Biomarkers Illustrate Link Between Aerobic Exercise, Cognitive Function in Older Adults

Myokine cathepsin B, brain-derived neurotrophic factor, and klotho were all found to be influential in delaying the progression of Alzheimer disease.

A study of older adults with familial and genetic risks for Alzheimer disease found that increased physical activity and exercise training may delay or prevent the onset of the disease, according to a press release from Florida Atlantic University.

In older adults, aerobic exercise has been shown to increase gray and white matter volume, enhance blood flow, and improve memory function. The ability to measure the effects of exercise on systemic biomarkers associated with risks for Alzheimer disease and relating them to important metabolomic alterations may help improve prevention, monitoring, and treatment strategies. However, the researchers said systemic biomarkers that can measure these impacts are lacking.

To address this problem, the investigative team hypothesized that 3 specific biomarkers, which are implicated in learning and memory, would increase following exercise training in older adults. They also theorized that these biomarkers would correlate with cognition and metabolomics markers of brain health.

“Human studies often utilize expensive and low throughput brain imaging analyses that are not practical for large population-wide studies,” said corresponding author Henriette van Praag, PhD, from the Florida Atlantic University Schmidt College of Medicine and Brain Institute, in the press release. “Systemic biomarkers that can measure the effect of exercise interventions on Alzheimer’s-related outcomes quickly and at low-cost could be used to inform disease progression and to develop novel therapeutic targets.”

The team examined myokine Cathepsin B (CTSB), brain-derived neurotrophic factor (BDNF), and klotho, as well as metabolomics. All of these have been increasingly used to understand biochemical pathways that may be impacted by Alzheimer disease.

According to the study, CTSB is a lysosomal enzyme that is secreted from muscle into circulation after exercise and is associated with memory function and adult hippocampal neurogenesis. BDNF is upregulated in the rodent hippocampus and cortex by running and is important for neurogenesis, synaptic plasticity, and memory function. Finally, klotho is a circulating protein that can improve cognition and synaptic function and has been linked with neurodegenerative disease.

The study authors performed a metabolomics analysis in blood samples of 23 asymptomatic late middle-aged adults who had familial and genetic risk factors for Alzheimer disease. The adults had participated in the aeRobic Exercise and Cognitive Health (REACH) pilot study at the University of Wisconsin, in which they were divided into 2 groups: usual physical activity and enhanced physical activity. Those in the enhanced group underwent 26 weeks of supervised treadmill training and blood samples from both groups were taken at baseline and after 26 weeks.

The results of the study showed that plasma CTSB levels increased following the 26-week structured aerobic exercise program. Furthermore, verbal learning and memory had positive correlations with this change in CTSB, although they were not linked to BDNF or klotho. This finding suggests that CTSB may be a useful biomarker for cognitive changes relevant to hippocampal function.

Plasma BDNF levels decreased in conjunction with metabolomic changes, including reductions in ceramides, sphingolipids, phospholipids, and changes in gut microbiome metabolites and redox homeostasis. Multiple lipid metabolites relevant to Alzheimer’s disease were modified by exercise in ways that could be neuroprotective, according to the study. Serum klotho was unchanged but was associated with cardiorespiratory fitness.

“The positive association between CTSB and cognition, and the substantial modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function and brain health in asymptomatic individuals at risk for Alzheimer’s disease,” van Praag concluded in the press release.


Study shows aerobic exercise helps cognitive function in older adults. News release. Florida Atlantic University. June 10, 2021. Accessed June 22, 2021.