Cristy Phillips, Mehmet Akif Baktir, Devsmita Das, Bill Lin, Ahmad Salehi
Alzheimer disease (AD) is a primary cause of cognitive dysfunction in the elderly population worldwide. Despite the allocation of enormous amounts of funding and resources to studying this brain disorder, there are no effective pharmacological treatments for reducing the severity of pathology and restoring cognitive function in affected people. Recent reports on the failure of multiple clinical trials for AD have highlighted the need to diversify further the search for new therapeutic strategies for cognitive dysfunction. Thus, studies detailing the neuroprotective effects of physical activity (PA) on the brain in AD were reviewed, and mechanisms by which PA might mitigate AD-related cognitive decline were explored. A MEDLINE database search was used to generate a list of studies conducted between January 2007 and September 2014 (n=394). These studies, along with key references, were screened to identify those that assessed the effects of PA on AD-related biomarkers and cognitive function. The search was not limited on the basis of intensity, frequency, duration, or mode of activity. However, studies in which PA was combined with another intervention (eg, diet, pharmacotherapeutics, ovariectomy, cognitive training, behavioral therapy), and studies not written in English were excluded. Thirty-eight animal and human studies met entry criteria. Most of the studies suggested that PA attenuates neuropathology and positively affects cognitive function in AD. Although the literature lacked sufficient evidence to support precise PA guidelines, convergent evidence does suggest that the incorporation of regular PA into daily routines mitigates AD-related symptoms, especially when deployed earlier in the disease process. Here the protocols used to alter the progression of AD-related neuropathology and cognitive decline are highlighted, and the implications for physical therapist practice are discussed.
Alzheimer disease (AD) is a chronic, neurodegenerative disorder that adversely affects neurons in the brain, ultimately resulting in loss of memory and language, behavioral disturbances, and dependence on caregivers. The strongest risk factor for AD is aging, and the risk doubles every 5 years after the age of 65 years. Increasing population, longevity, and economic prosperity have contributed to concern about a dementia epidemic in the aging population. Currently, 26 million people are affected by AD worldwide; the number of affected people is expected to approximate 106 million by the year 2050, provoking serious clinical, social, ethical, and economic problems.
The gradual decline in brain functioning caused by AD has been associated with several characteristic features, including changes in synaptic number and function, neurogenesis, and neurotrophin levels, plaques and neurofibrillary tangles (NFTs), and abnormal circadian rhythms. The progression of these features is considered critical to the development of impairments in cognition, defined here as the unique combination of attention, learning, memory, language, visuospatial skills, and executive function. Notably, many pathological features precede AD-related cognitive decline by decades, prompting the notion that there is ample time to mitigate symptom progression. However, despite the window of opportunity, currently available pharmacotherapies (eg, donepezil HC1 [Aricept, Eisai Co Ltd, Tokyo, Japan], galanthamine HBr [Razadyne, Janssen Pharmaceuticals Inc, Beerse, Belgium], rivastigmine tartrate [Exelon, Novartis Pharmaceuticals Corp, Basel, Switzerland], and memantine HC1 [Namenda, Forest Laboratories Inc, New York, New York]) offer transient symptomatic relief only. Given the lack of disease-modifying options, it is imperative to diversify the search for feasible and effective interventions. This realization has prompted great interest in the use of physical activity (PA) to attenuate the severity of neuropathological features associated with cognitive decline in AD.
Physical activities are those that require energy expenditure and involve bodily movements produced by skeletal muscles. Physical exercise has been defined as a subcategory of PA that connotes purposeful, planned, and structured endeavors undertaken to improve skill or physical fitness level. Convergent evidence suggests that PA can alter the progression of AD-related neuropathology and cognitive decline, leading to the incorporation of PA into basic clinical management protocols for AD.1 Because it is important that physical therapists understand the means by which PA can be beneficial, from both self-education and patient education perspectives, the aims of this review are to discuss key features of AD pathology, explore the putative mechanisms by which PA might mitigate these features, review protocols used to effectuate the positive effects of PA on AD in both animal and clinical studies, and highlight implications for physical therapists.
Pathological Features of AD
Amyloid plaques and NFTs are characteristic features of AD. Amyloid plaques comprise a potentially toxic protein called amyloid beta (Aβ). In AD, the plaques are heterogeneously interspersed throughout the brain. Neurofibrillary tangles are abnormal forms of twisted protein threads found inside axons and comprising insoluble tau. For many years, it has been thought that plaques and NFTs may cause the neuronal damage seen in AD. However, such an overly simplistic concept has yielded to contemporary conceptualizations in which AD is viewed as a multifactorial disease arising from several abnormal complex features and processes (Fig. 1/See PDF).
We systematically reviewed how PA might be deployed to alter the more salient features of AD and, in turn, mitigate cognitive decline. Infused in this discussion is an integration of data derived from both rodent and human studies. This “mixed presentation” is necessary given the obvious limits for experimental manipulation of brain tissue in living humans. Admittedly, evidence from rodents is not a substitute for human studies. Rather, the aim of rodent investigations is to generate preclinical data to expedite the pace of discovery, bolster epidemiological research, and bridge the temporal lag between knowledge creation and clinical trials. With this caveat in mind, we present a mixture of convergent data suggesting that PA benefits brain function and cognition in AD.
This review was designed and conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.
In an attempt to capture relevant data, we conducted a computer-based search of MEDLINE and performed manual searches of key references to identify studies that investigated the effect of PA on the brain in AD and putative mechanisms by which PA might mitigate cognitive decline in AD. Key word search criteria combined the terms “Alzheimers” and “exercise.” This search was used to generate a list of relevant studies conducted between January 2007 and September 2014 (n=394).
Peer-reviewed intervention studies that assessed the effects of exercise on characteristic features associated with AD and cognitive decline were included in the present review. No restrictions were placed on intensity, frequency, duration, or mode of intervention. However, multifactorial studies that combined exercise with other interventions (eg, diet, pharmacotherapeutics, ovariectomy, cognitive training, or behavioral therapy) were excluded, as were studies not written in English.
Literature searches and data abstraction were conducted independently by one investigator using a standardized template and confirmed by 2 other reviewers. Disagreements were resolved by discussion among the investigators until consensus was reached.
Figure 2 (see link) shows an overview of study flow. Information pertaining to participants, study characteristics, biomedical measurements, and cognition was extracted with an unmasked standardized method as described above. Tables 1 and 2 show summaries of study characteristics and findings, organized by animal and human studies.
Putative Effects of PA on Aβ Production and Accumulation
A characteristic feature of AD is the accumulation of amyloid plaques in the brain. The accumulation of Aβ is thought to result from increased production or reduced clearance of this molecule (or both). It has been shown that mutations and polymorphisms in genes—such as those for amyloid precursor protein (APP), presenilins 1 and 2, apolipoprotein E, and sortilin-related receptor 1 —result in increased accumulation of Aβ, failure of clearance mechanisms, and formation of amyloid plaques. Amyloid plaque formation is problematic because the accumulation of amyloid plaques is believed to trigger a cascade of events that lead to dysfunction and death of neighboring neurons. Knowledge of the adverse effects of Aβ has led to the hypothesis that a reduction in harmful Aβ accumulation might prevent neuronal degeneration, especially in people at high risk for AD.
Accordingly, most studies investigating the relationship between PA and Aβ deposition have been performed with transgenic mice overexpressing the APP gene, a model known to increase Aβ accumulation in the brain. Using such a model, Adlard et al provided mice with a running wheel for 1 and 5 months. At the end of training, both groups exhibited a decreased number of Aβ deposits in the frontal cortex and hippocampus, along with improved spatial learning. These outcomes appear to have been mediated by alterations in APP processing. Similarly, forced treadmill training 5 days per week for 5 to 12 weeks was shown to significantly reduce Aβ deposition in the brain and improve learning. Conversely, Parachikova et al failed to detect alterations in Aβ and tau levels in models of AD involving middle-age and older mice and 3 weeks of free running; it seems plausible that advanced neuropathology in the mice, in conjunction with the brevity of the study, contributed to these negative results (Tab. 1/See PDF). Consistent with the hypothesis that PA modulates Aβ turnover, the Australian Imaging, Biomarkers and Lifestyle Study of Ageing demonstrated that higher levels of self-reported PA were associated with a significant reduction in plasma Aβ deposition during aging in people who were healthy. Moreover, a negative trend between PA levels and Aβ deposition in the brain was found, although this trend did not reach statistical significance. In a study conducted in the United States, Liang et al reported a negative correlation between PA (eg, self-reported voluntary walking, jogging, and running for a 10-year-period) and Aβ deposition. Interestingly, people who were middle-aged or older and met or exceeded the American Heart Association’s guidelines (30 minutes of moderate exercise 5 days per week) showed a significantly lower level of Aβ than controls. Together, this evidence suggests that PA decreases pathological Aβ deposition in the brain during normal aging and the early stages of AD.
Evidence That PA Alters Tau Accumulation
Microtubules are structures that facilitate the transport of a variety of molecules (eg, nutrients and growth factors) bidirectionally between the cell body and axon terminals in neurons. Typically, tau proteins bind to microtubules and stabilize them. However, chemical alterations of tau by various kinases and phosphatases produce a form of tau with altered biological function and interrupt its binding to microtubules. Consequently, tau proteins disengage from microtubules and clump together with other tau threads. Lacking appropriate stabilization, the microtubules disassemble and become enmeshed with the tau threads, forming NFTs. The collapse of microtubules and tau assembly results in significant alterations in internal transport and, consequently, atrophy and dysfunction of neurons.
Indeed, the pattern of axonal transport collapse, NTT formation, and neurodegeneration is well characterized in AD. Neurofibrillary tangles appear first in the transentorhinal region and later in the hippocampal formation before spreading outward to the rest of the brain (Fig. 1/See PDF). Given that a 4- to 8-fold increase in tau phosphorylation has been reported in postmortem brain samples from people with AD and that tau pathology interrupts the vital process of intracellular neuronal transport, it is generally held that tau pathology plays an important role in inducing neurodegeneration in AD.
Interestingly, evidence has suggested that PA reduces the level of tau deposition by modifying the activity of tau-related kinases and phosphatases. Leent et al demonstrated that mice overexpressing the gene for abnormal tau showed a significant increase in glycogen synthase kinase 3β levels. This enzyme is believed to play a vital role in tau phosphorylation and accumulation. Notably, treadmill training for 12 weeks led to a significant reduction in glycogen synthase kinase 3β levels, suggesting that exercise can reduce tau phosphorylation. In another model of AD, Um et al demonstrated that 3 months of treadmill training of extremely old mice led to a significant reduction in tau phosphorylation in the hippocampus. In yet another model, Belarbi et al demonstrated that 9 months of free access to a running wheel decreased the early stages of NFT formation in the hippocampal region and improved spatial learning. Together, the results of these preclinical studies suggest that PA might provide a means to alleviate tau pathology and improve cognitive function in AD.
Evidence That PA Alters Synaptic Function and Number of Synapses
As fundamental sites of communication between neurons, synapses play an important role in cognition. Alterations in synapses adversely affect cognitive function by altering local and regional communication, which is essential for proper brain function. Indeed, the loss of synapses is an invariant and early characteristic of AD, and there is a strong relationship between the degree of synaptic loss and the severity of cognitive decline. Quantification of synaptic markers in postmortem samples from people with AD has revealed a reduction in the number of synapses in areas of the brain vitally important for learning and memory, particularly the association cortices and hippocampal region. Altered expression of synaptic proteins occurs early during the progression of AD, with concomitant disruption in neuronal communication. As AD progresses, neurons increasingly shrink and lose more and more synaptic connections. By the final stages of the disease, significant neuronal loss and brain atrophy have occurred to the point at which the ability to acquire and encode new memories has been lost.
Transgenic mouse models of AD have shown similar alterations in synaptic function, along with concomitant deficits in spatial learning and memory. However, chronic PA in the form of free access to a running wheel for 4, 6, and 24 weeks has been shown to significantly improve the synaptic properties of the hippocampus and spatial learning (Tab. 1/See PDF). The lack of noninvasive methods for the study of synaptic function precludes direct examination in humans, prompting the use of proxy measures. For instance, Pajonk et al showed that people who were healthy and regularly participated in PA (eg, aerobic exercise 3 times per week, 30 minutes per session, for 12 weeks) demonstrated improved hippocampal volume, as studied by magnetic resonance imaging; this finding could be attributed to increased neuronal numbers, their projections, number of synapses, or a combination of these. Together, the results of these studies make it seem plausible that PA might promote synaptic function and cognitive function in AD, particularly in the hippocampus.
Evidence That PA Restores Neurogenesis
In mammals, an estimated 700 neurons are produced daily in a process called neurogenesis. This process occurs in 2 regions of the adult brain: the subventricular zone and the subgranular zone of the hippocampus. Many of the 20,000,000 neurons generated over the course of a lifetime migrate to the dentate gyrus of the hippocampus and become integrated into circuits that play a vital role in learning and memory. However, several intrinsic factors (eg, growth factors, cytokines, hormones) and extrinsic factors (eg, PA, pharmacological agents, hippocampus-dependent learning tasks) can alter the rate of neurogenesis. Such is the case in aging and AD, in which several known and unknown factors compromise neurogenesis.
Notably, rodent studies have suggested that PA can potently induce neurogenesis in the dentate gyrus of the hippocampus, a brain structure that is vitally important for learning and memory and yet is vulnerable in AD. This knowledge has led to the suggestion that PA might be deployed to mitigate AD-related decrements in neurogenesis. Indeed, Marlatt et al demonstrated that both short-term (1 month) and longterm (9 months) free access to a running wheel led to a significant increase in neurogenesis in the hippocampus in a mouse model of AD (eg, 3xAD, mice overexpressing APP, TAU, and PS1). Using another rodent model of AD, Kim et al injected Aβ—a protein that accumulates in plaques in the brain—into the brain ventricles of rats, inducing significant cognitive dysfunction and a reduction in neurogenesis. Next, they exposed the rats to treadmill training (30 minutes per day, 5 days per week, for 4 weeks), partially restoring hippocampal neurogenesis53 (Tab. 1/See PDF). An improvement in the rate of neurogenesis is an important target in AD because enhanced neurogenesis in animal models has been positively correlated with improvements in learning and memory, and the blockade of neurogenesis after PA has been shown to negate improvements in memory and learning.
Further attesting to the importance of neurogenesis in memory and learning is a recent clinical study demonstrating a positive association between neurogenesis and declarative memory function in humans. Thus, the idea that hippocampal neurogenesis can be positively affected by PA offers considerable hope for exploiting newly born cells to reestablish hippocampal brain circuits that have been damaged as a result of the progression of AD.
Evidence That PA Increases Neurotrophin Levels
Neurotrophins—vital proteins in the brain—are known to contribute to the survival, growth, and maintenance of neurons, enabling them to participate in a variety of specific functions, including learning and memory. Failure in neurotrophin release, binding, and action plays a significant role in neurodegenerative disorders, particularly AD. Indeed, it has been shown that brain-derived neurotrophic factor (BDNF)—one of the most widely distributed neurotrophins in the brain—plays a vital role in the maintenance of neurons that underlie cognition, including those that undergo degeneration in AD. Moreover, a host of BDNF-related abnormalities have been reported in AD. It has been shown that levels of BDNF in serum decrease during the course of AD and that the decrease correlates well with the severity of dementia; postmortem brain samples from people with AD exhibit reduced BDNF gene expression; a common variation in the BDNF gene is associated with late-stage AD65; the gene encoding BDNF is associated with AD-related depression; there is an inverse relationship between the presence of NFTs and BDNF levels; and BDNF levels in mouse models of AD correlate well with the severity of AD neuropathology.
Because of the responsiveness of BDNF to PA, multiple laboratories have focused on BDNF in recent-years. It has been shown that mouse models of AD that express the human apolipoprotein e4 allele exhibit increased levels of hippocampal BDNF and its TrkB receptors after 6 weeks of voluntary wheel running. Such a finding is important because the apolipoprotein E e4 allele has been shown to be a major risk factor for AD and because increased levels of BDNF might preserve neuronal function in models affected by this genetic background. Using another transgenic mouse model of AD, Belarbi et al demonstrated that 9 months of voluntary free wheel running significantly increased BDNF levels in the brain. Notably, other investigators have shown that voluntary running is associated with rapid increases in BDNF gene expression in the hippocampus and that these changes endure for weeks. Paralleling these findings, in people who were healthy and people who had AD, acute aerobic PA (until the heart rate reached 85% of the maximum capacity) was shown to increase plasma BDNF levels, a significant finding given that plasma BDNF levels are linked to alterations in brain BDNF levels.
Given that PA alters levels of BDNF and that normalized neurotrophin levels are often associated with concomitant improvements in cognition, it seems plausible that PA could be deployed to mitigate cognitive dysfunction in AD without necessarily reversing extant neuropathology.
Evidence That PA Positively Alters Inflammation and Immune Function
Inflammation is a complex cellular and molecular defense mechanism designed to protect against stress, infection, and injury. In the brain, this process is characterized by the activation of inflammatory cells (eg, astrocytes and microglia) and the release of inflammatory molecules, such as interleukin 1β, interleukin 6, and tumor necrosis factor α. Secreted inflammatory molecules recruit other immune cells, such as monocytes and lymphocytes, to cross the blood-brain barrier and induce neuroinflammation in the brain. Several studies have implicated overactive neuroinflammatory processes in AD. For example, it has been shown that there are elevated levels of inflammatory molecules in regions adjacent to Aβ plaques as well as in cerebrospinal fluid, altered lymphocyte and macrophage distributions in the brain, and increased activation of inflammatory cells (including astrocytes and microglia); in addition, a reduced risk of dementia has been reported in people receiving antiinflammatory drugs. Whether the relationship of the immune response to AD is primary or secondary has yet to be determined; nevertheless, the suggestion that PA might play an anti-inflammatory role in AD by mitigating neuronal dysfunction, the occurrence of Aβ pathology, and neurodegeneration warrants close consideration.
Animal and human studies have shown that PA reduces markers of neuroinflammation in AD. Nichol and colleagues3981 demonstrated that transgenic mice overexpressing APP showed increased levels of inflammatory markers (eg, interleukin 1β and tumor necrosis factor a) in the brain but that 3 weeks of free wheel running reduced the levels of these inflammatory markers to normal; these findings coincide with improvements in spatial learning. This evidence makes it seem plausible that PA induces the release of anti-inflammatory (interleukin 6) and adaptive (CXCL1 and CXCL12) immune molecules from the muscle and brain, mitigating an exaggerated inflammatory response. Bolstering these findings are the results of epidemiological studies demonstrating that habitual PA is correlated with reduced systemic inflammation. Moreover, a randomized controlled trial (RCT) in aging adults who were healthy and participated in progressive aerobic activity (15 minutes increasing to 40 minutes) 2 times per week for 6 months revealed significant improvements in immune system function. Similar results were found in a study of elderly women participating in aerobic exercise (60 minutes per session, 3 times per week, for 16 weeks).
Notably, several human studies have failed to replicate the positive effects of PA on immune function in young and elderly people, possibly reflecting influences that have not been taken into account. Nevertheless, current exercise guidelines issued by the American College of Sports Medicine and the Surgeon General suggest that moderate exercise (5-60 minutes at 40%-60% of aerobic capacity) can be used to induce positive immune health. This notion is reaffirmed by a consensus statement drafted by international experts in the field of exercise immunology; this statement suggests that moderate levels of regular exercise might be particularly beneficial in elderly people, a population at high risk for AD. Together, this evidence suggests that moderate levels of PA might modulate AD pathology by decreasing systemic inflammation and altering immune function.
Evidence That PA Affects Circadian Rhythms
Many physiological processes, such as feeding behavior, motor activity, hormonal secretion, and autonomic nervous system functions, exhibit naturally occurring rhythms that are commonly referred to as circadian rhythmicity. Central to circadian rhythmicity is the suprachiasmatic nucleus (SCN), a structure located in the anterior hypothalamus and comprising neurons that regulate different body functions according to rhythms that vary with the 24-hour night-day light cycle. More specifically, the SCN receives direct inputs from the retina, and these cues regulate its pattern of activity. Other major sources of input to the SCN include brain-stem nuclei and the somatosensory cortex.
Disturbances in SCN function have been linked to neuropathological changes. It has been shown that complete bilateral destruction of the SCN leads to a day-night reversal in wake-sleep rhythmicity. Moreover, sleep alterations have been associated with SCN abnormalities in several neurodegenerative disorders, including AD. The SCN exhibits a higher level of neuropathology in people with AD than in controls, resulting in a significant loss of SCN neurons and sleep fragmentation symptoms. Indeed, 25% to 40% of people with mild to moderate AD exhibit significant sleep problems, including a decrease in amplitude in circadian rhythms and a phase delay. These changes in sleep patterns seem to precede cognitive symptoms in people with AD, with decrements in sleep quality paralleling both cognitive dysfunction and the progression of AD pathology.
Given that both intrinsic and extrinsic factors are capable of regulating SCN activity, it seems plausible that modifiable factors such as PA, light exposure, and pharmacotherapeutics (eg, melatonin) could be used to assuage rhythmic abnormalities and sleep fragmentation in AD. It appears that PA can modulate SCN activity by either regulating body temperature or altering the activity of several brain regions that project to the SCN (eg, raphe nucleus, pineal gland). Consequently, PA has been used to qualitatively and quantitatively improve atypical sleep symptoms across patient populations.
In a recent cross-sectional study examining levels of PA in people diagnosed with lung cancer, a significant positive correlation was noted between self-reported levels of PA— which included light activities (eg, cooking, slow walking, driving, and performing light manual work), moderate activities (eg, playing golf, cycling less than 9.6 km [6 miles] per hour, walking 3.2-4.8 km [2-3 miles] per hour, loading and unloading goods), and vigorous activities (eg, swimming, jogging, hiking, gymnastics, and dancing)—and overall sleep time and quality. Similarly, in another cross-sectional study, Hooghiemstra et al noted that people with early-onset dementia exhibited disturbances in rest-activity rhythm variables. More importantly, they noted a significant negative correlation between PA, as measured by the number of daily steps taken, and the severity of rest-activity rhythm disturbances; this finding led them to advocate for increased ambulatory activities for people with dementia. However, to our knowledge, only one interventional study has examined the effects of PA on sleep quantity and quality in AD. Nascimento et al reported that 6 months of PA (eg, walking, circuit training, stretching, balance, agility) decreased the frequency of sleep disturbances in people with mild to moderate AD.
Given that circadian rhythm abnormalities and sleep fragmentation are the most common causes of institutionalization for people with AD, more research is needed to understand how PA improves circadian rhythms and, in turn, cognitive function. Thus, although the practical implications of these findings remain to be clarified, they suggest that the treatment of sleep abnormalities is an emerging approach for mitigating AD-related symptoms.
Evidence That PA Improves Cognition in People With AD
Current research on AD has demonstrated the feasibility of implementing PA to improve cognitive function (Tab. 2/See PDF). Most RCTs have reported positive associations between PA and cognitive function. Most of the PA training ranges in the extant RCTs were designed to facilitate active participation for 2 to 3 hours per week for aduration of 3 months or longer, although 2 programs had a 6-week duration. The modalities used in the programs varied, with all programs having some form of locomotor activity as a core component, except one. Three programs included locomotion in addition to balance and strength training. For most of the programs, a positive association between PA and cognitive function was noted. More specifically, a positive correlation between cognitive status and PA was noted for most of the programs, but a decrease in the rate of cognitive decline was noted for one program. The one program failing to show positive effects of PA on cognition was implemented by caregivers in the home environment. Of particular note in the latter study were depressive scores that were significantly higher in the group of people participating in PA than in people in the control group, suggesting that depressive symptoms might have limited the positive effects of PA on cognition in that study.
Extensive variations existed in the studies reviewed with regard to age, sex, the presence of movement-limiting factors, diagnosis (AD plus vascular dementia versus pure AD), and cognitive tests, yet all reported positive results. Nevertheless, these extant RCTs are few and leave many questions unresolved. These studies need to be replicated as larger RCTs while disentangling the effects of genetically homogeneous groups (eg, matching for apolipoprotein E genotype), duration (6 weeks, 12 months, and 24 weeks), and disease stage. Moreover, studies in which PA and cognitive changes are combined with biomarker analysis (eg, Aβ and tau levels in cerebrospinal fluid and plasma and in vivo imaging for assessment of brain structural alterations as well as Aβ and tau accumulation) and cognitive assessment are needed.
Implications for Physical Therapists, Unresolved Issues, and Future Directions
Finding an effective treatment for AD-related cognitive decline is an unmet goal. However, considerable progress has been made in better understanding implicated features and processes. Here we presented biomedical evidence that supports the role of PA in optimizing multiple mechanistic pathways believed to underlie the disease process involved in cognitive decline in AD. The data suggested that PA might be used as a preventive therapeutic approach for people who are healthy or asymptomatic and for treating people with evidence of clinical cognitive impairment so as to delay the onset of full-blown symptoms. Earlier application of PA to mitigate pathological processes and to assuage cognitive decline is imperative given recent evidence from clinical trials suggesting that interventions applied earlier in the course of AD are more likely to achieve disease modification, whereas those applied later have a significant but more limited effect after the emergence of neuronal degeneration. However, the success of prevention campaigns will require significant changes in philosophy and approach. PA must be advocated as a preventive therapeutic approach, with the goal of reducing neuropathology by promoting the initiation of good health habits that delay progression and overt cognitive decline. This preventive approach must be paralleled with research efforts aimed at revealing the effects of PA at different points in the disease continuum.
There is clearly an urgent need to identify the optimum mode, intensity, and duration of PA that might alter AD-related pathology. Several studies have suggested that exercise interventions combining various modalities, such as aerobic and strength training activities, are m ore effective in enhancing cognitive health in humans than interventions emphasizing aerobic activities alone. For instance, a meta-analysis by Colcombe and Kramer revealed that people w ho participated in a combination of aerobic and strength training activities showed greater gains in cognition than those w ho participated in aerobic activities alone (effect sizes of 0.59 versus 0.41, n = 101, P < .0 5 ). Similarly, a meta-analysis by Smith et al revealed that interventions consisting of aerobic and strength training activities improved attention, processing speed, and working memory to a greater extent than aerobic exercises alone in both people w ho w ere healthy and those with mild cognitive impairment (MCI)IH9; this effect likely was mediated by alterations in hippocampal volume. Hippocampal atrophy has been linked to increased risk of progression from MCI to AD, and the reversal of cognitive status from MCI to norm al cognition has been linked to greater hippocampal volume. Notably, 1 year of aerobic exercise of moderate intensity was shown to improve memory and hippocampal volume in older adults w ho w ere healthy, effectively reversing age-related loss of volume by 1 to 2 years. Directly applying these data, Makizako et al demonstrated that hippocampal volume was the link between moderate PA and memory augmentation in people with MCI and that longer durations of moderate PA could result in increased hippocampal volume and improved memory.
Together, these findings suggest that PA elicits compensatory mechanisms in the brains of people with extant neuropathology and, in turn, improves cognitive function. Nevertheless, the dosages (frequency, intensity, and duration) that effectively elicit neuroprotective effects have not been fully determined. One study showed that people w ho w ere middle-aged, healthy, and exercised 2 times per w eek for 20 to 30 minutes reduced the risk for AD by half.114 However, it seems likely that people with cognitive impairments will require higher dosages of PA to positively affect cognitive function. According to Heyn et al, moderate exercise (3 6 -4 5 minutes per session, 3 or 4 times per week, for 14.5- 23.4 weeks) had a strong positive effect on cognition in elderly people with cognitive dysfunction ranging from MCI to dementia. Similarly, Lautenschlager et al showed that 150 minutes of moderate exercise (50 minutes per session, 3 times per w eek, for 24 weeks) had a positive effect on cognitive function in people with MCI.
In contrast to earlier studies relating different aspects of cognitive function to PA without considering underlying brain changes, w e investigated how PA alters key features of AD pathology and, in turn, might be used to improve cognitive function. In summary, the data presented here suggest that moderate PA—a target that is practical, well tolerated, and likely to optimize exercise adherence—can be used to improve cognitive function and reduce the slope of cognitive decline in people with dementia of the AD type. It is imperative that physical therapists stay informed about new developments in the field of exercise neuroscience to function as independent and skilled practitioners.
1 California Workgroup on Guidelines for Alzheimer’s Disease Management. Guidelines fo r Alzheimer’s Disease Management: Final Report. Los Angeles, California: Department of Health Services, State of California; 2008.
2 Salehi A, Kleschevnikov A, Mobley WC. Pharmacological Mechanisms in Alzheimer’s Therapeutics. New York, NY: Springer; 2007.
3 Williams JW. Preventing Alzheimer’s Disease and Cognitive Decline. Rockville, MD: Agency for Healthcare Research and Quality; 2010.
4 Sperling RA, Aisen PS, Beckett I.A, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations front the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280-292.
5 Felsenstein KM, Candelario KM, Steindler DA, Borchelt DR. Regenerative medicine in Alzheimer’s disease. Transl Res. 2014;163:432-438.
6 Breitner JC, Baker LD, Montine TJ, et al. Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimers Dement. 2011;7:402-411.
7 Gregory MA, Gill DP, Petrella RJ. Brain health and exercise in older adults. Curr Sports Med Rep. 2013;12:256-271.
8 Bherer L, Erickson KI, Liu-Ambrose T. A review of the effects of physical activity and exercise on cognitive and brain functions in older adults. J Aging Res. 2013; 2013:657508.
9 Rolland Y, Abelian van Kan G, Vellas 13. Physical activity and Alzheimer’s disease: from prevention to therapeutic perspectives. J Am Med Dir Assoc. 2008;9:390-405.
10 Yu F, Kolanowski AM, Strumpf NE, Eslinger PJ. Improving cognition and function through exercise intervention in Alzheimer’s disease. J Nurs Scholarsh. 2006;38:358-365.
11 Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clin Proc. 2011;86:876-884.
12 Glenner GG, Wong CW, Quaranta V, Eanes ED. The amyloid deposits in Alzheimer’s disease: their nature and pathogenesis. Appl Pathol. 1984;2:357-369.
13 Huang HC, Jiang ZF. Accumulated amyloid-beta peptide and hyperphosphorylated tau protein: relationship and links in Alzheimer’s disease. J Alzheimers Dis. 2009;16:15-27.
14 Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6:e 1000100.
15 De-Paula VJ, Radanovic M, Diniz BS, Forlenza OV. Alzheimer’s disease. Subcell Biochem. 2012;65:329-352.
16 Jackson A, Crossman AR. Nucleus tegmenti pedunculopontinus: efferent connections with special reference to the basal ganglia, studied in the rat by anterograde and retrograde transport of horseradish peroxidase. Neuroscience. 1983; 10:725-765.
17 Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353-356.
18 Adlard PA, Perreau VM, Pop V, Cotntan CW. Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer’s disease. J Neurosci. 2005;25:4217-4221.
19 Um HS, Kang EB, KooJH, et al. Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer’s disease. Neurosci Res. 2011;69: 161-173.
20 Kang EB, Kwon IS, Koo JH, et al. Treadmill exercise represses neuronal cell death and inflammation during Aβ-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice. Apoptosis. 2013; 18: 1332-1347.
21 Ke HC, Huang HJ, Liang KC, Hsieh-Li HM. Selective improvement of cognitive function in adult and aged APP/PS1 transgenic mice by continuous non-shock treadmill exercise. Brain Res. 2011; 1403:1-11.
22 Parachikova A, Nichol KE, Cotman CW. Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiol Dis. 2008;30:121-129.
23 Brown BM, Peiffer JJ, Taddei K, et al. Physical activity and amyloid-beta plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing. Mol Psychiatry. 2013; 18:875-881.
24 Liang KY, Mintun MA, Fagan AM, et al. Exercise and Alzheimer’s disease biomarkers in cognitively normal older adults. Ann Neurol. 2010;68:311-318.
25 Mondragon-Rodriguez S, Perty G, Zhu X, et al. Phosphorylation of tau protein as the link between oxidative stress, mitochondrial dysfunction, and connectivity failure: implications for Alzheimer’s disease. Oxid Med Cell Longev. 2013;2013: 940603.
26 Lee HG, Perry G, Moreira PI, et al. Tau phosphorylation in Alzheimer’s disease: pathogen or protector? Trends Mol Med. 2005;11:164-169.
27 Delacourte A, David JP, Sergeant N, et al. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology. 1999;52: 1158-1165.
28 Kliatoon S, Grundke-Iqbal 1. Iqbal K. Brain levels of microtubule-associated protein tau are elevated in Alzheimer’s disease: a radioimmuno-slot-blot assay for nanograms of the protein. J Neurochem. 1992;59:750-753.
29 Iqbal K, Alonso Adel C, Chen S, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2005;1739:198-210.
30 Franco R, Cedazo-Minguez A. Successful therapies for Alzheimer’s disease: why so many in animal models and none in humans? Front Pharmacol. 2014;5:146.
31 Pei JJ, Gong CX, Iqbal K, et al. Subcellular distribution of protein phosphatases and abnormally phosphorylated tau in the temporal cortex from Alzheimer’s disease and control brains. J Neural Transm. 1998;105:69-83.
32 Leem YH, Lim HJ, Shim SB, et al. Repression of tau hyperphosphorylation by chronic endurance exercise in aged transgenic mouse model of tauopathies. J Neurosci Res. 2009;87:2561-2570.
33 Belarbi K, Bumouf S, Femandez-Gomez FJ, et al. Beneficial effects of exercise in a transgenic mouse model of Alzheimer’s disease-like tau pathology. Neurobiol Dis. 2011;43:486-494.
34 Shankar GM, Walsh DM. Alzheimer’s disease: synaptic dysfunction and AJ3. Mol Neurodegener. 2009;4:48.
35 Davies CA, Mann DM, Sumpter PQ, Yates PO. A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci. 1987;78:151-164.
36 Masliah E, Mallory M, Alford M, et al. Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology. 2001;56: 127-129.
37 Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002;25:789-791.
38 Garcia-Mesa Y, Lopez-Ramos JC, Gimenez-Llort L, et al. Physical exercise protects against Alzheimer’s disease in 3xTg-AD mice. J Alzheimers Dis. 2011; 24:421-454.
39 Nichol K, Deeny SP, Seif J, et al. Exercise improves cognition and hippocampal plasticity in APOE epsilon4 mice. Alzheimers Dement. 2009;5:287-294.
40 Pajonk FG, Wobrock T, Gruber O, et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry. 2010;67:133-143.
41 Cotman CW, Berchtold NC. Physical activity and the maintenance of cognition: learning from animal models. Alzheimers Dement. 2007;3(2 suppl):S30- S37.
42 Spalding KL, Bergmann O, Alkass K, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153:1219-1227.
43 Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol. 1965;124:319-335.
44 Cameron HA, McKay RD. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol. 2001;435:406-417.
45 van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA. 1999; 96:13427-13431.
46 Vivar C, van Praag H. Functional circuits of new neurons in the dentate gyrus. Front Neural Circuits. 2013;7:15.
47 Mu Y, Gage FH. Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Mol Neurodegener. 2011;6:85.
48 Lazarov O, Marr RA. Neurogenesis and Alzheimer’s disease: at the crossroads. Exp Neurol. 2010;223:267-281.
49 Scoville WB, Milner B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957;20:11-21.
50 O’Keefe J, Nadel L, Keightley S, Kill D. Fornix lesions selectively abolish place learning in the rat. Exp Neurol. 1975;48: 152-166.
51 Fox NC, Warrington EK, Stevens JM, Rossor MN. Atrophy of the hippocampal formation in early familial Alzheimer’s disease: a longitudinal MRI study of at-risk members of a family with an amyloid precursor protein 717Val-Gly mutation. Ann N Y Acad Sci. 1996;777:226-232. 1058
52 Marlatt MW, Potter MC, Bayer TA, et al. Prolonged running, not fluoxetine treatment, increases neurogenesis, but does not alter neuropathology, in the 3xTg mouse model of Alzheimer’s disease. Curr Top Behav Neurosci. 2013:15:313-340.
53 Kim BK, Shin MS, Kim CJ, et al. Treadmill exercise improves short-term memory by enhancing neurogenesis in amyloid betainduced Alzheimer disease rats. J Exerc Rehabil. 2014;10:2-8.
54 Mustroph ML, Chen S, Desai SC, et al. Aerobic exercise is the critical variable in an enriched environment that increases hippocampal neurogenesis and water maze learning in male C57BL/6J mice. Neuroscience. 2012;219:62-71.
55 Creer DJ, Romberg C, Saksida LM, et al. Running enhances spatial pattern separation in mice. Proc Natl Acad Sci USA. 2010;107:2367-2372.
56 Van der Borght K, Havekes R, Bos T, et al. Exercise improves memory acquisition and retrieval in the Y-maze task: relationship with hippocampal neurogenesis. Behav Neurosci. 2007;121:324-334.
57 Clark PJ, Brzezinska WJ, Thomas MW, et al. Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice. Neuroscience. 2008; 155:1048 -1058.
58 Coras R, Siebzehnrubl FA, Pauli E, et al. Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans. Brain. 2010;133:3359-3372.
59 Salehi A, Delcroix JD, Swaab DF. Alzheimer’s disease and NGF signaling. J Neural Transm. 2004;111:323-345.
60 Fahnestock M, Garzon D, Holsinger RM, Michalski B. Neurotrophic factors and Alzheimer’s disease: are we focusing on the wrong molecule? J Neural Transtn Suppl. 2002;62:241-252.
61 Akbarian S, Rios M, Liu RJ, et al. Brainderived neurotrophic factor is essential for opiate-induced plasticity of noradrenergic neurons. J Neurosci. 2002;22: 4153-4162.
62 Laske C, Stransky E, Leyhe T, et al. BDNF serum and CSF concentrations in Alzheimer’s disease, normal pressure hydrocephalus and healthy controls. J Psychiatr Res. 2007;41:387-394.
63 Connor B, Young D, Yan Q, et al. Brainderived neurotrophic factor is reduced in Alzheimer’s disease. Brain Res Mol Brain Res. 1997;49:71-81.
64 Holsinger RM, Schnarr J, Henry P, et al. Quantitation of BDNF mRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer’s disease. Brain Res Mol Brain Res. 2000;76:347- 354.
65 Riemenschneider M, Schwarz S, Wagenpfeil S, et al. A polymorphism of the brain-derived neurotrophic factor (BDNF) is associated with Alzheimer’s disease in patients lacking the apolipoprotein E epsilon4 allele. Mol Psychiatry. 2002;7:782-785.
66 Borroni B, Grassi M, Archetti S, et al. BDNF genetic variations increase the risk of Alzheimer’s disease-related depression. J Alzheimers Dis. 2009:18:867-875.
67 Murer MG, Boissiere F, Yan Q, et al. An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer’s disease. Neuroscience. 1999;88:1015-1032.
68 Peng S, Garzon DJ, Marchese M, et al. Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer’s disease. J Neurosci. 2009:29: 9321-9329.
69 Phillips C, Baktir MA, Srivatsan M, Salehi A. Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling. Front Cell Neurosci. 2014;8:170.
70 Park JS, Hoke A. Treadmill exercise induced functional recovery after peripheral nerve repair is associated with increased levels of neurotrophic factors. PloS One. 20l4;9:e90245.
71 Ashford J. POE genotype effects on Alzheimer’s disease onset and epidemiology.J Mol Neurosci. 2004;23:157-165.
72 Coelho FG, Andrade LP, Pedroso RV, et al. Multimodal exercise intervention improves frontal cognitive functions and gait in Alzheimer’s disease: a controlled trial. Geriatr GerontolInt. 2013; 13:198- 203.
73 Stranahan AM, Zhou Y, Martin B, Maudsley S. Pharmacomimetics of exercise: novel approaches for hippocampallytargeted neuroprotective agents. Curr MedChem. 2009;16:4668-4678.
74 Salehi A, Verhaagen J, Swaab DF. Progress in brain research. In: Van Leeuwen FW, Salehi A, Giger RJ, et al, eds. Neuronal Degeneration and Regeneration: From Basic Mechanisms to Prospects fo r Therapy. Amsterdam, the Netherlands: Elsevier; 1998:71-89.
75 Eming SA, Krieg T, Davidson JM. Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol. 2007;127:514-525.
76 Allan SM, Rothwell NJ. Inflammation in central nervous system injury. Philos Trans R Soc Lond B Biol Sci. 2003;358: 1669-1677.
77 Das S, Basil A. Inflammation: a new candidate in modulating adult neurogenesis. J Neurosci Res. 2008:86:1199-1208.
78 Johnston H, Boutin H, Allan SM. Assessing the contribution of inflammation in models of Alzheimer’s disease. Biochem Soc Trans. 2011;39:886-890.
79 Rubio-Perez JM, Morillas-Ruiz JM. A review: inflammatory process in Alzheimer’s disease, role of cytokines. ScientiflcWorldJoumal. 2012:2012:756357.
80 Britschgi M, Wyss-Coray T. Systemic and acquired immune responses in Alzheimer’s disease. Int Rev Neurobiol. 2007; 82:205-233.
81 Nichol KE, Parachikova Al, Cotman CW. Three weeks of running wheel exposure improves cognitive performance in the aged Tg2576 mouse. Behav Brain Res. 2007;184:124-132.
82 Nybo L, Nielsen B, Pedersen BK, et al. Interleukin-6 release from the human brain during prolonged exercise. J Physiol. 2002;542:991-995.
83 Steensberg A, Osada T, Sacchetti M, et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol. 2000; 15: 237-242.
84 Leem YH, Lee YI, Son HJ, Lee SH. Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/ htau23. Biochem Biophys Res Cornmun. 2011;406:359-365.
85 Souza LC, Filho CB, Goes AT, et al. Neuroprotective effect of physical exercise in a mouse model of Alzheimer’s disease induced by β-amyloid1_40 peptide. Neurotox Res. 2013;24:148-163.
86 Walsh NP, Gleeson M, Pyne DB, et al. Position statement, part two: maintaining immune health. Exerc Immunol Rev. 2011;17:64-103.
87 Woods JA, Ceddia MA, Wolters BW, et al. Effects of 6 months of moderate aerobic exercise training on immune function in the elderly. Mech Ageing Dev. 1999:109: 1-19.
88 Crist DM, Mackinnon LT, Thompson RF, et al. Physical exercise increases natural cellular-mediated tumor cytotoxicity in elderly women. Gerontology. 1989:35: 66-71.
89 Office of the Surgeon General. The Surgeon General’s Vision fo r a Healthy and Fit Nation. Rockville, MD: US Public Health Service; 2010.
90 Teo W, Newton MJ, McGuigan MR. Circadian rhythms in exercise performance: implications for hormonal and muscular adaptation. J Sports Sci Med. 2011; 10: 600- 606.
91 Swaab DF. Suprachiasmatic nucleus (SCN) and pineal gland. In: Aminoff MB, Swaab DF, eds. Handbook o f Clinical Neurology. Vol 2003. Amsterdam, the Netherlands: Elsevier; 2003:63-123.
92 Ju YE, Lucey BP, Holtzman DM. Sleep and Alzheimer disease pathology: a bidirectional relationship. Nat Rev Neurol. 2014;10:115-119.
93 Buxton OM, Lee CW, L’HermiteBaleriaux M, et al. Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase. Am J Physiol Regul Integr Comp Physiol. 2003;284:R714-R724.
94 Kim SJ, Benloucif S, Reid KJ, et al. Phaseshifting response to light in older adults. J Physiol. 2014;592:189-202.
95 Morris CJ, Aeschbach D, Scheer FA. Circadian system, sleep and endocrinology. Mol Cell Endocrinol. 2012;349:91-104.
96 Chen HM, Wu YC, Tsai CM, et al. Relationships of circadian rhythms and physical activity with objective sleep parameters in lung cancer patients. Cancer Nurs. 2014 Jun 18 [Epub ahead of print], doi: 10.1097/NCC.0000000000000163.
97 Hooghiemstra AM, Eggermont I.H, Scheltens P, et al. The rest-activity rhythm and physical activity in early-onset dementia. Alzheimer Dis Assoc Disord. 2015:29: 45-49.
98 Nascimento CM, Ayan C, Cancela JM, et al. Effect of a multimodal exercise program on sleep disturbances and instrumental activities of daily living performance on Parkinson’s and Alzheimer’s disease patients. Geriatr Gerontol Int. 2014:14:259-266.
99 Vitiello MV, Borson S. Sleep disturbances in patients with Alzheimer’s disease: epidemiology, pathophysiology and treatment. CNS Drugs. 2001:15:777-796.
100 Wulff K, Gatti S, WettsteinJG, Foster RG. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci. 2010; 11:589- 599.
101 Kemoun G, Thibaud M, Roumagne N, et al. Effects of a physical training programme on cognitive function and walking efficiency in elderly persons with dementia. Dement Geriatr Cogn Disord. 2010;29:109-114.
102 Vreugdenhil A, CannellJ, Davies A, Razay G. A community-based exercise programme to improve functional ability in people with Alzheimer’s disease: a randomized controlled trial. Scand J Caring Sci. 2012;26:12-19.
103 Yaguez L, Shaw KN, Morris R, Matthews D. The effects on cognitive functions of a movement-based intervention in patients with Alzheimer’s type dementia: a pilot study. Int J Geriatr Psychiatry. 2011;26: 173-181.’
104 de Andrade LP, Gobbi ET, Coelho FG, et al. Benefits of multimodal exercise intervention for postural control and frontal cognitive functions in individuals with Alzheimer’s disease: a controlled trial. J Am Geriatr Soc. 2013:61:1919-1926.
105 Steinberg M, Leoutsakos JM, Podewils LJ, Lyketsos CG. Evaluation of a home-based exercise program in the treatment of Alzheimer’s disease: the Maximizing Independence in Dementia (MIND) study. Int J Geriatr Psychiatry. 2009;24:680-685.
106 Venturelli M, Scarsini R, Schena F. Sixmonth walking program changes cognitive and ADL performance in patients with Alzheimer. Am J Alzheimers Dis Other Demen. 2011;26:381-388.
107 Schneider LS, Mangialasche F, Andreasen N, et al. Clinical trials and late-stage drug development for Alzheimer’s disease: an appraisal from 1984 to 2014. J Intern Med. 2014;275:251-283.
108 Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci. 2003; 14:125-130.
109 Smith PJ, Blumenthal JA, Hoffman BM, et al. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med. 2010;72:239-252.
110 Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA. 2011:108:3017-3022.
111 Makizako H, Liu-Ambrose T, Shimada H, et al. Moderate-intensity physical activity, hippocampal volume, and memory in older adults with mild cognitive impairment. J Gerontol A Biol Sci Med Sci. 2015:70:480-486.
112 Apostolova LG, Dutton RA, Dinov ID, et al. Conversion of mild cognitive impairment to Alzheimer disease predicted by hippocampal atrophy maps. Arch Neurol. 2006;63:693-699.
113 Devanand DP, Pradhaban G, Liu X, et al. Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. Neurology. 2007;68: 828-836.
114 Rovio S, Kareholt I, Helkala EL, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. lancet Neurol. 2005;4:705-711.
115 Heyn P, Abreu BC, Ottenbacher KJ. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil. 2004;85:1694-1704.
116 Lautenschlager NT, Cox KL, Flicker L, et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008:300:1027-1037.
117 Alvarez-Lopez MJ, Castro-Freire M, CosinTomas M, et al. Long-term exercise modulates hippocampal gene expression in senescent female mice. J Alzheimers Dis. 2013;33:1177-1190.
118 Rodrigues L, Dutra MF, IlhaJ, et al. Treadmill training restores spatial cognitive deficits and neurochemical alterations in the hippocampus of rats submitted to an intracerebroventricular administration of streptozotocin. J Neural Tratism. 2010; 117:1295-1305.
119 Mirochnic S, Wolf S, Staufenbiel M, Kempermann G. Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease. Hippocampus. 2009;19:1008-1018.
120 Wang Q, Xu Z, Tang J, et al. Voluntary exercise counteracts Aj325-35-induced memory impairment in mice. Behav Brain Res. 2013;256:618-625.
121 Liu HL, Zhao G, Zhang H, Shi LD. Longterm treadmill exercise inhibits the progression of Alzheimer’s disease-like neuropathology in the hippocampus of APP/ PS1 transgenic mice. Behav Brain Res. 2013;256:261-272.
122 Dao AT, Zagaar MA, Levine AT, et al. Treadmill exercise prevents learning and memory impairment in Alzheimer’s disease-like pathology. Curr Alzheimer Res. 2013;10:507-515.
123 Richter H, Ambree O, Lewejohann L, et al. Wheel-running in a transgenic mouse model of Alzheimer’s disease: protection or symptom? Behav Brain Res. 2008;190:74-84.
124 Hoveida R, Alaei H, Oryan S, et al. Treadmill running improves spatial memory in an animal model of Alzheimer’s disease. Behav Brain Res. 2011;216:270-274.
125 Yuede CM, Zimmerman SD, Dong II, et al. Effects of voluntary and forced exercise on plaque deposition, hippocampal volume, and behavior in the Tg2576 mouse model of Alzheimer’s disease. Neurobiol Dis. 2009:35:426-432.
126 Revilla S, Sunol C, Garcia-Mesa Y, et al. Physical exercise improves synaptic dysfunction and recovers the loss of survival factors in 3xTg-AD mouse brain. Neuropharmacology. 2014;81:55-63.
127 Gimenez-Llort L, Garcia Y, Buccieri K, et al. Gender-specific neuroimmunoendocrine response to treadmill exercise in 3xTg-AD mice. Int J Alzheimers Dis. 2010;2010:128354.
128 Um HS, Kang EB, Leem YH, et al. Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer’s disease in an NSE/ APPsw-transgenic model. Int J Mol Med. 2008;22:529-539.
129 Coelho FG, Vital TM, Stein AM, et al. Acute aerobic exercise increases brainderived neurotrophic factor levels in elderly with Phillips_Cristy_The Link Between Physical Activity and Cognitive Dysfunction in Alzheimer Disease_07.15_Alzheimer’sAlzheimer’s disease. J Alzheimers Dis. 2014;39:401-408.