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

Abstract

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.

Figure 1

Study design and effects of exercise on circulating biomarkers. (A) Overview of study design, exercise training intervention [Usual Physical activity (UPA) or Enhanced Physical Activity (EPA)], and blood sample analyses. The list of outcomes is specific to the present report; other outcomes were measured as part of the trial and are described elsewhere (35). (B–D) Effects of the 26-week aerobic exercise intervention on systemic biomarkers. (B) Plasma CTSB increased in the EPA group post-intervention as compared to baseline. (C) Plasma BNDF decreased in the EPA group. (D) Serum klotho levels did not change with exercise. (E) Plasma-derived metabolites by super pathway. ** p < 0.01 Cathepsin B (CTSB); brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).

Figure 2

Correlations between changes in systemic biomarkers with cognitive and cardiorespiratory fitness measures. (A) Change in CTSB was significantly correlated with verbal learning and memory assessed by the CVLT Total recall score. (B) Change in CTSB was correlated, albeit not significantly, with executive function on the D-KEFS CWI. (C) There was no correlation between CTSB change and cardiorespiratory fitness. (D–F) Change in BDNF was not significantly correlated with cognitive performance or cardiorespiratory fitness. (G, H) Change in klotho was not significantly correlated with cognitive performance. (I) Change in klotho was significantly correlated with cardiorespiratory fitness. A decrease in the raw D-KEFS CWI scores indicates improvement on this outcome, so D-KEFS CWI scores were inverted such that a positive change indicates improvement in this figure. * p <.05. Usual Physical Activity (UPA); Enhanced Physical Activity (EPA); cathepsin B (CTSB); brain-derived neurotrophic factor (BDNF); cardiorespiratory fitness (VO₂peak); California Verbal Learning Test (CVLT); Delis-Kaplan Executive Function System Color-Word Interference (D-KEFS CWI).

Figure 3

Changes in sphingolipid metabolism and BDNF. (A, C, E) Changes in (A) sphingosine (C) spinganine and (E) sphinganine-1-phosphate correlated closely with change in BDNF. (B, D, F) Box plots showing levels of these three metabolites were reduced post-intervention in the EPA group. (G) Schematic pathway of sphingolipid metabolism. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. *p < .05. brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).

Figure 4

Alterations in phospholipid metabolism and BDNF. (A, C, E) Changes in (A) glycero-phosphoethanolamine (C) phosphoethanolamine and (E) choline phosphate correlated closely with change in BDNF. (B, D, F) Box plots showing levels of these three metabolites were reduced post-intervention in the EPA group. (G) Schematic of the phospholipid metabolic pathway. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. *p < .05. brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).

Figure 5

Changes in markers of oxidative stress and BDNF. (A) Schematic of the redox pathway. (B–D) Exercise training resulted in changes in redox homeostasis with an increase in (B) methionine sulfoxide, and decreases in (C) taurine and (D) hypotaurine. Changes in (E) taurine and (F) hypotaurine were closely associated with changes in BDNF. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. *p < .05. brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).

Figure 6

Differences in molecules originating from the gut microbiome, and BDNF and CTSB (A) Change in CTSB was significantly associated with a change indoleproprionate (IPA), but not with (B) serotonin. (C) Change in BDNF showed a weak but non-significant correlation with IPA and (D) a significant correlation with serotonin. (E) IPA and (F) serotonin levels were lower post-intervention in the EPA group. Raw metabolite values were normalized in terms of raw area counts by log transformation and rescaled to set the median equal to 1. ^† .05 < p < .10. cathepsin B (CTSB); brain-derived neurotrophic factor (BDNF); Usual Physical Activity (UPA); Enhanced Physical Activity (EPA).