Edited by: Ignacio Torres-Aleman, Achucarro Basque Center for Neuroscience, Spain
Reviewed by: Vanessa Castelli, University of L’Aquila, Italy; Hailong Song, University of Pennsylvania, United States
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A growing body of evidence clearly indicates the beneficial effects of physical activity (PA) on cognition. The importance of PA is now being reevaluated due to the increase in sedentary behavior in older adults during the COVID-19 pandemic. Although many studies in humans have revealed that PA helps to preserve brain health, the underlying mechanisms have not yet been fully elucidated. In this review, which mainly focuses on studies in humans, we comprehensively summarize the mechanisms underlying the beneficial effects of PA or exercise on brain health, particularly cognition. The most intensively studied mechanisms of the beneficial effects of PA involve an increase in brain-derived neurotrophic factor (BDNF) and preservation of brain volume, especially that of the hippocampus. Nonetheless, the mutual associations between these two factors remain unclear. For example, although BDNF presumably affects brain volume by inhibiting neuronal death and/or increasing neurogenesis, human data on this issue are scarce. It also remains to be determined whether PA modulates amyloid and tau metabolism. However, recent advances in blood-based biomarkers are expected to help elucidate the beneficial effects of PA on the brain. Clinical data suggest that PA functionally modulates cognition independently of neurodegeneration, and the mechanisms involved include modulation of functional connectivity, neuronal compensation, neuronal resource allocation, and neuronal efficiency. However, these mechanisms are as yet not fully understood. A clear understanding of the mechanisms involved could help motivate inactive persons to change their behavior. More accumulation of evidence in this field is awaited.
Cognitive decline and dementia are major health concerns worldwide. A major cause of dementia is Alzheimer’s disease (AD) and very recently pharmacological treatment with aducanumab was approved in the United States for AD. However, the effects of this drug are far from a “cure” and other therapeutics are needed.
Cumulative research results clearly indicate the beneficial effects of physical activity (PA) on brain health, and some reports have suggested that physical inactivity in older adults caused by COVID-19 pandemic-related lockdowns have had a negative impact on brain health (
Physical activity has been found to have a positive impact on cognition in a wide range of individuals, from those who are cognitively normal to those who have dementia (
This review, which largely focuses on human studies, describes the various mechanisms of the brain-protective effects induced by PA. We divide the beneficial mechanisms of PA or exercise into several components and review the structural, physiological, anti-neurodegenerative, and functional effects of PA or exercise (
Hypothetical mechanisms underlying the beneficial effects of PA on brain health.
1. Structural mechanism |
The volume of the brain declines with aging, starting in midlife (
Many interventional trials have also shown the positive impact of PA on brain volume. Some studies showed that PA interventions reduced the development of brain atrophy compared with controls (
Brain volume changes associated with PA levels.
718 community-dwelling older adults (mean age 66) | Cross-sectional | High sedentary levels associated with lower hippocampal volumes | |
75 community-dwelling older adults (mean age 60.5) | Cross-sectional | Higher PA levels associated with increased cerebral gray matter volume in prefrontal and cingulate cortex | |
299 participants recruited from a Medicare database (mean age 78) | Longitudinal (9 years) | Higher PA levels associated with greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later | |
1842 participants who attended a preventive medical check-up (mean age 64) | Cross-sectional | PA associated with greater global and frontal mean thickness | |
203 community-dwelling older adults (mean age 54) | Longitudinal (3.6 years) | Higher PA levels associated with less thinning of left prefrontal cortex | |
155 (52 experimental) community-dwelling older women (mean age 70) | Resistance training twice a week for 2 years | Resistance training reduced cortical white matter atrophy | |
59 (half experimental) older subjects without neurological defects (mean age 66.5) | Aerobic exercise intervention for 6 months | Significant increases in brain volume, in both gray and white matter regions | |
62 (21 tai chi chuan, 16 Baduanjin) health volunteers (mean age 62) | Tai chi chuan and Baduanjin exercise (60 min for 5 days a week) for 12 weeks | Significant increases in gray matter volume in insula, medial temporal lobe, and putamen after 12 weeks of exercise |
Although the precise mechanisms remain to be elucidated, the neuroprotective effects of PA may be exerted through increased brain-derived neurotrophic factor (BDNF) and blood flow or reduced oxidative stress and amyloid accumulation (as discussed below). Recently, the MAPT study reported that more physically active individuals had lower blood concentrations of neurofilament light chain, a well-established biomarker of neurodegeneration (
White matter plays a crucial role in cognition by connecting different brain regions to enable efficient signal transmission. White matter in adult brains exhibits plasticity involving myelin formation and remodeling (
Small vessel disease is represented by white matter lesions (WMLs). T2-weighted or fluid-attenuated MRI images visualize WMLs as diffuse high-signal areas. WMLs have been linked to cognitive impairment (
A systematic review concluded that PA reduced stroke risk (
Brain-derived neurotrophic factor is a neurotrophin that influences neuronal survival, differentiation, synapse generation, and long-term potentiation (
BDNF findings associated with PA levels.
135 (73 experimental) MCI or AD from 5 studies | Systematic review of RCTs | PA interventions increased plasma BDNF | |
52 (26 experimental) healthy older adults (mean age 68.3) | 90-min dance twice a week for 18 months | Significant increase in BDNF in dance group | |
52 (26 experimental) healthy older adults (mean age 68.3) | 90-min dance twice a week for 6 months | Significant increase in BDNF in dance group |
Although the precise cause of the exercise-associated plasma BDNF increase has not yet been fully elucidated, some studies have shown increased BDNF in samples from the internal jugular vein after acute training (
Circulating insulin-like growth factor 1 (IGF-1) passes through the blood–brain barrier, exerts neuroprotective effects, and induces synaptic plasticity (
Cerebral blood flow decreases with aging and may be associated with cognitive decline (
Angiogenesis may also be involved in the ability of PA to increase blood flow (
Alzheimer’s disease is a major neurodegenerative disease and is the leading cause of dementia. The main pathological features of AD are accumulation of amyloid β (Aβ; senile plaques) and intracellular accumulation of hyper-phosphorylated tau (neurofibrillary tangles). PA has been associated with reduced risk of AD (
Although cerebrospinal fluid biomarkers and amyloid PET imaging are the most frequently applied modalities in this field, the applicability of plasma biomarkers is gradually improving. Many observational studies involving measures of Aβ in cerebrospinal fluid (
Amyloid β findings associated with PA levels.
546 cognitively healthy older adults (mean age 69.6) | Cross-sectional | PET and plasma Aβ | Lower plasma Aβ1-42/1-40 and brain amyloid observed in participants reporting higher PA levels | |
85 cognitive health older adults (mean age 64.3) | Cross-sectional | CSF Aβ | Engagement in moderate PA associated with higher Aβ42 | |
69 older adults (age 55–88) | Cross-sectional | PET | Active individuals who followed exercise guidelines had significantly lower Pittsburgh Compound-B binding | |
139 presymptomatic mutation carriers for familial AD | Cross-sectional | CSF Aβ and PET | Individuals with low PA levels had higher mean levels of brain amyloid compared with those with high PA levels on PET but no difference in CSFAβ | |
149 cognitively normal older adults (mean age 83) | Longitudinal for 9–13 years | Plasma Aβ | Higher baseline PA levels associated with lower levels of plasma Aβ in subsequent assessments | |
287 cognitively normal older adults (mean age 72) | Cross-sectional | PET | Midlife cognitive activity not related to Aβ deposition | |
49 cognitively normal older adults (mean age 87.8, range 84–94 years) | Cross-sectional | PET | Higher self-reported PA in the last year associated with lower Aβ load | |
201 cognitively normal adults (mean age 65) | Cross-sectional | PET | Sedentary lifestyle associated with higher Aβ deposition | |
276 cognitively normal older adults (age 55–88; 95 for CSF and 181 for PET) | Longitudinal for 10 years | CSF Aβ and PET | Baseline PA did not impact longitudinal change in Aβ in CSF or on PET | |
326 community-dwelling older adults (mean age: 76) | Cross-sectional | PET | Self-reported higher mid- and late-life leisure-time PA not associated with amyloid burden | |
271 older adults with normal or mildly impaired cognition (mean age 74.7) | Cross-sectional | PET | PA not significantly associated with Aβ deposition | |
MCI and AD population | Systematic review of 18 RCTs | CSF and plasma Aβ, and PET | AD pathological markers rarely investigated and the results inconclusive; most studies had relatively small sample size and limited duration |
Observational studies, mainly retrospective in nature, have suggested that individuals with higher PA tend to have biomarker profiles indicative of lower Aβ deposition in the brain (
Researchers have investigated the effects of PA on tau-related biomarkers. Some cross-sectional studies involving cerebrospinal fluid biomarkers (
Acute exercise increases oxidative stress, but regular PA is expected to regulate the cellular redox state of the brain, and PA-induced redox adaptation may contribute to the neuroprotective effects of PA (
Nonetheless, studies of individuals with dementia or MCI are rare. Only
Inflammation is one of the major mechanisms of neurodegeneration (
Plasma IL-6 levels decrease in response to aerobic exercise in both MCI (
Functional MRI enables functionally connected brain regions to be identified by measuring simultaneous activations
Physical activity might somehow help to recruit new neuronal circuits that would be involved in processing tasks. An interesting fMRI study suggested that 6-week dance exercise training led to the involvement of the motor-related network during highly cognitive-demanding memory tasks, possibly as a compensatory mechanism. Exercise may accelerate the involvement of new networks in the cognitive process (
Event-related potentials are generated in response to specific events or stimuli such as audio sound. Studies involving the P3 component, the major focus of studies of event-related potentials, showed that exercise increases the amplitude of P3, possibly suggesting that exercise enhances the allocation of neural resources as part of a compensatory mechanism (
Exercise may increase neuronal efficiency. An fMRI study demonstrated that an exercise group had lower BOLD signals in the hippocampus and para-hippocampal gyrus compared with a non-exercise group during a memory-encoding task. Because the BOLD signal reflects brain activity in a specific region, lower BOLD signals during a certain task mean that the task was performed with less burden, which probably reflects higher neuronal efficiency in the hippocampus and para-hippocampal gyrus in the exercise group (
Synaptic plasticity (long-term potentiation and long-term depression) is a biological model for learning and memory processes. Animal studies have demonstrated that PA controls synaptic plasticity (
Numerous studies have established the beneficial effects of PA on brain health. Here, we attempted to comprehensively review the potential mechanisms underlying the effects of PA on brain health. Elucidation of the mechanisms may help to establish the optimal interventional approach in terms of therapeutic effects or even lead to the development of therapeutic mimics.
Increasing PA is a relatively safe and cheap way to maintain health, including brain health. However, sedentary people often struggle to modify their behavior. Clear messages explaining the intensity and frequency of exercise required to protect brain health may help motivate them to change their behavior and lifestyle. Moreover, improved understanding of the mechanisms of the effects is expected be important for behavioral change. People may want to know how PA works, and a clearer understanding of the mechanisms involved could help encourage behavioral change.
Several mechanisms have been summarized in the current review. Each mechanism is speculated to exert its effect both independently and interrelatedly (
Schematic view of the mechanisms underlying the beneficial effects of PA on brain health. BDNF, brain-derived neurotrophic factor; PA, physical activity.
The most intensively studied topic and the one with the most accumulated evidence regarding the impact of PA on brain health is the increase in blood BDNF levels. However, the source of the BDNF production induced by PA is inconclusive, so it remains unclear whether the increase of BDNF in the blood actually reflects the increase of BDNF in the brain. Moreover, the underlying mechanisms by which increased BDNF affects human brain function have not been completely elucidated. BDNF is presumed to be associated with neuronal survival and neurogenesis, and it may also preserve white matter structure (
More importantly, the mechanisms by which PA affects human brain volume remain to be elucidated. BDNF may at least partly help to support brain volume preservation, possibly through neuronal survival and/or neurogenesis. However, it is not yet clear whether the preservation/increase of brain volume is due to the preservation/increase of the number of neurons in humans. There is room for further research. It also remains to be elucidated how an increase in BDNF might contribute to the preservation of brain volume in humans. The relative contribution of neurogenesis and prevention of neuronal death to the preservation of brain volume is not yet fully understood. Although BDNF has effects on neuronal preservation, PA may also counteract neurodegeneration through pathways different from those of BDNF, including antioxidative and anti-inflammatory effects.
Epidemiological evidence indicates that PA reduces the risk of clinically diagnosed AD (
Some studies of AD-related biomarkers suggest that PA may directly modify AD-related pathologies. However, taken together, the results of these studies are as yet inconclusive. In particular, insufficient evidence has been accumulated from randomized controlled studies (
To conclude, numerous studies have been conducted in this field and a substantial amount of evidence has been accumulated. Two points have been clarified so far, namely, the association of PA with increased blood levels of BDNF and its association with brain volume preservation. However, much remains to be elucidated. For example, the mechanism by which circulating BDNF affects the brain as well as the association between increased BDNF levels and neurogenesis in people are unclear. Although animal studies have demonstrated that BDNF increases neurogenesis in the hippocampus, the contribution of BDNF to neurogenesis in the context of human brain health, especially in older adults, has yet to be clarified. In addition, even though the effects of PA on AD-related pathologies have been extensively studied, the research results are inconsistent, and so it remains unclear whether PA is associated with less AD-related pathologies. Many of the studies conducted in this field have been small in scale and have employed cross-sectional designs. Larger longitudinal studies or RCTs are needed to understand the associations between PA and AD-related pathologies. In this review, many other potential mechanisms were discussed. Although these mechanisms are interesting and could possibly be correct, at this point clear evidence is lacking. It would be very important for people, especially those who lead sedentary lives, to know how PA affects their brain because such knowledge has the potential to motivate them to increase their PA. Also, elucidation of the mechanisms may lead to the development of effective exercise programs as well as methods for efficiently monitoring the benefits. A more in-depth and clearer understanding of the mechanisms underlying the effects of PA on brain health is therefore needed. The advancement of this research field is eagerly expected.
HU designed the review and wrote the draft. TS and HA contributed the content and edited the draft. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
This work was financially supported by the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP20de0107002 and 17dk0207040h0001. The sponsors had no role in the design and conduct of the study.