton’s program and lab, the T32 program was a great fit with what I wanted to study – how to understand and treat diseases tied to aberrant aging.” 

McLean explained that two back-to-back T32 classes, taken over a year, detail the therapeutic development pipeline from drug discovery to clinical trial. 

“They take you from identifying molecular targets implicated in Alzheimer’s and computer modeling to potentially modifying the target through preclinical testing for safety and efficacy and how to design clinical trials,” he said. “It’s a unique set of classes and expertise, from molecular biologists to clinical trial experts to biomedical ethics and leadership.” 

He began to consider translational research as a career during undergraduate school when his grandmother was diagnosed with dementia. 

“That personal angle motivated me in part to move in a translational direction,” he said. “Can we better understand how memory works to preserve and protect it against diseases that obliterate it?” 

McLean’s research projects focus on Alzheimer’s disease risk, including genetic risk factors such as the APOE4 gene. One copy of the gene increases the Alzheimer’s risk by three-fold more than normal; with two copies, the risk is 15-fold higher. 

“It’s a common and an incredibly important risk factor to understand,” he said. “We’ve discovered behavioral, inflammatory and metabolic dysregulation associated with this risk factor in mouse models. Analyzing gene activity profiles in each type of cell in the brain is advancing both our understanding of how the brain develops Alzheimer’s and importantly what our therapeutic strategy needs to target.” 

Another project focuses on why a woman’s risk of developing Alzheimer’s is twice that of a man’s. McLean and his co-workers are looking for clues in the transition to menopause in female rats. 

In a related study, McLean is part of a team focused on the hippocampus, a brain region associated with memory and one of the earliest areas to be affected in Alzheimer’s. Researchers are using an RNA sequencing technique in rodent models to see how and which brain cell types are affected by a loss of ovarian hormones. That will allow them to identify precise new therapeutic targets to protect those cell types. 

Family ties

As a freshman at Florida State University, Sydney Ragsdale watched a close uncle slowly decline into dementia. She knew she wanted to do something to help others with Alzheimer’s and other neurodegenerative diseases.

She considered medicine as a career, but after taking advanced placement biology classes in high school, she became interested in studying the brain. As an undergraduate at Florida State University, she majored in behavioral neuroscience. 

In her sophomore year, she joined a research lab focused on issues with spatial navigation, an early sign of Alzheimer’s disease. “One of the first signs I saw with my uncle was that he would get lost and didn’t know where he was going,” she said. 

While researching graduate schools, she came across Brinton’s research. 

“I always had translational research in my mind, to apply what we did in the lab to help people,” said Ragsdale, who joined the Brinton Lab last September. “The NIH-NIA T32 AZ-TRADD fellowship is perfect for me as Dr. Brinton’s translational research work embodies my career goals.”

Ragsdale is part of two research projects, both of which involve menopausal hormonal therapy and Alzheimer’s. She and another T32 graduate student have been studying the effects of menopausal hormonal therapy in mouse models with a human version of the APOE4 gene. 

“We are seeing the effects of estrogen therapy during that perimenopausal hormonal transition period,” she said. “Our earlier research pinpointed that as a critical time for giving estrogen therapy as a therapeutic approach.”

She has begun working with McLean on the hippocampus project to better understand the effects of estrogen therapy on the brain’s hypothalamus.

“Hormonal therapy is an exciting research avenue and I’m hoping to be involved in clinical trials eventually,” Ragsdale said.

“The T32 broadened my view about what each stage of therapeutic development requires,” McLean said. “I want to identify common overlapping biological pathways in Alzheimer’s disease and related dementias and be part of the growing field of precision therapeutics.” McLean plans to continue to pursue Alzheimer’s research in a postdoctoral fellowship.