New Evidence for Biomarkers of Dementia and Value of Aerobic Exercise in Preventing Cognitive Decline

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Senior Women with Gentle Smile
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A new study has shown that plasma myokine Cathepsin B (CTSB) is significantly increased in adults after a prolonged aerobic exercise program and associated with improved cognitive performance. The researchers used blood samples of asymptomatic late middle-aged adults with familial and genetic risk for AD who underwent prolonged aerobic training. The study also suggests that brain derived neurotrophic factor (BDNF), klotho, and metabolic profiling may be helpful in predicting and tracking progress of dementia.

Results of the study were published in Frontiers in Endocrinology.

Increasing evidence shows that physical activity and exercise training may delay or prevent the onset of Alzheimer’s disease (AD). In aging humans, aerobic exercise training increases gray and white matter volume, enhances blood flow, and improves memory function. However, proven biomarkers that can measure exercise’s effects on brain function and that link to relevant metabolic responses are lacking.

This study was led by Henriette van Praag, PhD, from Florida Atlantic University’s Schmidt College of Medicine and Brain Institute, and Ozioma Okonkwo, PhD, from Wisconsin Alzheimer’s Disease Research Center and Department of Medicine at the University of Wisconsin-Madison.

The researchers looked at whether three specific biomarkers, previously implicated in learning and memory, would increase in older adults following exercise training and correlate with cognition and metabolomics markers of brain health: Plasma CTSB, BDNF, and klotho. The researchers also looked at metabolomics, which are increasingly used in studies of AD biochemical pathways. In particular, ceramides, sphingolipids, and glycerophospholipids have been proposed as AD biomarkers, and have been linked to cognitive function and mood regulation.

Analyses were carried out on blood samples of 23 asymptomatic, late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50 percent female) who participated in the “aeRobic Exercise And Cognitive Health (REACH) Pilot Study” at the University of Wisconsin. The participants were divided into two groups: usual physical activity (UPA) and enhanced physical activity (EPA). The EPA group underwent 26 weeks of supervised treadmill training. Blood samples for both groups were taken at baseline and at the end of the training program.

Results showed that plasma CTSB levels were increased following the structured aerobic exercise training. Verbal learning and memory correlated positively with change in CTSB levels but was not related to BDNF or klotho. The correlation between CTSB and verbal learning and memory, the researchers say, suggests that CTSB may be useful as a marker for cognitive changes relevant to hippocampal function after exercise in a population at risk for dementia.

Plasma BDNF levels decreased in conjunction with metabolomic changes, including reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis. Multiple lipid metabolites relevant to AD were modified by exercise in a manner that may be neuroprotective. Serum klotho was unchanged but was associated with cardiorespiratory fitness.

“Our findings position CTSB, BDNF, and klotho as exercise biomarkers for evaluating the effect of lifestyle interventions on brain function,” said van Praag. “Human studies often utilize expensive and low throughput brain imaging analyses that are not practical for large population-wide studies. 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.”

CTSB, a lysosomal enzyme, is secreted from muscle into circulation after exercise and is associated with memory function and adult hippocampal neurogenesis. Older adults with cognitive impairment have lower serum and brain CTSB levels. BDNF is a protein that is upregulated in the rodent hippocampus and cortex by running and is important for adult neurogenesis, synaptic plasticity, and memory function. Klotho is a circulating protein that can enhance cognition and synaptic function and is associated with resilience to neurodegenerative disease, possibly by supporting brain structures responsible for memory and learning.

“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,” said van Praag.

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