Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer's Disease

Front Endocrinol (Lausanne). 2021 May 20:12:660181. doi: 10.3389/fendo.2021.660181. eCollection 2021.


Increasing evidence indicates that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking. To begin to address this issue, we utilized blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50% female) who underwent 26 weeks of supervised treadmill training. Systemic biomarkers implicated in learning and memory, including the myokine Cathepsin B (CTSB), brain-derived neurotrophic factor (BDNF), and klotho, as well as metabolomics were evaluated. Here we show that aerobic exercise training increases plasma CTSB and that changes in CTSB, but not BDNF or klotho, correlate with cognitive performance. BDNF levels decreased with exercise training. Klotho levels were unchanged by training, but closely associated with change in VO2peak. Metabolomic analysis revealed increased levels of polyunsaturated free fatty acids (PUFAs), reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis, with exercise. Multiple metabolites (~30%) correlated with changes in BDNF, but not CSTB or klotho. The positive association between CTSB and cognition, and the modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function. Overall, our analyses indicate metabolic regulation of exercise-induced plasma BDNF changes and provide evidence that CTSB is a marker of cognitive changes in late middle-aged adults at risk for dementia.

Keywords: Alzheimer’s disease; BDNF; Cathepsin B; cognition; exercise; human; klotho; metabolomics.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease*
  • Biomarkers / blood
  • Brain-Derived Neurotrophic Factor / blood*
  • Cathepsin B / blood*
  • Cognition*
  • Exercise*
  • Fatty Acids, Omega-3 / blood
  • Female
  • Gastrointestinal Microbiome
  • Humans
  • Hydroxyproline / blood
  • Klotho Proteins / blood*
  • Lipid Metabolism
  • Male
  • Metabolomics
  • Middle Aged
  • Proline / analogs & derivatives
  • Proline / blood
  • Risk Factors


  • Biomarkers
  • Brain-Derived Neurotrophic Factor
  • Fatty Acids, Omega-3
  • KLB protein, human
  • N-methylproline
  • BDNF protein, human
  • Proline
  • Klotho Proteins
  • CTSB protein, human
  • Cathepsin B
  • Hydroxyproline