University of Oklahoma researcher leads efforts to unravel mysteries of cognitive decline

An estimated 76,000 Oklahomans are living with Alzheimer's disease, a number that has surged by 13% in just five years. Yet, despite the increasing need for effective treatments, therapies for age-related dementia have largely failed to slow or halt the disease's progression.

Now, a University of Oklahoma researcher, backed by $2.2 million in federal funding, is leading efforts to unravel the mysteries of cognitive decline in aging – potentially opening the door to new, life-changing medications in the process.

Most treatments for Alzheimer's use antibodies to target a pathogenic protein that gets deposited in the brain, but that approach is too late in the game. Once you've lost neurons to disease progression, you can't get them back."

 Sreemathi Logan, Ph.D., Assistant Professor, Department of Biochemistry and Physiology, OU College of Medicine

"Our work aims to provide alternate strategies for identifying and targeting Alzheimer's and other cognitive impairments," she said.

Aging is the greatest risk factor for dementia, but the mechanisms linking aging to cognition decline are largely unknown. To gain insights into how this process works, Logan is studying molecular variations in the brains of older mice that may be translated to humans.

Logan and colleagues at the Oklahoma Center for Geroscience and Healthy Brain Aging developed a nocturnal testing model to assess an animal's ability to relearn a simple task.

By using a specially designed cage, the researchers could observe how mice behave in a motivated learning and memory task through a four-night experiment. While younger mice adapt easily to changes in spatial learning, many, but not all, older mice struggle. By dividing older mice into cognitively "intact" and "impaired" subgroups, the researchers then study the brains of the impaired mice. This is an important aspect of the testing as it translates to humans: Not all aged individuals experience cognitive decline, but many experience the debilitating condition of dementia in old age.

A focus of the grant is understanding the mechanism of astrogliosis, an abnormal increase in the number of astrocytes – special cells in the brain that are critical for maintaining the health of neurons – during aging. A key research question is whether impairments in astrocyte mitochondrial function drive reactive astrogliosis associated with cognitive impairment. 

Logan and members of her lab are working to address this research question in collaboration with the Geroscience Center of Biomedical Research Excellence and the Oklahoma Nathan Shock Center, both on the OU Health Sciences campus, and the Oklahoma Medical Research Foundation.

"Changes in astrocyte metabolism can severely affect how neurons communicate, influencing cognition and other functions," Logan said.

The researchers' goal is to identify specific markers within the aged astrocytes that might be targeted with small molecule inhibitors or activators so that they can promote cognition. Such an approach would diverge from current antibody-based therapies.

"We're looking at over-expression of target proteins that can benefit astrocyte metabolism and see if that improves cognition," Logan said. "That's one avenue we're trying to take to see how we can intervene within cells to improve cognition as we get older."

Logan's research has drawn interest from other funders, including the Hevolution Foundation, a nonprofit working to enhance aging research. That work seeks to understand the metabolic factors, including obesity, that influence age-related cognition.

With this new award – a five-year grant from the National Institute of Aging – Logan aims to pinpoint the pertinent mechanisms that drive dementia in older adults and, ultimately, inspire the development of novel treatments for these devastating conditions.

Caring for dementia patients carries a steep cost. In Oklahoma, nearly 11% of residents older than 65 are living with Alzheimer's, slightly more than the national average. Because most individuals with Alzheimer's live at home, more than 108,000 family caregivers across the state are shouldering the heavy responsibility of daily care. According to the Alzheimer's Association, this caregiving burden is the equivalent of $3 billion in unpaid nursing.

"We're trying to look at an earlier time point within the disease process so we can intervene," Logan said, adding that her study is the first to address the molecular determinants of cognitive heterogeneity – the disparity in cognitive function – in aging. This work in the Logan Lab is coordinated by Matthew Baier, a doctoral student in biochemistry and physiology at the OU College of Medicine.

"If we can identify the metabolic pathways within astrocytes of people with cognitive dysfunction, we could also identify specific protein targets that are affecting cognition in older brains. Doing that would be a game changer."