A workout medication?

For numerous years, scholars have identified a correlation between physical activity and the development of cognitive ailments such as Alzheimer’s — however, increasing physical activity isn’t feasible for a lot of patients. A recent research investigates how to replicate those advantages without needing to go to the gym.

“It is well-established that exercise has numerous positive effects on the brain and combats Alzheimer’s disease,” stated senior author Christiane Wrann, assistant professor of medicine at the Cardiovascular Research Center at Massachusetts General Hospital and Harvard Medical School. “Instead of suggesting the exercise, we genuinely want to activate these molecular pathways via pharmacology to enhance cognitive abilities in these patients.”

As per the Centers for Disease Control, approximately 6.7 million adults in the United States are affected by Alzheimer’s disease. This figure is projected to double by the year 2060.

Wrann references studies and meta-analyses that indicate endurance activities, like walking, slow cognitive decline in Alzheimer’s and dementia. A 2022 study revealed that walking about 4,000 steps daily reduced the risk of developing Alzheimer’s by 25 percent, while walking 10,000 steps a day lowered the risk by 50 percent. However, age-related frailty and various other factors may render exercise challenging for patients experiencing cognitive decline, Wrann noted.

“For individuals who can engage in exercise, I would always encourage them to do so,” she remarked. “There’s a significant patient population that simply lacks the ability to exercise sufficiently to gain all these benefits.”

Consequently, Wrann indicated that her team has been driven to delve into how physical activity influences our cells at a molecular level. To achieve this, she detailed that researchers employed a technique known as single-nuclei RNA sequencing. By obtaining samples from mice, her team examined the cells in the hippocampus — the brain region vital for memory and learning that is affected early in Alzheimer’s disease.

“What you can do is take a section of tissue containing all the cells in their proper positions and conditions,” she explained. “Then you process it, allowing you to examine every individual cell. You compile a complete list of ‘ingredients’ present inside the cell — the gene expression.”

Researchers subsequently compare healthy brain tissue to that of Alzheimer’s patients, gaining a deeper understanding of cell interactions and their responses to physical activity. Both control mice and Alzheimer’s mice underwent aerobic exercise — running on a wheel — prior to sample collection. The team confirmed their findings by correlating the outcomes with a comprehensive data set of human Alzheimer’s brain tissue.

“Instead of suggesting the exercise, we genuinely want to activate these molecular pathways via pharmacology to enhance cognitive capabilities in these patients.”

“We comprehend which cell communicates with which other cell, and what information they exchange,” Wrann stated. “We also know what transpires in an Alzheimer’s brain. Additionally, we understand the effects of exercise on an Alzheimer’s brain.”

Specifically, researchers successfully identified the metabolic gene ATPPIF1 as a crucial element in decelerating Alzheimer’s progression. It facilitates the formation of new neurons in the brain — a concept known as neuroplasticity, essential for learning and memory.

“We know that in Alzheimer’s, the activity of this gene diminishes, and then it is rejuvenated during exercise,” Wrann said. “This gene assists nerve cells in enduring harmful conditions, promoting their proliferation and the formation of synapses.”

According to Wrann, the subsequent steps toward translating their findings into therapies will involve utilizing gene therapy in human subjects.

“In contemporary biomedical science, we possess various methods to modulate the activity of these genes,” she stated. “This is part of our ongoing work — extending beyond this study to determine the optimal approach to modify the activity levels of this gene and identify potential drug candidates for human use.”

Although cognitive disorders like Alzheimer’s can benefit from exercise and the associated gene stimulation, Wrann emphasizes that a cure remains elusive.

“It is abundantly clear that the onset of the disease is postponed. Thus, individuals with higher levels of physical activity either do not develop dementia or do so at a later stage. Some studies also indicate a reduction in cognitive decline,” she explained. “However, if one is in advanced dementia, it becomes increasingly complex, as the capacity to engage in an exercise routine is significantly impaired at that phase.”

---

This research was supported by grants from the National Institutes of Health.