Summary: Researchers have identified three blood-based biomarkers that help explain how aerobic exercise improves cognitive function in older adults at risk for Alzheimer’s disease.
Source: FAU
Growing evidence indicates that regular physical activity and structured aerobic exercise can delay or reduce the risk of Alzheimer’s disease (AD). In older adults, aerobic training has been linked to increases in gray and white matter volume, improved cerebral blood flow, and better memory performance.
Measuring systemic biomarkers that reflect exercise-driven changes in brain health—and connecting those markers to metabolomic shifts—could improve prevention, monitoring, and treatment strategies. Until now, however, reliable blood-based indicators that both respond to exercise and relate to metabolic pathways tied to cognitive health have been limited.
To address this gap, investigators led by Henriette van Praag, Ph.D., of Florida Atlantic University’s Schmidt College of Medicine and Brain Institute, together with Ozioma Okonkwo, Ph.D., of the Wisconsin Alzheimer’s Disease Research Center and the University of Wisconsin–Madison, tested whether three candidate biomarkers known to influence learning and memory would rise after aerobic training in older adults and align with cognitive and metabolomic measures. The biomarkers examined were the myokine Cathepsin B (CTSB), brain-derived neurotrophic factor (BDNF), and the longevity protein klotho. The team also performed untargeted metabolomic profiling to identify biochemical pathways affected by exercise that may be relevant to AD.
The study analyzed blood samples from 23 asymptomatic, late middle-aged adults with familial or genetic risk for Alzheimer’s disease (mean age 65 years; 50% female). Participants enrolled in the aeRobic Exercise And Cognitive Health (REACH) Pilot Study (NCT02384993) at the University of Wisconsin. They were assigned to either usual physical activity (UPA) or enhanced physical activity (EPA). Those in the EPA group completed 26 weeks of supervised treadmill training. Blood samples were collected at the start of the study and after 26 weeks of intervention.
Published in Frontiers in Endocrinology, the results showed that plasma CTSB increased after 26 weeks of structured aerobic exercise in this at-risk group. Importantly, improvements in verbal learning and memory correlated positively with changes in CTSB, while no such correlation was observed for BDNF or klotho. This link between CTSB and memory performance suggests CTSB may serve as a useful blood marker for hippocampal-related cognitive benefits following exercise in populations at risk for dementia.
BDNF concentrations in plasma decreased with exercise training and were associated with widespread metabolomic shifts. Exercise reduced several lipid species implicated in AD, including ceramides, sphingolipids, and certain phospholipids, and altered gut-microbiome-related metabolites and redox-related metabolites. Many of these lipid changes are consistent with neuroprotective effects. Serum klotho levels did not change significantly after training but were closely associated with improvements in cardiorespiratory fitness (VO2peak).
Van Praag noted that human studies commonly rely on costly, low-throughput brain imaging, which is impractical for large-scale screening or public health programs. Readily measurable systemic biomarkers that reflect exercise effects on Alzheimer’s-related outcomes could provide a lower-cost, scalable approach for tracking disease progression and evaluating lifestyle interventions.
CTSB is a lysosomal enzyme released from muscle into the bloodstream after exercise and has been linked experimentally to adult hippocampal neurogenesis and memory. Prior research has documented lower CTSB levels in older adults with cognitive impairment. BDNF, well-studied in animal models, supports synaptic plasticity, adult neurogenesis, and memory formation and is typically increased in hippocampus and cortex after running in rodents. Klotho is a circulating protein associated with enhanced cognition and synaptic resilience and has been implicated in resistance to neurodegenerative processes.
“The positive association between CTSB and cognition, together with exercise-driven reductions in lipid metabolites tied to dementia, strengthens the evidence that aerobic training benefits brain function in asymptomatic adults at risk for Alzheimer’s disease,” van Praag said.
Co-first authors of the study are Julian M. Gaitan, an exercise physiologist at the University of Wisconsin–Madison, and Hyo Youl Moon, Ph.D., of Seoul National University. Additional co-authors include Matthew Stremlau, Ph.D. (National Institute on Aging, NIH); Dena B. Dubal, M.D. (University of California, San Francisco); and Dane B. Cook, Ph.D. (University of Wisconsin–Madison School of Education).
Funding: This research was supported by grants from the Alzheimer’s Association (NIRGD-305257), the Extendicare Foundation, and the National Institutes of Health (K23 AG045957, R01AG027161, P50 AG033514, UL1RR025011). Additional support came from the NIA Intramural Research Program, the FAU Brain Institute, Jupiter Life Sciences Initiative, and the Florida Department of Health’s Ed and Ethel Moore Alzheimer’s Disease Research program.
About this exercise and cognition research news
Source: FAU
Contact: Gisele Galoustian – FAU
Image: The image is in the public domain
Original Research: Open access. “Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer’s Disease” by Henriette van Praag et al., Frontiers in Endocrinology (DOI: 10.3389/fendo.2021.660181)
Abstract
Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer’s Disease
Physical activity and structured aerobic exercise show promise for delaying or preventing Alzheimer’s disease, but validated, low-cost systemic biomarkers that reflect exercise effects on brain function and link to metabolic pathways are limited. To address this, the study evaluated blood samples from 23 asymptomatic, late middle-aged adults with familial or genetic risk for AD (mean age 65, 50% female) who completed 26 weeks of supervised treadmill training. The analysis focused on CTSB, BDNF, and klotho, together with metabolomic profiling.
Key findings: aerobic training increased plasma CTSB and the change in CTSB correlated with improvements in verbal learning and memory. Plasma BDNF decreased after training and showed associations with a broad set of metabolomic changes, including increased polyunsaturated free fatty acids and reductions in ceramides, sphingo- and phospholipids. Klotho levels were stable with training but closely related to improvements in VO2peak. Approximately 30% of measured metabolites correlated with changes in BDNF, while CTSB and klotho showed fewer metabolite correlations.
These results suggest that CTSB could serve as a blood-based marker of exercise-related cognitive change, and that exercise modifies lipid and metabolic pathways implicated in dementia risk. Together, the data support aerobic training as a beneficial intervention for brain health in late middle-aged adults at risk for Alzheimer’s disease.