Preventive Strategies for Cognitive Decline and Dementia: Benefits of Aerobic Physical Activity, Especially Open-Skill Exercise

s there is no curative treatment for dementia, including Alzheimer's disease (AD), it is important to establish an optimal nonpharmaceutical preventive intervention. Physical inactivity is a representative modi able risk factor for dementia, especially for AD in later life (>65 years). As physical activity and exercise are inexpensive and easy to initiate, they may represent an effective nonpharmaceutical intervention for the maintenance of cognitive function. Several studies have reported that physical activity and exercise interventions are effective in preventing cognitive de- cline and dementia. This review outlines the effects of physical activity and exercise-associated interventions in older adults with and without cognitive impairment and subsequently summarizes their possible mechanisms. Furthermore, this review describes the differences between two types of physical exercise—open-skill exercise (OSE) and closed-skill exercise (CSE)—in terms of their effects on cognitive function. Aerobic physical activity and exercise interventions are particularly useful in preventing cognitive decline and dementia, with OSE exerting a stronger protective effect on cognitive functions than CSE. Therefore, the need to actively promote physical activity and exercise interventions worldwide is emphasized. Keywords: physical inactivity; physical activity; exercise; aerobic; open-skill; closed-skill; cognitive decline; dementia; mild cognitive impairment; Alzheimer's disease 1. Introduction With aging, the global prevalence of dementia has increased exponentially. Currently, more than 55 million people live with dementia worldwide, and this number is expected to reach 78 and 139 million by 2030 and

activity and exercise interventions worldwide is emphasized. Keywords: physical inactivity; physical activity; exercise; aerobic; open-skill; closed-skill; cognitive decline; dementia; mild cognitive impairment; Alzheimer's disease 1. Introduction With aging, the global prevalence of dementia has increased exponentially. Currently, more than 55 million people live with dementia worldwide, and this number is expected to reach 78 and 139 million by 2030 and 2050, respectively [1]. The number of dementia cases is expected to increase in every country, particularly in low- and middle-income countries [2]. Dementia negatively impacts the physical, psychological, social, and economic status of patients and places a heavy burden on caregivers, families, and society [1]; therefore, dementia-associated care is one of the biggest challenges worldwide. Dementia can be caused by various diseases and injuries that primarily or secondarily affect the brain [1]. Alzheimer's disease (AD) is the most common cause of dementia, accounting for 60–80% of all clinical cases [1,2]. Moreover, mild cognitive impairment (MCI) is known as the prodromal stage of dementia. Amnestic MCI is widely considered as a precursor to clinical AD [3], and the global population with MCI is increasing more rapidly than that with AD [4]. Unfortunately, considering the current absence of available effective disease-modifying treatments for dementia, immediate efforts with nonpharmaceutical interventions are needed to prevent the development of MCI and progression of MCI to dementia. Currently, twelve modi able risk factors for dementia have been identi ed: low levels of education, hearing loss, traumatic brain injury, hypertension, alcohol, obesity, smoking, depression, social isolation, physical inactivity, air pollution, and diabetes [5]. Modifying Brain Sci.2023,13, 521.

Brain Sci.2023,13, 521 2 of 13 these risk factors may prevent or delay up to 40% of dementia cases. Among them, physical inactivity is one of the later-life (>65 years) risk factors for dementia [5], particularly AD [6], and can in uence the cognitive reserve and trigger neuropathological development. In contrast, physical activity or exercise is a low-cost and accessible nonpharmaceutical intervention for the primary and secondary prevention of dementia [6]. Several studies have demonstrated that physical activity and exercise interventions can prevent cognitive decline in healthy older adults [7–12] and patients with MCI [7,13–18]. In addition, the World Health Organization (WHO) guidelines recommend physical activity, particularly aerobic physical activity, for reducing the risk of cognitive decline [19]. Therefore, physical activity and exercise interventions can be an ideal preventive strategy, particularly in developing countries. Physical exercise can be classi ed into open-skill exercise (OSE) and closed-skill ex- ercise (CSE). OSE (e.g., table tennis, tennis, and badminton) is performed in dynamic, externally paced, and more unpredictable environments, whereas CSE (e.g., running and cycling) is performed in relatively consistent, self-adjustable, and more predictable envi- ronments [20]. In recent years, the difference in the effects of OSE and CSE on cognitive function has attracted the attention of the scienti c community. A systematic review [21] and meta-analysis [22] indicated that OSE can lead to greater improvements in cognitive function in healthy older adults than CSE. Consequently, physical activity and exercise, especially aerobic OSE, may be effective in preventing cognitive decline and dementia. This review outlines the cognitive bene ts of physical activity and exercise in healthy older adults and patients with MCI and dementia. Moreover, it discusses the possible mechanisms through which physical activity contributes to the maintenance and improve- ment of cognitive functions. Subsequently, differences in the effects of OSE and CSE on cognitive function as well as those in the effects within OSE are analyzed. This review emphasizes the bene cial effects of aerobic physical activity and exercise, especially OSE, on the prevention of cognitive decline and dementia. 2. Effects of Physical Activity and Exercise Interventions on the Prevention of Cognitive

functions. Subsequently, differences in the effects of OSE and CSE on cognitive function as well as those in the effects within OSE are analyzed. This review emphasizes the bene cial effects of aerobic physical activity and exercise, especially OSE, on the prevention of cognitive decline and dementia. 2. Effects of Physical Activity and Exercise Interventions on the Prevention of Cognitive Decline and Dementia A physically active lifestyle is associated with brain health [19]. In large observational studies with decades of follow-up, physically active people are less likely to develop cogni- tive decline, all-cause dementia, AD, and vascular dementia than inactivepeople [23–26]. In a recent systematic review and meta-analysis [27], older adults were divided into three groupsdepending on the duration of physical activity: inactive (<1 h per week), moderately active (>1 h in two sessions per week), and highly active (>2 h in three sessions per week) groups. This study demonstrated that the moderately and highly active groups had lower risks of developing all-cause dementia (22% and 23%, respectively), AD (28% and 32%, respectively), and vascular dementia (46% and 28%, respectively) compared with the physically inactive group [27]. A meta-analysis of several aerobic exercise intervention studies demonstrated that improving tness can enhance cognitive functions, particularly executive function [8]. Fur- thermore, a systematic review of randomized controlled trials covering the adult lifespan revealed improvements in attention and processing speed, executive function, and memory after aerobic exercise interventions [9]. Aerobic exercise interventions may also improve the memory of patients with MCI [7,13,14]. A systematic review of randomized controlled trials examining cognitively impaired individuals revealed that the increased physical activity was associated with improvements in global cognition, executive function, attention, and memory [13]. Another study reported that physical activity interventions can signi cantly improve immediate memory from baseline to the end of a 6-month interval in patients with amnestic MCI but cannot preserve cognitive functions across all MCI subtypes [14]. Therefore, the effects of aerobic exercise interventions may be speci c to the amnestic subtype of MCI.

immediate memory from baseline to the end of a 6-month interval in patients with amnestic MCI but cannot preserve cognitive functions across all MCI subtypes [14]. Therefore, the effects of aerobic exercise interventions may be speci c to the amnestic subtype of MCI.

Brain Sci.2023,13, 521 3 of 13 Evidence regarding improved cognition due to physical activity among patients with dementia is inconsistent [7]. A meta-analysis revealed greater improvements in cognition in patients performing physical activity than in controls [15]; moreover, a recent umbrella review concluded that physical activity/exercise exerts a positive effect on several cognitive and noncognitive outcomes in patients with MCI and dementia [16]. However, other meta- analyses have reported lesser or no bene ts of physical activity [17,18]. Accordingly, physical activity and exercise interventions can be an effective, economi- cally attractive, nonpharmacological strategy to mitigate the deleterious effects of aging and disease on cognition and brain health [28]. However, as neurodegeneration progresses in dementia, it may be dif cult to improve cognitive function through physical activity interventions alone. Therefore, the importance of early physical activity interventions should be emphasized to delay cognitive decline in healthy older adults, patients with MCI, and those with early-stage dementia [29]. Various guidelines exist regarding the minimum physical activity level required to exert a positive impact on brain health and prevent dementia [10,19,30,31]. The following are excerpts from the WHO guidelines on physical activity, especially aerobic physical activity, to prevent cognitive decline and dementia in adults aged 65 years [19] (Table). Table 1.WHO global recommendations on physical activity for health. Adults Aged 65 Years (1)Older adults should perform at least 150 min of moderate-intensity aerobic physical activity throughout the week, at least 75 min of vigorous-intensity aerobic physical activity throughout the week, or an equivalent combination of moderate- and vigorous-intensity activities. (2)Aerobic activity should be performed in bouts of at least 10 min. (3)For additional health bene ts, adults aged 65 years should increase the duration of moderate-intensity aerobic physical activity to 300 min per week or engage in 150 min of vigorous-intensity aerobic physical activity per week or an equivalent combination of moderate- and vigorous-intensity activities. (4)Adults in this age group with poor mobility should perform physical activities to enhance balance and prevent falls for 3 days per week. (5)Muscle-strengthening activities involving major muscle groups should be performed for 2 days per week. (6)When

week or engage in 150 min of vigorous-intensity aerobic physical activity per week or an equivalent combination of moderate- and vigorous-intensity activities. (4)Adults in this age group with poor mobility should perform physical activities to enhance balance and prevent falls for 3 days per week. (5)Muscle-strengthening activities involving major muscle groups should be performed for 2 days per week. (6)When adults in this age group cannot perform the recommended levels of physical activity due to health conditions, they should be as physically active as possible based on their abilities and conditions. Abbreviation: WHO, World Health Organization. 3. Possible Mechanisms Underlying the Effects of Physical Activity and Exercise Interventions on Cognitive Decline and Dementia Prevention The effects of physical activity on cognitive function are mediated by various brain mechanisms, including improvement in cardiovascular risk factors, increased neurotrophic factor expression, enhanced amyloid- turnover, increased cerebral blood ow (CBF), and decreased in ammatory responses [7,32,33] (Table). Cardiovascular risk factors, such as diabetes, hypertension, hyperlipidemia, and obe- sity, cause hardening of cerebral blood vessels, small vessel damage, strokes, and reduced CBF [7]. These cerebrovascular changes ultimately lead to cognitive decline. Regular physi- cal activity can prevent these risk factors, thereby reducing the risk of neurodegeneration through improvement in general cardiovascular health [23]. Therefore, reducing cardiovas- cular risk factors through physical activity may be one of the most effective strategies for preventing age-related cognitive decline and dementia. Physical activity, particularly aerobic exercise, is known to increase the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF) [7,32–36]. BDNF is a neurotrophin essential for neuroplasticity, from neurogenesis to neuronal survival

Brain Sci.2023,13, 521 4 of 13 and from synaptogenesis to cognition, as well as regulation of energy homeostasis [34]. Increased BDNF expression correlates with the amount of exercise [34] and is considered as a biomarker of bene cial effects of exercise on cognitive function [21]. Aerobic exercise training increases the size of the anterior hippocampus in older adults, thereby leading to improvements in spatial memory. This increase in hippocampal volume is associated with greater serum BDNF levels [35]. IGF-1 and VEGF play important roles in neurogenesis and angiogenesis and promote BDNF expression in the hippocampus [7]. Physical exercise increases IGF-1 levels in older adults with and without cognitive impairment, which is associated with improved cognitive performance in this population [37–40]. Similarly, post- exercise elevations in VEGF levels have been reported in older adults with and without cognitive impairment [41,42]. Elevated VEGF levels are associated with improved cognitive function [43]. Therefore, increased expression of neurotrophic factors may be an important mechanism for preventing cognitive decline. Table 2. Possible mechanisms of the effects of physical activity and exercise interventions on cognitive decline and dementia prevention. Possible Mechanisms (1)Improvement in cardiovascular factors (e.g., diabetes, hypertension, hyperlipidemia, and obesity) (2)Increased neurotrophic factor expression (e.g., BDNF, IGF-1, and VEGF) (3)Increased amyloid- turnover (4)Increased cerebral blood ow (5)Decreased in ammatory responses (e.g., CRP, IL-6, and TNF- ) Abbreviation: BDNF, brain-derived neurotrophic factor; CRP, C-reactive protein; IGF-1, insulin-like growth factor 1; IL-6, interleukin-6; TNF- , tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor. Amyloid- plaques are a pathological hallmark of AD [2]. A longitudinal study in older adults showed that higher physical activity levels at baseline were associated with lower plasma amyloid- levels 9–13 years later. In addition, higher amyloid- levels at year 9 indicate a greater risk of cognitive impairment at year 13. These ndings suggest that amyloid- levels can mediate the relationship between physical activity and cognitive impairment [36]. Moreover, in a study using amyloid positron emission tomography, physical activity levels were inversely correlated with brain amyloid- levels in older adults [44]. Accordingly, physical activity is believed to promote amyloid- turnover and may contribute to

risk of cognitive impairment at year 13. These ndings suggest that amyloid- levels can mediate the relationship between physical activity and cognitive impairment [36]. Moreover, in a study using amyloid positron emission tomography, physical activity levels were inversely correlated with brain amyloid- levels in older adults [44]. Accordingly, physical activity is believed to promote amyloid- turnover and may contribute to the prevention of cognitive decline. CBF decreases with age, thereby accelerating the decline in cognitive function and increasing the risk of developing dementia in the general population [32]. Physical activ- ity is known to increase CBF, which may help maintain cerebral perfusion and prevent atrophy [33]. Regular physical activity can increase the regional gray and white matter volumes in brain regions important for memory, executive function, emotional regula- tion, and internally directed cognition, such as the hippocampus, prefrontal cortex, and cingulate cortex [33]. However, although moderate-to-vigorous aerobic exercise training increases global CBF and improves cognitive function in patients with amnestic MCI [45], these effects were not observed in patients with mild to moderate AD [46]. Therefore, CBF should be targeted in healthy older adults or patients with MCI to prevent or postpone AD pathology. Regular physical activity reduces neuroin ammation in the elderly. That is, it reduces serum concentrations of in ammatory markers, such as C-reactive protein, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF- ) [32]. Decreased levels of these in ammatory markers are associated with better performance in cognitive tests [32]. A multimodal physical exercise program effectively reduced peripheral TNF- and IL-6 concentrations in both patients with normal cognitive function and those with MCI as well as improved

Brain Sci.2023,13, 521 5 of 13 cognitive function in patients with MCI [47]. Moreover, aerobic exercise improves immune system function in healthy older adults by increasing the activity of natural killer cells and proliferation of T lymphocytes, hematopoietic stem cells, and endothelial progenitor cells [32]. Accordingly, physical activity and exercise, especially aerobic exercise, can prevent and delay cognitive decline and dementia through anatomical, cellular, and molecular level changes in the brain [32]. 4. Differential Effects of OSE and CSE on the Prevention of Cognitive Decline and Dementia Physical activity is de ned as any bodily movement produced by skeletal muscles that results in energy expenditure. Physical exercise is a subset of physical activity that is planned, structured, and repetitive and has a nal or intermediate objective of improving or maintaining physical tness [48]. Furthermore, physical exercise can be classi ed as OSE or CSE depending on its special environmental and task-associated requirements. OSE involves active decision-making, ongoing adaptability, and unpredictable environments in which participants must alter responses to randomly occurring external stimuli. OSE is predominantly perceptual and externally paced. In contrast, CSE is performed in a relatively stable and predictable environment in which motor movements follow set patterns. CSE- related skills tend to be self-paced as there are fewer cognitive demands and decision- making requirements [21,22,49] (Table). Table 3.Differences in the characteristics of OSE and CSE.OSE CSE Special environments - - Task requirements - - - - Special environments - - Task requirements - - - Abbreviation: CSE, closed-skill exercise; OSE, open-skill exercise. CSE is further classi ed into categories 1 and 2, whereas OSE is classi ed into cate- gories 3 and 4 [49]. In category 1 of CSE, the form of movement is fairly xed for the speci c type of sport, and the environmental and task requirements are primarily constant during the execution of the movement (e.g., gymnastics). In category 2 of CSE, the movements consist of a continuum from closed to open skills. The environmental conditions are already known (e.g., athletics disciplines); therefore, these conditions could be implemented in the pre-existing program of the movement. In

c type of sport, and the environmental and task requirements are primarily constant during the execution of the movement (e.g., gymnastics). In category 2 of CSE, the movements consist of a continuum from closed to open skills. The environmental conditions are already known (e.g., athletics disciplines); therefore, these conditions could be implemented in the pre-existing program of the movement. In category 3 of OSE, athletes can foresee situational conditions to a limited extent (e.g., nature sports such as sur ng and skiing). In category 4 of OSE, athletes cannot predict the diverse environment at all (e.g., combat and team sports); consequently, they need to react rapidly and dynamically to constantly changing movement requirements. Representative examples of OSE and CSE are shown in Table49]. Recent systematic reviews and meta-analyses have investigated the differential ef- fects of OSE and CSE on various cognitive functions (e.g., inhibitory control, working memory, cognitive exibility, planning, decision-making, problem solving, processing speed, perception, attention, and memory) in a wide range of people, from children to older adults [21,22,49]. The characteristics of the studies comparing the effects of OSE and CSE on cognitive function in the elderly [50–58] are summarized in Table. The most frequently evaluated sports in OSE were tennis, table tennis, and badminton, whereas those in CSE were swimming, running, and athletics [49]. A systematic review by Gu et al. [21]

Brain Sci.2023,13, 521 6 of 13 showed that OSE can lead to greater improvements in cognitive function in both children and older adults. These ndings were con rmed by a meta-analysis by Zhu et al. [22] who demonstrated that OSE was more advantageous in improving cognitive functions, particularly executive functions such as inhibitory control and cognitive exibility (effect size for OSE versus CSE: overall cognitive performance, 0.304; inhibitory control, 0.247; and cognitive exibility, 0.360). Similarly, a meta-analysis and systematic review by Heilmann et al. [49] favored OSE over CSE for the development of executive functions (effect size for OSE versus CSE: overall cognitive performance, 0.174; cognitive exibility, 0.210; inhibitory control, 0.191; and working memory, 0.138). Table 4.Representative examples of OSE and CSE. Adapted from Heilmann et al. [49]. OSE CSE Category 4 - - - - - - - - - - - - - - Category 3 - - Category 2 - - Category 1 - - - - - - - - - Abbreviations: CSE, closed-skill exercise; OSE, open-skill exercise. All these studies suggest that OSE is more effective than CSE in improving some aspects of cognitive function across all age groups. The superiority of OSE in maintaining cognitive function may be attributed to the higher cognitive demands of OSE. Further, OSE requires more social interaction than CSE [56], which might also explain the superiority of OSE. However, older adults participating in ball and racket projects have higher health and physical awareness [59]. Thus, people who are cognitively and physically healthy are likely to engage in OSE rather than CSE, whereas those with cognitive or physical problems cannot engage in OSE, thereby reversing the causal relations. Accordingly, further longitudinal studies with well-randomized groups are needed to examine the causes of OSE superiority. Some studies have also investigated the effects of OSE and CSE on neurotrophic factors or cytokines [20,60]. Hung et al. [60] investigated the acute effect of OSE and CSE on BDNF level in the blood of young men. They revealed that OSE can lead to a higher BDNF release than CSE. Behrendt et al. [20] examined

The article discusses aerobic physical activity's role in preventing cognitive decline and dementia.