For years, scientists have observed the positive impact of exercise on cognitive disorders such as Alzheimer’s disease. However, for many patients, increasing physical activity is not feasible due to mobility issues. A groundbreaking study published in Nature Neuroscience explores how to replicate these cognitive benefits pharmacologically, offering hope to those who cannot engage in physical exercise.
“We know that exercise does so many good things to the brain and against Alzheimer’s disease,” said Christiane Wrann, the study’s senior author and assistant professor of medicine at the Cardiovascular Research Center at Massachusetts General Hospital and Harvard Medical School. “Instead of prescribing the exercise, we actually want to activate these molecular pathways using pharmacology to improve cognitive function in these patients.”
According to the Centers for Disease Control, approximately 6.7 million adults in the United States are living with Alzheimer’s disease, a number expected to double by 2060. Wrann’s research points to the benefits of endurance exercise, such as walking, which has been shown to slow cognitive decline. A 2022 study highlighted that walking 4,000 steps daily could reduce the risk of developing Alzheimer’s by 25%, while 10,000 steps could cut the risk by half. Yet, many patients face physical limitations that prevent them from reaping these benefits.
Unraveling the Molecular Impact of Exercise
Wrann’s team has been driven to understand how exercise influences cells at a molecular level. Utilizing single-nuclei RNA sequencing technology, researchers have examined the hippocampus—a brain region crucial for memory and learning that is affected early in Alzheimer’s disease. This method allows scientists to analyze the gene expression within individual cells, offering insights into cellular interactions and responses to exercise.
“What you can do is you can take a piece of tissue that has all the cells exactly where they are and how they are supposed to be,” Wrann explained. “And then you put it through this procedure, and you can check every single cell. You get the whole list of ‘ingredients’ that are inside the cell—the gene expression.”
By comparing healthy brains to those affected by Alzheimer’s, researchers have identified key differences in cellular communication and response to exercise. Both control and Alzheimer’s model mice were subjected to aerobic exercise, such as running on a wheel, before their brain samples were analyzed. The findings were validated against a large dataset of human Alzheimer’s brain tissue.
Key Discoveries and Future Directions
One of the significant discoveries from the study is the identification of the metabolic gene ATPPIF1, which plays a crucial role in slowing Alzheimer’s progression. This gene is vital for neuroplasticity, the brain’s ability to create new neurons essential for learning and memory.
“We know that in Alzheimer’s the activity of the gene is reduced, and then it’s restored in the running exercise,” Wrann said. “Having this gene helps nerve cells to survive noxious stimuli, helps them to proliferate and inform synapses.”
Looking ahead, Wrann’s team aims to translate these findings into treatments through gene therapy in human subjects. “In modern biomedical science, we have a lot of ways to modulate the activity of these genes,” she noted. “And this is part of the work we are now doing—going beyond the study to figure out what the best approach is to change activity levels of this gene and find the drug candidate you would want to use in a human.”
Implications for Alzheimer’s Treatment
While exercise and the associated gene stimulation offer benefits for cognitive diseases like Alzheimer’s, a cure remains elusive. “One thing that is very clear is that the onset of disease is later. So people that have more physical activity, they either don’t get dementia, or they get it later. And there are some studies that show a slowing down of the cognitive decline,” Wrann said. “If you are in complete dementia, then it starts to get more complicated, because even the ability to partake in an exercise regimen is greatly reduced right at that stage.”
This research represents a significant step forward in understanding how to harness the benefits of exercise for those unable to engage in physical activity. As scientists continue to explore pharmacological pathways to mimic these effects, the potential for new treatments offers hope to millions affected by Alzheimer’s disease.
For further details, refer to the study by Joana F. da Rocha et al., “Protective exercise responses in the dentate gyrus of Alzheimer’s disease mouse model revealed with single-nucleus RNA-sequencing,” published in Nature Neuroscience.
