Association Between Exercise Capacity and Late Onset of Dementia, Alzheimer Disease, and Cognitive Impairment

doi:10.1016/j.mayocp.2016.10.020

Mayo Clinic Proceedings

Volume 92, Issue 2, February 2017, Pages 211-217

https://doi.org/10.1016/j.mayocp.2016.10.020 Get rights and content

Abstract

Objective

To address the association between exercise capacity and the onset of dementia, Alzheimer disease, and cognitive impairment.

Patients and Methods

For 6104 consecutive veteran patients (mean ± SD age: 59.2±11.4 years) referred for treadmill exercise testing, the combined end point of dementia, Alzheimer disease, and cognitive impairment was abstracted from the Veterans Affairs computerized patient record system.

Results

After mean ± SD follow-up of 10.3±5.5 years, 353 patients (5.8%) developed the composite end point at a mean ± SD age of 76.7±10.3 years. After correction for confounders in multivariate Cox proportional hazards regression, higher age at exercise testing (hazard ratio [HR]=1.08; 95% CI, 1.07-1.09; P<.001), current smoking (HR=1.44; 95% CI, 1.08-1.93; P=.01), and exercise capacity (HR=0.92; 95% CI, 0.89-0.96; P<.001) emerged as predictors of cognitive impairment. Each 1–metabolic equivalent increase in exercise capacity conferred a nearly 8% reduction in the incidence of cognitive impairment. Meeting the recommendations for daily activity was not associated with a delay in onset of cognitive impairment (HR=1.07; 95% CI, 0.86-1.32; P=.55).

Conclusion

Exercise capacity is strongly associated with cognitive function; the inverse association between fitness and cognitive impairment provides an additional impetus for health care providers to promote physical activity.

Section snippets

Study Participants

The study population consisted of 6104 veterans from the Veterans Exercise Testing Study cohort.²³ As described previously,23, 24 the Veterans Exercise Testing Study began in 1987 and is an ongoing, prospective evaluation of veterans referred for exercise testing for clinical reasons that was designed to address exercise test, clinical, and lifestyle factors and their association with health outcomes. From these exercise tests, the medical history was abstracted from the Veterans Affairs

Results

Patient characteristics are displayed in Table 1. After mean ± SD follow-up of 10.3±5.5 years, 353 patients (5.8%) developed the combined end point of cognitive impairment at a mean ± SD age of 76.7±10.3 years.

Independent risk factors for cognitive impairment in the univariate model were higher age, lower BMI, lower exercise capacity, history of CVD, current smoker, and use of angiotensin-converting enzyme (ACE) inhibitors, antihypertensive agents, or statins (Table 2). After correction for

Discussion

The present results suggest a strong association between objectively determined physical fitness and the development of cognitive impairment. This association holds true even after correction for multiple cardiovascular risk factors.

Conclusion

Exercise capacity is independently and inversely associated with the onset of dementia, Alzheimer disease, and cognitive impairment even after correction for multiple cardiovascular risk factors, such as smoking and physical inactivity. The inverse association between fitness and cognitive impairment provides an additional impetus for health care providers to promote physical activity.

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Alzheimer’s disease (AD) is closely related to hippocampal synapse loss, which can be alleviated by running exercise. However, further studies are needed to determine whether running exercise reduces synapse loss in the hippocampus in an AD model by regulating microglia. Ten-month-old male wild-type mice and APP/PS1 mice were randomly divided into control and running groups. All mice in the running groups were subjected to voluntary running exercise for four months. After the behavioral tests, immunohistochemistry, stereological methods, immunofluorescence staining, 3D reconstruction, western blotting and RNA-Seq were performed. Running exercise improved the spatial learning and memory abilities of APP/PS1 mice and increased the total number of dendritic spines, the levels of the PSD-95 and Synapsin Ia/b proteins, the colocalization of PSD-95 and neuronal dendrites (MAP-2) and the number of PSD-95-contacting astrocytes (GFAP) in the hippocampi of APP/PS1 mice. Moreover, running exercise reduced the relative expression of CD68 and Iba-1, the number of Iba-1⁺ microglia and the colocalization of PSD-95 and Iba-1⁺ microglia in the hippocampi of APP/PS1 mice. The RNA-Seq results showed that some differentially expressed genes (DEGs) related to the complement system (Cd59b, Serping1, Cfh, A2m, and Trem2) were upregulated in the hippocampi of APP/PS1 mice, while running exercise downregulated the C3 gene. At the protein level, running exercise also reduced the expression of advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGE), C1q and C3 in the hippocampus and AGEs and RAGE in hippocampal microglia in APP/PS1 mice. Furthermore, the Col6a3, Scn5a, Cxcl5, Tdg and Clec4n genes were upregulated in the hippocampi of APP/PS1 mice but downregulated after running, and these genes were associated with the C3 and RAGE genes according to protein–protein interaction (PPI) analysis. These findings indicate that long-term voluntary exercise might protect hippocampal synapses and affect the function and activation of microglia, the AGE/RAGE signaling pathway in microglia and the C1q/C3 complement system in the hippocampus in APP/PS1 mice, and these effects may be related to the Col6a3, Scn5a, Cxcl5, Tdg and Clec4n genes. The current results provide an important basis for identifying targets for the prevention and treatment of AD.
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A study in 6104 older adults found higher CRF, estimated based on performance in a graded treadmill exercise test, associated with reduced risk of clinical diagnosis of cognitive impairment, AD, or any dementia within a mean follow-up time of 10.3 years. Having a CRF estimate of less than 6 METs was associated with a 4.42-fold greater risk relative to an estimate of more than 12 METs, and a 1-MET increase in CRF was associated with approximately 8% reduction in the risk of cognitive impairment (Müller et al., 2017). Other studies have also found higher CRF associated with a slower decline in cognitive functions over time (Barnes et al., 2003; Wendell et al., 2014; Pentikäinen et al., 2019).
Alzheimer’s disease (AD) is the most common cause of dementia and there is currently no cure. Novel approaches to treat AD and curb the rapidly increasing worldwide prevalence and costs of dementia are needed. Physical inactivity is a significant modifiable risk factor for AD, estimated to contribute to 12.7% of AD cases worldwide. Exercise interventions in humans and animals have shown beneficial effects of exercise on brain plasticity and cognitive functions. In animal studies, exercise also improved AD pathology. The mechanisms underlying these effects of exercise seem to be associated mainly with exercise performance or cardiorespiratory fitness. In addition, exercise-induced molecules of peripheral origin seem to play an important role. Since exercise affects the whole body, there likely is no single therapeutic target that could mimic all the benefits of exercise. However, systemic strategies may be a viable means to convey broad therapeutic effects in AD patients. Here, we review the potential of physical activity and exercise training in AD prevention and treatment, shining light on recently discovered underlying mechanisms and concluding with a view on future development of exercise-free treatment strategies for AD.
Four-month treadmill exercise prevents the decline in spatial learning and memory abilities and the loss of spinophilin-immunoreactive puncta in the hippocampus of APP/PS1 transgenic mice
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Our team performed a 4-month treadmill exercise intervention on APP/PS1 transgenic mice at 6 months of age (before behavioral changes) and found that a treadmill exercise intervention had a positive effect on the spatial learning and memory abilities of transgenic AD mice before the onset of behavioral changes (Zhang et al., 2017). Moreover, in many recent large clinical studies, researchers found that exercise can effectively reduce the risk of morbidity in asymptomatic preclinical AD and improve cognitive abilities and brain function in patients with mild AD (Huang et al., 2016; Norton et al., 2014; Frederiksen et al., 2014; Öhman et al., 2016; Müller et al., 2017; Yang et al., 2015). However, the role of exercise in patients with advanced AD was not clear.
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Morris water maze testing revealed that while the learning and memory abilities in sedentary APP/PS1 mice were significantly worse than those in wild-type control mice, the learning and memory abilities in running APP/PS1 mice were significantly better than those in sedentary APP/PS1 mice. The stereological results showed that the spinophilin-immunoreactive puncta numbers of the CA1, CA2–3 and DG in the hippocampus of sedentary APP/PS1 mice were significantly lower than those of wild-type control mice and that the numbers of these spines in the CA1, CA2–3 and DG in the hippocampus of running APP/PS1 mice were significantly higher than those of sedentary APP/PS1 mice. Moreover, a running-induced improvement in spatial learning and memory abilities was significantly correlated with running-induced increases in the spinophilin-immunoreactive puncta numbers in the CA1 and DG of the hippocampus.
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In the first study, baseline fitness predicted cognition 25 years later118; in the other, baseline fitness was associated with slower cognitive decline over decades of aging.119 In a cohort of military veterans, better baseline fitness predicted a significantly lower risk of cognitive impairment at mean follow-up of 10 years.120 Several cross-sectional studies have reported that better fitness was concurrently associated with better cognitive scores,121-125 although in another study, this was found only in seniors and not in young adults.126
No medications are proven to slow the progression of Parkinson disease (PD). Of special concern with longer-standing PD is cognitive decline, as well as motor symptoms unresponsive to dopamine replacement therapy. Not fully recognized is the substantial accumulating evidence that long-term aerobic exercise may attenuate PD progression. Randomized controlled trial proof will not be forthcoming due to many complicating methodological factors. However, extensive and diverse avenues of scientific investigation converge to argue that aerobic exercise and cardiovascular fitness directly influence cerebral mechanisms mediating PD progression. To objectively assess the evidence for a PD exercise benefit, a comprehensive PubMed literature search was conducted, with an unbiased focus on exercise influences on parkinsonism, cognition, brain structure, and brain function. This aggregate literature provides a compelling argument for regular aerobic-type exercise and cardiovascular fitness attenuating PD progression.
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: Grant Support: This study was supported by a Marie Curie International Research Staff Exchange Scheme Fellowship within the Seventh European Community Framework Programme (J.M.).

View full text

Original articleAssociation Between Exercise Capacity and Late Onset of Dementia, Alzheimer Disease, and Cognitive Impairment

Abstract

Objective

Patients and Methods

Results

Conclusion

Section snippets

Study Participants

Results

Discussion

Conclusion

Alzheimers Dement

J Diabetes Complications

Neurobiol Aging

Am J Med

Am J Med

J Am Coll Cardiol

Neuroscience

J Am Coll Cardiol

Lancet

Lancet Neurol

Lancet

Mayo Clin Proc

Obes Res Clin Pract

Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association

Circulation

Cardiovascular disease risk factors and cognition in the elderly

Curr Cardiovasc Risk Rep

Physical activity in relation to cognitive decline in elderly men: the FINE Study

Neurology

Physical activity, including walking, and cognitive function in older women

JAMA

Early adult to midlife cardiovascular risk factors and cognitive function

Circulation

Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease

Ann Intern Med

Apolipoprotein E epsilon4 magnifies lifestyle risks for dementia: a population-based study

J Cell Mol Med

Physical exercise and cognitive performance in the elderly: current perspectives

Clin Interv Aging

Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial

JAMA

Effects of aerobic exercise on mild cognitive impairment: a controlled trial

Arch Neurol

Effects of two different intensities of aerobic exercise on elderly people with mild cognitive impairment: a randomized pilot study

Clin Rehabil

Original article
Association Between Exercise Capacity and Late Onset of Dementia, Alzheimer Disease, and Cognitive Impairment