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

Julian M Gaitán,Henriette Van Praag,Ozioma C Okonkwo,Dena B Dubal,Hyo Youl Moon,Matthew Stremlau,Dane B Cook

doi:10.3389/fendo.2021.660181

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.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disease
Participants were randomized after baseline assessment to either Usual Physical Activity (UPA) or Enhanced Physical Activity (EPA) using 1:1 block randomization accounting for age and sex
One participant was excluded after baseline assessment due to an adverse finding on ultrasound imaging, and one discontinued participation in EPA due to an unexpected surgery, resulting in 23 participants completing the study

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disease. The accumulation of amyloid plaques and neurofibrillary tangles result in a progressive loss of brain function that inevitably leads to mental and physical disability [1]. To date there are no effective treatment options for AD patients, and recent pharmacological trials have resulted in failure [3]. Lifestyle interventions such as exercise training that may delay the onset of neurodegenerative conditions have become increasingly imperative [4, 5]. Aerobic exercise training increases gray and white matter volume, enhances blood flow, and improves memory function [5, 6]. Systemic biomarkers that can measure the effect of exercise interventions on AD-related outcomes quickly and at low-cost could be used to inform disease progression and for the development of novel therapeutic targets

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