Prevention and Treatment of Alzheimer’s Disease: Biological Mechanisms of Exercise

Abstract

Alzheimer’s disease (AD) is the most common form of dementia. With an aging population and no disease modifying treatments available, AD is quickly becoming a global pandemic. A substantial body of research indicates that lifestyle behaviors contribute to the development of AD, and that it may be worthwhile to approach AD like other chronic diseases such as cardiovascular disease, in which prevention is paramount. Exercise is an important lifestyle behavior that may influence the course and pathology of AD, but the biological mechanisms underpinning these effects remain unclear. This review focuses on how exercise can modify four possible mechanisms which are involved with the pathology of AD: oxidative stress, inflammation, peripheral organ and metabolic health, and direct interaction with AD pathology. Exercise is just one of many lifestyle behaviors that may assist in preventing AD, but understanding the systemic and neurobiological mechanisms by which exercise affects AD could help guide the development of novel pharmaceutical agents and non-pharmacological personalized lifestyle interventions for at-risk populations.

Keywords

Aging Alzheimer’s disease amyloid cardiovascular exercise inflammation insulin oxidative stress tau

INTRODUCTION

Alzheimer’s disease (AD) is a neurodegenerative disease that typically affects older populations and is the leading cause of dementia worldwide. Unlike normal aging, which involves predictable decline across several cognitive domains such as executive function, processing speed, and working and episodic memory, AD is characterized by early and progressive cognitive impairment caused by a decades-long process of neuronal dysfunction [1]. The global prevalence of AD is projected to triple by 2050 in parallel with an increasingly aged population [2]. This will create a severe economic burden, as the worldwide cost of care for dementia is expected to increase from USD$818 billion in 2015 to USD$2 trillion by 2030 [3]. Moreover, there are currently no viable disease-modifying agents for AD, and clinical trials on novel pharmaceutical treatments have experienced an extremely high failure rate [4]. The failure to develop disease-modifying agents may be due, in part, to the lack of effective diagnostics capable of identifying AD in its infancy, which has resulted in clinical trial participants enrolling when the disease is already at a more advanced stage when interventions are less effective. Current pharmaceutical treatments also fail to address the root cause of AD, providing only modest improvements to patients’ livelihood by addressing certain symptoms of the disease. Additionally, these treatments are often accompanied by uncomfortable side effects including nausea, dizziness, and weight loss [5, 6].

The vast majority of AD cases are sporadic, with genetic factors accounting for less than 5% of all cases [7]. Unlike the link between smoking and lung cancer, the causes of sporadic AD are more difficult to identify. There are a number of modifiable lifestyle-related risk factors associated with AD including physical inactivity, poor diet, socioeconomic status, low education, and obesity, among others [8]. These modifiable risk factors are estimated to account for a third of all AD cases [9], which raises the question as to whether and how lifestyle behaviors influence underlying AD pathology. This, alongside research suggesting that AD pathology can begin decades prior to the onset of symptoms [10 –12], indicates an increasing need for preventative treatment options. A better understanding of how lifestyle factors are biologically involved with the underlying mechanisms of AD can guide the development of novel disease-modifying drugs and encourage the implementation of preventative measures alongside medication.

Exercise has long been used to manage and prevent chronic diseases such as type 2 diabetes (T2DM) [13], arthritis [14], depression [15], and cardiovascular disease (CVD) [16]. Exercise is a core component of health and wellbeing, with the World Health Organization and the American College of Sports Medicine recommending 150 minutes of moderate or 75 minutes of vigorous physical activity per week and muscle-strengthening activities on two or more days a week [17, 18]. However, the number of people worldwide meeting this requirement varies greatly. In the UK and the Netherlands approximately two-thirds of adults achieve the recommended levels, while in the USA only 1 in 5 meet recommendations [19 –21]. Furthermore, for individuals in the UK and USA, this number continues to decline with advancing age [20, 21]. Reaching the recommended levels of activity can have profound physiological and neurological effects. Aside from the more obvious benefits such as improved cardiovascular health and increased muscle mass, exercise also reduces oxidative stress (OS) and inflammation, and stimulates hippocampal plasticity, all of which can contribute to improved cognition [22 –25].

While adhering to recommended exercise guidelines is unlikely to prevent AD altogether, it may delay disease onset on the order of months to years, improving the quality of life for older adults, and significantly reducing the global burden of AD [26, 27]. The purpose of this review is to investigate how exercise (primarily aerobic) can protect against AD pathology. Specific attention will be paid to how aerobic exercise can modulate four biological processes involved in AD: 1) OS, 2) inflammation, 3) peripheral organ health, and 4) amyloid-beta (Aβ) and tau accumulation. Collectively, this review aims to illustrate how exercise affects the underlying mechanisms of AD to help guide the implementation of exercise as a preventative measure for those at risk of developing the disease.

METHODOLOGY

All empirical articles included in this review were published in peer-reviewed journals. No restriction was placed on the study setting, country, year or language in which the article was originally published. A study was included in the review if it had multiple subjects (no case reports or studies) and included human, animal, and in vitro studies.

Google searches were performed to identify additional articles that may have been missed in database searches. A Boolean search strategy was conducted with the following keywords and logic: (“exercise” OR “physical activity” OR “fitness” OR “health” OR “wellness” OR “insulin” OR “diabetes” OR “cardiovascular” OR “oxidative stress” OR “inflammation” OR “aging” OR “liver” OR “kidney” OR “amyloid” OR “tau”) AND (“Alzheimer’s disease” OR “dementia” OR “cognitive impairment” OR “cognitive decline”) and all their derivatives as well as the bibliographies of relevant papers.

RISK FACTORS FOR ALZHEIMER’S DISEASE

The current prevalence of AD in Americans over the age of 65 is 1 in 10, and risk of developing AD doubles every five years after the age of 65 [28, 29]. There are some non-modifiable risk factors associated with AD such as race and ethnicity [29], sex [30, 31], and genetic contributions [7]. However, there also exist a number of modifiable risk factors including physical inactivity, hypertension, poor diet, poor sleep behavior, low cognitive stimulation, low levels of social interaction, and low education attainment [8 , 32–36]. Furthermore, largely preventable chronic diseases such as T2DM and CVD are associated with AD [8].

The existence of these modifiable risk factors indicate that the development of AD may be prevented or at least mitigated (Fig. 1). Some risk factors are not easily modifiable, such as low educational attainment, which is largely dependent on socioeconomic factors [37]. Low social interaction can also be difficult to address but is particularly important in at-risk patients, for example, older adults in nursing homes [38]. Other prevalent risk factors that should be noted include those such as traumatic brain injury and depression [39, 40]. Physical activity is a relatively simple yet highly important factor to target, as it can easily be integrated into most people’s lives and may mitigate AD onset or progression. Furthermore, exercise plays a foundational role in reducing cardiovascular risk factors (e.g., hypertension), which can further reduce AD risk.

Fig.1

Risk factors of Alzheimer’s disease (AD). Many factors influence one’s risk of AD, but a substantial number are modifiable (highlighted in bold) and offer an opportunity to reduce AD risk through lifestyle modification. Organ dysfunction, low education, and traumatic brain injury may be modifiable but are subject to genetic, socioeconomic, and other risk factors. MCI, mild cognitive impairment.

Many of the aforementioned modifiable risk factors for AD are also strongly associated with other chronic diseases such as CVD, T2DM, and liver and kidney disease. Risk factors associated with CVD, are particularly important as they also relate to AD and include hypertension, hypercholesterolemia, T2DM, and a high body mass index (BMI) [32]. Hypertension and hypercholesterolemia appear to be most problematic in mid-life for dementia risk [41, 42]. How exactly these factors influence AD is unclear. Studies have suggested that hypertension thins the insular cortex and reduces plasma Aβ levels, which are associated with increased AD risk [35, 36], and hypercholesterolemia is thought to promote Aβ deposition and dementia risk [43]. Poor lifestyle habits, such as low levels of exercise, can cause metabolic dysfunction resulting in T2DM, increasing AD risk by upwards of 50% [44, 45]. Once severe metabolic dysfunction is established, it may be irreparable by exercise [46]. In summary, a substantial number of the known AD risk factors are modifiable through exercise. This provides an opportunity to address these risk factors through lifestyle-based intervention, ultimately delaying or even preventing the development of AD.

ALZHEIMER’S DISEASE PATHOLOGY

Neuropathologically, AD is characterized by the accumulation of Aβ and neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau (P-tau), leading to neuronal loss [47]. Aβ is an insoluble 37–43 amino acid peptide formed when amyloid-beta protein precursor (AβPP) is cleaved by β-secretase (BACE-1) and γ-secretase. Aβ typically begins to accumulate in the brain extracellularly around midlife [12]. The clearance of toxic Aβ in the brain is accomplished by cells such as microglia, astrocytes, and neurons, as well as enzymes such as neprilysin (NEP) and insulin degrading enzyme (IDE) [48]. Although Aβ has been the major focus of AD research, amyloid burden is only weakly correlated with the cognitive state of a patient [49 –51]. However, research indicates Aβ may play a key role initiating downstream AD pathology [52, 53].

The other hallmark of AD neuropathology is the formation of intracellular NFTs. These tangles can drive diseases known as tauopathies which include atypical Parkinsonian diseases (e.g., progressive supranuclear palsy, corticobasal syndrome, multiple systems atrophy) as well as frontotemporal dementia syndromes such as behavioral variant frontotemporal dementia [54, 55]. The earliest effects of P-tau and subsequent formation of NFTs are hindered axonal transport, synaptic loss, and neuroinflammation [56]. These tangles do not cause rapid neuronal degradation, as neurons containing tangles can survive for decades [57], nevertheless, P-tau levels correlate well with symptoms of AD and dementia [58]. Though the characteristically slow pace of AD pathology progression presents problems for the diagnosis of AD, it also provides a large therapeutic window in which early intervention may prevent or delay the onset of the disease.

The extensive preclinical phase of AD led to the development of biomarker-based phases to define AD (preclinical, mild cognitive impairment, and AD) to provide researchers with a common framework to delineate AD progression [59]. This classification system has since been updated to view AD as a continuum, rather than composed of distinct phases. In this updated model, the severity of Aβ, P-tau, and neurodegeneration in an individual determined by neuroimaging and cerebrospinal fluid (CSF) tests places them on a biomarker-based continuum of AD pathology [60, 61]. Importantly, the classification of AD with a biomarker continuum provides a foundation for basic research and clinical trials to build upon, and also creates earlier therapeutic opportunities that did not exist with only a symptom-based classification system.

EXERCISE AND ALZHEIMER’S DISEASE

Engaging in regular physical activity is important for maintaining overall wellbeing, and a body of evidence suggests exercise can help mitigate cognitive decline and AD [8 , 62–77]. The vast majority of studies examining this subject use aerobic exercise as the measure for activity levels or as an intervention. Consequently, our knowledge on the mechanisms of exercise interventions as they relate to AD is overwhelmingly based on aerobic exercise, though it is likely that different forms of exercise have overlapping mechanisms. For the purposes of this review, all references to exercise-based interventions for AD are aerobic, unless otherwise mentioned. The biological mechanisms underpinning the effects of exercise on AD are currently unclear but are postulated to include reductions in OS and inflammation, improved systemic health, and interaction with Aβ and tau pathology.

Exercise and oxidative stress

Free radical formation is usually in balance with antioxidant mechanisms; however, pathological changes can alter this balance causing free radical production to outweigh antioxidant capacity causing OS [78]. OS may be the earliest measurable biological event in the AD pathological cascade and be responsible for triggering all other AD pathologies [79, 80]. Free radicals originate from multiple sources, including as byproducts of mitochondrial activity, metal accumulation, and Aβ and P-tau accumulation [81]. Free radicals cause damage to lipids, proteins, and DNA, and the brain is especially vulnerable to OS given its high metabolism and low cellular regeneration rate [82]. OS damage can alter protein structure and hinder enzymes such as glutamine synthetase, resulting in neuronal excitotoxicity [83].

As free radicals are naturally occurring molecules the body has innate antioxidant mechanisms to process them. Glutathione, produced by astrocytes, is the most abundant antioxidant in the brain [84]. Other endogenous antioxidants include superoxide dismutase (SOD), glutathione peroxidase, and catalase, which all help clear free radicals and reduce OS [81]. Data shows that AD patients have compromised antioxidant defenses as indicated by reduced activity of glutathione and SOD, resulting in an increased OS burden [85]. This is supported by AD patients exhibiting increased OS damage in brain lipids, DNA, Aβ plaques, and NFTs [85, 86]. Furthermore, OS seems to be both a cause and effect of Aβ deposits (the accumulation of OS produces Aβ deposits, and Aβ deposits produce additional OS), possibly by upregulating BACE-1 and γ-secretase, but downregulating α-secretase, resulting in more toxic amyloid species being formed [81, 87–89 , 81, 87–89].

Increasing endogenous antioxidant levels can remove Aβ, lower protein oxidation, and improve memory in mice [90], whereas deficiencies in endogenous antioxidants cause Aβ oligomerization and cognitive impairment [91]. This is in line with studies showing AD patients have diminished antioxidant capacity, resulting in reduced clearance of free radicals and greater AD pathology [92, 93]. Together, this implies that OS plays an important role in initiating and mediating AD pathology, ultimately suggesting that reducing OS may be a viable component of treatment. This could be done by enhancing antioxidant mechanisms to reduce levels of OS in AD patients [94, 95], which may be partially achievable from exercise [22, 96].

Low-level OS is a natural part of human physiology, but exercise can promote physiological adaptation to OS-induced stress and help prevent OS-associated diseases such as CVD, T2DM, and AD [97]. During a stressful event, such as a bout of exercise, additional metabolic demands result in free radical production, primarily originating in skeletal muscle [98]. Sources of OS in muscles include the metabolic processes of mitochondria, and the activity of NADPH oxidase, phospholipase A2, and xanthine oxidase [99]. Free radicals are produced during exercise by mitochondria and NADPH oxidase due to increased adenosine triphosphate utilization [100]. Concurrently, phospholipase A2 stimulates NADPH oxidase and arachidonic acid, causing damage such as lipid peroxidation, which is an outcome of OS that damages membranes and produces toxic byproducts [100, 101]. Even though stressors such as exercise acutely raise free radical production [102], it seems that chronic exercise acts as a hormetic signal to upregulate endogenous antioxidant systems [22, 96]. In turn, this helps to maintain or even decrease the accumulated oxidative damage accrued from regular exercise over time [103].

The damaging effects of OS from acute exercise in humans depends on training status. In a recent study, Park and Kwak [104] compared the effect of aerobic training on individuals who 1) had previous aerobic training, 2) had previous anaerobic training, or 3) had no prior training. They found that trained individuals (regardless of exercise type) had no differences in OS markers post exercise, but untrained individuals had significantly raised OS marker levels and lower antioxidant capacity post-exercise. Additionally, muscle damage caused by exercise initiates a more intense inflammatory and OS response in untrained individuals [99]. However, it is important to note that these human studies are not examining OS in the context of the brain or AD and this concept requires further research. Although the brain may be somewhat more protected against the OS produced by exercise compared to the periphery [105], evidence still suggests brain and cognitive degradation is, at least to some extent, associated with oxidative damage [106, 107].

The available information regarding the effects of exercise on neural OS and AD biomarkers is extremely limited in humans, but animal studies show promising results. In rats, exercise has been shown to reduce oxidative damage in the brain and improve cognitive function [108, 109]. However, a study examining the effects of lifelong exercise in mice did find reduced cerebellar lipid and DNA oxidative damage [110]. Furthermore, this study found that beginning exercise in later life still attenuated lipid peroxidation, but not DNA oxidative damage [110]. Finally, OS exacerbates tau-induced cell cycle activation leading to cell death and neurodegeneration, but can be prevented by antioxidant treatment [111].

In the context of AD, multiple animal models have confirmed the positive effects of exercise on OS. In a study using the 3xTG mouse model (Swedish APP, PS1, and MAPT mutations), exercise reduced markers of lipid peroxidation and increased glutathione levels in the cortex, which can ameliorate oxidative damage [112]. The same group then demonstrated that sedentary 3xTG mice had significantly raised levels of cortical OS, but that these levels were restored to normal levels through exercise [113]. Furthermore, NSE/APPsw (Swedish APP mutation) mice that exercised for 16 weeks had significantly higher levels of antioxidant enzymes SOD1 and catalase in the brain [114]. Similarly, a study using TgCRND8 (Swedish and Indiana APP mutations) mice found that exercise reduced cerebral OS and upregulated production of SOD1 and SOD2 [115]. This is also supported in a rat model of AD, whereby 8 weeks of exercise significantly raised SOD activity and concurrently reduced malondialdehyde levels (a marker for lipid peroxidation) in the hippocampus [116]. Additionally, APP/PS1 (Swedish APP and PS1 mutations) mice that underwent forced running for 20 weeks had higher levels of SOD2 and suppressed mitochondrial DNA damage from OS in hippocampal derived mitochondria [117]. However, in another study of 10-month-old APP/PS1 mice, 6 weeks of voluntary exercise combined with antioxidant treatment still did not reduce hippocampal OS [118]. This indicates that either the intervention was too short, initiated too late in life, or that voluntary running may be insufficient to induce neurological change in this mouse model. Therefore, animal studies support the theory that exercise can reduce OS in the brains of both wild-type and AD mice. Biochemically, this is likely due to the upregulation of antioxidant enzymes, which has been demonstrated in humans, but whether these results translate to neural OS or AD patients requires further investigation.

Exercise and inflammation

Either as a driver or consequence, inflammation plays a key role in both chronic and acute diseases. Recent evidence suggests inflammation may be at the forefront of AD progression and pathology rather than simply a byproduct of AD pathology [119 –123]. According to the amyloid hypothesis, neuroinflammation should follow amyloid deposition. However, evidence suggests that the immune system is involved much earlier in AD pathology [119]. Although further research is required to discern the use of inflammation as an AD biomarker [124]. The long-term effects of inflammation on AD are supported by epidemiological research indicating that chronic NSAID use can decrease AD risk [125]. However, a recent meta-analysis was unable to find a benefit of NSAID use for AD in randomized trials [126].

Microglia, the resident immune cells in the brain, are responsible for releasing inflammatory cytokines upon binding to Aβ [127]. The role of microglia in AD is of great interest, as recent genetic studies have confirmed microglia associated mutations such as TREM2 and TYROBP, which can impair phagocytosis, contribute to AD pathology [123 , 129]. Microglia assist in the clearance of Aβ through many mechanisms including phagocytosis, but are still unable to prevent buildup during AD [127, 130]. Although proper microglia function protects against AD, microglial overactivation, which is often seen in AD, can result in multiple negative consequences including synaptic loss and increased tau pathology [131, 132].

Aging is associated with changes in microglial morphology resulting in poorer function [133]. This also coincides with microglial function impairment correlating to Aβ levels [134]. Aging also causes microglia to be primed to an active state, so upon secondary stimulation they respond by releasing excessive amounts of inflammatory cytokines including tumor necrosis factor alpha (TNF-α), and interleukin (IL) 1 and 6, among others [135, 136]. These immunological changes that occur during aging are associated with a low-grade chronic inflammation known as inflammaging [137]. This low level of inflammation is usually subclinical, but when combined with other aggravators of AD, may contribute to AD development.

Some of the most prominent markers of inflammaging are IL-6 and C-reactive protein (CRP) [138], both of which are associated with all-cause mortality [139]. Inflammaging also negatively impacts the function of macrophages, natural killer cells, and neutrophils, and reduces T and B cell count [140, 141]. Levels of IL-6 tend to increase with age, even in people without indication of disease [142, 143]. Under healthy conditions, IL-6 levels in the brain tend to remain low, but are upregulated in disease states [144]. IL-6 is a primary stimulator of the acute phase inflammatory response [144, 145] and can subsequently promote chronic inflammation, astrogliosis, and neurodegeneration [146]. Low serum IL-6 and CRP levels are indicators of successful aging and cognitive abilities, conversely, high levels are associated with poorer cognitive and physical performance [147]. Notably, being categorized as underweight or obese in BMI (<18.5 or >30 kg/m²) is also significantly associated with high IL-6 and CRP levels, indicating that maintaining a healthy weight is important throughout life from an inflammation standpoint [147]. These immune deficits and chronic low-grade inflammation may be a natural consequence of aging but can potentially be mitigated [138]. Exercise may be a feasible option for this as it can prevent aspects of immunosenescence and the inflammatory effects of sedentary behavior [148 –150], which could, in turn, prevent immune-associated AD pathology.

Acute bouts of exercise cause an immediate pro-inflammatory effect in response, though these effects are short-lived, and regular exercise can have beneficial anti-inflammatory effects [148]. The protective effects of regular exercise may be due to individuals who exercise having less inflammatory immune profiles, characterized by, among others, reduced IL-6, CRP levels, and raised IL-2 and IL-10 levels, relative to their sedentary counterparts [149 –152]. This unfavorable immune profile in sedentary individuals may be due to the activation of the ‘physical inactivity diseaseome’, resulting in chronic inflammation and leading to neurodegeneration and diabetes [153]. Therefore, inactivity causing chronic inflammation may mediate certain aspects of AD pathology and exercise is a possible means for prevention.

Aging and physical inactivity results in changes to the immune system, but exercise may be able to prevent some of these immune deficits. IL-6 and CRP are key inflammatory markers that tend to be elevated with advanced aging [138]. However, both markers appear to be reduced after exercise, which may help curb some of the associated chronic inflammation [151, 154, 155]. Exercise itself may only be partially responsible for these changes to the immune system, as even slight reductions in BMI (sometimes attributable to exercise) cause significant reductions in CRP and TNF-α levels [155]. IL-2 is an important immune regulator, playing a critical function in the maintenance of regulatory T-cells and preventing autoimmunity [156]. In APP/PS1 mice IL-2 activates regulatory T-cells, improves working memory, and decreases Aβ plaque load [157]. IL-2 levels in humans decrease with age [158], but one study demonstrated that when elderly women participated in long-term moderate aerobic and anaerobic exercise, IL-2 was raised to similar levels as in young women [150]. These results were substantiated by another study in which an elderly population engaging in regular walking resulted in CD8 cells expressing higher levels of IL-2 [159]. These changes may be attributable to aerobic, but not resistance, exercise causing T-helper 1 cells to express more CD28 which promotes IL-2 production [152, 160]. It is important to note, however, that the aforementioned data are all measuring systemic inflammation and may not be representative of the neuroinflammation in AD. It is currently not clear whether peripheral inflammation can affect brain health, although animal studies suggest this is the case [161]. As exercise interventions seem to have benefits in attenuating peripheral age-associated immune deficits [162], studies assessing the effect of exercise within the context of human AD will be needed to understand the role of exercise in AD

Currently, the best way to assess neuroinflammation is by using both wild-type and AD animal models, though results from animals have been mixed and the exact mechanisms remain unclear [163]. Aged wild-type mice exhibit a higher rate of microglia proliferation in the hippocampus than younger mice [164]. But 8 weeks of exercise resulted in lower microglial proliferation, enhanced neuronal survival, and increased expression of insulin-like growth factor 1, indicating a shift toward neuroprotection [164]. These results have also been found to apply in the amygdala [165], one of the earliest regions to atrophy in AD [166], and the septum [167], where nuclei have been shown to be enlarged prior to developing AD [168]. This suggests the beneficial effects of exercise on inflammation are not just local to the hippocampus. Furthermore, decreases in mRNA expression of TNF-α, IL-1β, and IL-6 were found in the septum after chronic exercise [167]. In Tg2576 (Swedish APP) mice, sedentary behavior increased IL-1β and TNF-α, but after three weeks of exercise, levels were reduced to those indistinguishable from wild-type mice [169]. These researchers also found that the three weeks of voluntary exercise increased levels of the cytokines CXCL1 and CXCL12 [170], which may be neuroprotective and help modulate neuron-glia communication to rescue cognitive deficits [171, 172]. Combined, these data indicate exercise can help reduce inflammation and increase neuroprotection in wild-type mice.

In an animal study investigating tau models of AD, chronic exercise reduced gliosis in a volume-dependent manner [173]. In the same study, TNF-α, IL-1β, and IL-6 were all reduced to control levels with exercise, along with inflammatory mediators such as COX2, p38, iNOS, and p-erk [173]. Further research by Ke et al. showed that five weeks of treadmill running reduced Aβ load (but not plaque number) and microglial activation in adult and aged APP/PS1 mice [174]. These data were similar to results from a 10-week exercise study, showing reduced inflammation and cognitive improvements during the Morris water maze in adult APP/PS1 mice [175]. However, data in animal AD models are not universal, as a similar experiment using the same model found no change in gliosis, Aβ levels, or cognitive abilities on the Morris water maze [118]. Overall, animal data in both wild-type and AD models indicate there is some benefit from exercise in reducing neuroinflammation, but additional research is needed to confirm these effects. Finally, this concept needs to be further investigated in humans. Neuroinflammation is currently difficult to measure in humans, but advances in imaging techniques may improve this in the future [176].

Exercise and systemic health

AD is typically thought of as a disorder of the brain, but due to AD’s relationship with other chronic diseases such as CVD and T2DM, the etiology of AD may extend beyond the brain. The production, storage, and clearance of Aβ outside the central nervous system (CNS) has led to the theory that systemic, as well as CNS-based, approaches to AD research and treatment are necessary [48]. Research suggests that up to 25% of central Aβ enters the periphery via the blood-brain barrier [177]. This is exemplified by a mouse parabiosis model, where improving peripheral clearance reduced brain Aβ by up to 80%, in addition to reducing tau phosphorylation, inflammation, and neuronal degradation [178]. Exercise can assist in maintaining systemic health which may enhance the peripheral clearance of Aβ.

Cardiovascular health

Maintaining cardiovascular health is a critical component of general health, but more recently, evidence suggests that it is also important for neurological health. This theory is supported by data showing that people who take antihypertensive medication to normalize their blood pressure also experience reduced risk for AD, particularly when treatment began in midlife [179 –181]. Furthermore, CVD and a low cardiac index are strongly associated with increased AD risk [182 –184]. This has been validated postmortem, as CVD patients exhibit significantly more Aβ plaques than control patients in the parahippocampal gyrus [185]. Poor vascular health can also accelerate the progression from mild cognitive impairment (MCI) to AD by up to 15% per year, a 10-fold greater rate than in a normal population [180]. Furthermore, improvements in cardiovascular fitness are associated with improved memory and reduced hippocampal atrophy in AD patients [74], and increased grey matter volume in elderly men [186].

Exercise is widely recommended for improving heart health and preventing CVD [187], which may consequently reduce the risk of AD. The direct mechanisms linking CVD and AD are unclear, although there is evidence that improvements in cerebral blood flow (CBF) may be responsible. Aging itself causes a marked decreased in CBF [188 –190], and AD patients have further reductions in CBF in the frontal, temporal, and parietal lobes of the brain [191 –194]. Lower CBF in these regions is associated with poorer executive and language function [192]. Additionally, low CBF in the temporal parietal lobes specifically is associated with increased Aβ burden [193], which possibly indicates why these regions are so severely affected in AD.

The evidence suggesting that exercise can improve CBF is still in its infancy. Due to cerebral autoregulation, large changes in peripheral blood flow do not greatly affect CBF [190]. Acute exercise does seem to cause a temporary rise in CBF, but this quickly reverts to normal, and chronic exercise has little effect on resting CBF [195 –197]. Thomas et al. [196] compared lifelong athletes to groups of sedentary elderly and young individuals. Although there was no difference in overall CBF between groups, the lifelong athletes had greater CBF in the regions of the default mode network (posterior cingulate cortex and precuneus), which is important in episodic memory formation and has abnormal activity in AD [196, 198]. Furthermore, the athletes had relatively lower age-related CBF decline in these areas [196]. Regular exercise can contribute to an estimated reduction of 10 years in CBF ‘aging’ which may assist in delaying AD [189]. While further research is needed before definite conclusions can be drawn, preventing age-related decline in CBF may be part of the mechanisms underlying the protective effects of exercise on the brain [188].

In addition to modulating CBF, exercise could also benefit brain health through reducing hypertension. Exercise is a well-accepted method for reducing hypertension, hence its inclusion in almost all hypertensive treatment regimens [199]. Hypertension is associated with AD especially in midlife [35 , 42] and mid to late life hypertension induces cortical thinning, even after accounting for cholesterol and BMI [36]. The exact physiological mechanisms of how hypertension influences AD biomarkers in humans are unclear. One possibility is that reduced blood pressure can improve CBF in grey matter [200], although other studies have been unable to find this [201]. Alternatively, chronic high blood pressure may damage blood vessels thereby reducing CBF and inhibiting Aβ clearance [35]. Though the neurobiological effects of hypertension are unclear, there is substantial pathological overlap between AD and vascular disease, where up to up to 60% of patients with AD pathology also have cerebrovascular lesions in the brain [183 , 203]. This can lessen the threshold for clinically relevant dementia due the additive effect of non-AD specific pathologies [203]. Although hypertension is a risk factor for CVD and AD, and exercise helps reduce hypertension, the underlying mechanisms are still speculative; additional data from animal models demonstrating the causal mechanisms are required.

Metabolic health

Metabolism is the process that produces or uses energy. Metabolic processes permeate nearly all aspects of biology, so any dysfunction has extensive effects in disease [204]. Hyperinsulinemia, hyperglycemia, and dyslipidemia are states which can contribute to AD pathology, and comorbidity of these states with chronic diseases such as T2DM and CVD has additive effects on cognitive decline [205, 206]. These metabolic dysfunctions can result in the development of T2DM, which has significant comorbidity with vascular diseases, increasing the risk of cognitive decline by upwards of 50% [44 , 207–209]. Together, this has pushed some researchers to define AD as ‘type 3 diabetes’ [210].

Patients with AD patients suffer from brain insulin resistance that leads to downregulation of insulin receptors, lower binding to insulin receptors, and impaired insulin signaling [211 –214]. Importantly, insulin is degraded by IDE, which is also able to bind to and degrade Aβ [213, 215, 216]. However, T2DM can cause missense mutations in IDE causing a loss of function and impaired degradation of Aβ [217]. High levels of insulin also impair the efflux of Aβ to the periphery [218] as well as the ability of IDE to degrade Aβ [213]. This excess insulin causes hyperinsulinemia and increased insulin resistance, contributing to the development of T2DM [219]. Hyperinsulinemia may also be an independent a risk factor for AD. In one study measuring serum insulin levels, 39% of people aged over 65 had hyperinsulinemia, leading to two-fold increased risk for developing AD [220]. Insulin sensitivity is improved through exercise, with physically active individuals having higher insulin sensitivity than matched controls [221]. The benefits of exercise on insulin sensitivity start to diminish two days after cessation of exercise, indicating that longitudinal consistency is needed for sustained benefits [222]. In terms of AD, increasing insulin sensitivity could allow more IDE to be unbound to insulin and therefore available to degrade Aβ. Acute exercise in rodents significantly increases IDE levels measured in muscle and liver [223, 224], and in humans there is raised IDE expression in the plasma after acute exercise [224]. Although raising peripheral IDE may be beneficial for Aβ degradation, these studies need to be confirmed by determining the effects of chronic exercise on brain IDE, particularly in the context of AD.

High blood sugar, known as hyperglycemia, may also contribute to cognitive decline. Hyperglycemia is a risk factor for dementia, especially in those with T2DM [225]. AD patients have deficits in hippocampal glucose metabolism beginning prior to clinical symptoms and correlating with clinical and pathological severity [226]. One study found that baseline glucose metabolism in the hippocampus can predict progression to AD with 80% accuracy and people with dementia experience faster declines in glucose metabolism [227]. Furthermore, mild or diabetic impairment in glucose metabolism is associated with more rapid cognitive decline, albeit only in women [228]. These data may be due to hyperglycemia producing more advanced glycosylated end products, which are seen at high levels in the brains of AD patients, and cause Aβ to aggregate faster [229].

Exercise consistently decreases blood glucose and is a well-established treatment option for T2DM [230]. During a single exercise session, glucose uptake by muscles can increase 50-fold, principally due to upregulation of the GLUT4 receptor [231, 232]. Exercise can improve glycemic control and prevent hyperglycemia for up to 24 hours post-exercise, with similar results occurring with aerobic and resistance training [233]. It should be noted that this enhanced glycemic control from exercise may not be a dose-dependent relationship, as increasing intensity or volume do not appear to provide additional benefits [230]. As with GLUT4, insulin-mediated glucose uptake is positively affected by exercise [232], but these effects are short-lived, as improvements in insulin-mediated glucose uptake dissipates after approximately 6 days [234]. One study using AD patients has demonstrated that 3 months of light exercise did not assist in glucose metabolism, but instead improved the availability and metabolism of ketones, potentially compensating for the impaired glucose metabolism of AD patients [235].

Dyslipidemia may also be involved in AD, although the mechanisms by which the two are related remain elusive [236]. In vitro, low cholesterol levels can assist in the reduction of Aβ production in hippocampal neurons and stimulates non-amyloidogenic production through α-secretase activity [237, 238]. Epidemiological data is conflicting regarding cholesterol and dyslipidemia, as studies measuring lipid levels later in life reveal no effect of dyslipidemia on AD risk [236]. However, studies with long follow-ups beginning in midlife, tend to find a harmful effect of hypercholesterolemia and low high-density lipoproteins for AD risk [236]. Exercise has also demonstrated positive effects for managing lipid levels and dyslipidemia [239], with these favorable effects being confirmed through meta-analyses [240, 241]. Benefits to lipid profiles from exercise remain for up to 15 days after cessation of exercise, denoting that consistency is important in maintaining a long-term healthy lipid profile, particularly as physical inactivity significantly raises LDL levels [242]. Finally, exercise is critical in managing weight and adiposity, which in turn assists in managing insulin resistance [243]. In summary, exercise can assist in regulating glucose, insulin, and lipid levels, albeit temporarily, and regularity is needed for sustained benefits. When maintained consistently, exercise can help prevent the onset of metabolic dysfunction, T2DM, and CVD, which are primary risk factors for AD.

Hepatic and renal health

The liver is a key location for Aβ clearance. Up to 60% of circulating Aβ peptides are cleared by hepatocytes in the liver [48 , 244]. Individuals with AD have significantly reduced levels of Aβ peptides in the liver, indicating the liver may be less effective at capturing and clearing Aβ [245]. Fat accumulation in the liver can impair function and is a risk factor for CVD [246, 247]. Impaired function can also significantly raise Aβ_40/42 levels, indicating hindered clearance [248]. Exercise increases the metabolic demands on the liver and attenuates the progression of liver diseases, but meaningful reductions to intrahepatic fat levels are only seen in long-term, regular exercisers [249, 250].

Renal function is also important for Aβ clearance [178]. Chronic kidney disease may be preventable by exercise [251, 252], which is important as it also increases risk of CVD, hypertension, as well as cognitive decline and all-cause dementia [253 –255]. One intervention study showed that a 12-week light exercise program improved glomerular filtration rate (a measure of kidney function) by 17% in humans, indicating exercise could be beneficial for the prevention of kidney disease and other subsequent AD risk factors [256].

Preventing kidney and liver associated diseases may reduce other risk factors of AD, such as CVD, and ensure optimal peripheral clearance of Aβ. Exercise is a low-risk preventative intervention that may improve peripheral Aβ clearance, however, existing data is sparse on the role of the liver and kidneys in AD, and significantly more research is needed to elucidate this relationship.

EFFECT OF EXERCISE ON Aβ AND TAU

Exercise and Aβ in animals

Exercise, both forced and voluntary, has shown mixed effects on the levels of Aβ in animal studies (Table 1). Most have reported positive effects on Aβ levels [113 , 257–268], with a few others reporting no change [112 , 269–271]. The effects of exercise on cognition are generally consistent, with most studies reporting improved performance on the Morris water maze [112–114 , 264–266], radial arm water maze [170], Barnes maze [263], Y-maze [117], and novel object recognition tests [268]. However, a small subset of investigations report no improvement in performance on the water maze test from exercise [118, 269, 270].

Table 1

Effect of exercise on Aβ levels in rodents. 18/23 show a positive effect on Aβ levels. 15/18 show positive effects on cognition

Model/sex/age	Intervention	Effect on Aβ	Effect on cognition	Reference/year
Mouse (NSE/APPsw, sex not indicated, 13 months)	60 min, 5x p/w for 4 months	Reduced Aβ₄₂	Improvement on MWM	[114] 2010
Mouse (APP/PS1, Male, 3 months)	30 min, 5x p/w for 5 months	Reduced Aβ₄₂ (hippo)	Improvement on Y-maze test	[117] 2014
Mouse (PS2, sex not indicated, 24 months)	60 min, 5x p/w for 3 months	Reduced Aβ₄₂ (cortex/hippo)	Improvement on MWM	[264] 2013
Mouse (APP/PS1, sex not indicated, 3 months and 12 month)	30 min, 5x p/w for 5 months	Reduced soluble Aβ_40/42, no change in Aβ plaque burden in aged mice, but reduced in young mice (hippo)	Improvement on MWM	[266] 2015
Mouse (APP/PS1, female, 3 months)	30 min, 5x p/w for 5 months	Reduced soluble Aβ_40/42 and plaque deposits (hippo)	Not tested	[267] 2013
Mouse (APP/PS1, male and female, 2 months)	60 min, 5x p/w for 2 months	Reduced Aβ_40/42 (hippo/amyg)	Not tested	[259] 2015
Mouse (CD1, female, 9 months)	20 min, 5x p/w for 2 or 4 months	Reduced Aβ (cortex)	Not tested	[260] 2014
Mouse (NSE/APPsw, sex not indicated, 13 months)	60 min, 5x p/w for 4 months	Reduced Aβ₄₂	Improvement on MWM	[261] 2008
Mouse (NSE/PS2n, sex not indicated, 24 months)	60 min, 5x p/w for 3 months	Reduced Aβ₄₂ (hippo)	Improvement on MWM	[262] 2011
Rat (D-galactose aged Sprague-Dawley, male, 4 months)	30–60 min, 5d p/w for 2 months	Reduced Aβ₄₂ (hippo)	Improvement on MWM	[116] 2013
Mouse (Tg2576, male and female, 5 months)	Voluntary or forced running 60 min, 5x p/w for 4 months	Reduced Aβ plaques (hippo/cortex). No change in soluble Aβ_40/42	Improvement in novel object recognition (voluntary only)	[268] 2009
Mouse (3xTG, male and female, 1–6 months)	Ad libitum for 1–6 months	No change in most groups, reduced Aβ₄₀ in young male mice only (hippo)	Reduced anxiety, improvement on MWM	[112] 2011
Mouse (3xTG, female, 12 months)	Ad libitum for 3 months	Reduced Aβ_40/42 (cortex)	Improvement on MWM, reduced dementia behavioral symptoms	[113] 2015
Mouse (APP/PS1, sex not indicated, 10 months)	Ad libitum for 6 weeks (with antioxidant therapy)	No change (cortex, hippo, hypothalamus)	No improvement on MWM	[118] 2013
Mouse (Tg2576, sex not indicated, 16–18 months)	Ad libitum for 3 weeks	35% decrease on aggregated Aβ but not significant (hippo). Reduced soluble Aβ₄₀ (cortex)	Not tested	[169] 2008
Mouse (Tg2576, sex not indicated, 15–19 months)	Ad libitum for 3 weeks	No effect	Improvement on radial arm water maze	[170] 2008
Mouse (TgCRND8, female, 1 months)	Ad libitum for 1 or 5 months	Reduced Aβ plaques (frontal cortex, cortex, hippo) and Aβ_40/42	Improvement on MWM	[265] 2005
Mouse (TgCRND8, female, 7 months)	Ad libitum for 5 months	Reduced plaque numbers (cortex) and improved Aβ efflux	Improvement in spatial learning and memory (Barnes maze test)	[263] 2016
Mouse (APPswe/ind, male and female, 2–3 months)	Ad libitum for 10 weeks (high fat diet)	Reduced soluble Aβ and plaque burden (hippo)	Improvement on MWM	[257] 2012
Mouse (APP-23, female, 10 weeks)	Ad libitum for 11 months	No change (cortex/hippo)	No improvement on MWM	[269] 2006
Mouse (J20 swe/ind, female, 2–3 months)	Ad libitum for 10 weeks (high fat diet)	Reduced Aβ plaques (hippo) and Aβ_40/42 fractions	Improvement on MWM	[258] 2013
Mouse (3xTG, female, 9 months)	Ad libitum for 11 months	No change (hippo)	No improvement in MWM	[270] 2013
Mouse (APP23, female, 6 or 18 months)	Ad libitum for 10 days	No change (hippo)	Not tested	[271] 2009

Hippo, hippocampus; amyg, amygdala; MWM, Morris water maze.

While the majority of the aforementioned studies demonstrate positive effects of exercise on Aβ and cognition, discrepancies in the data may be due to the wide range of transgenic animal strains, starting age, intervention type, and length of intervention used in the studies, which appear to influence the outcomes. For instance, nearly all studies using the APP/PS1 mouse model showed reduced Aβ levels after exercise [117 , 267], but studies using the 3xTG mouse model did not [112, 270]. However, in these cases all the APP/PS1 mice underwent a forced running protocol, whereas the 3xTG mice were on a voluntary running protocol, which may be affecting the final outcomes. Moreover, the age at which an exercise protocol is initiated warrants consideration. For example, Nichol et al. [169] used a 3-week protocol in 16-month-old mice and saw a 35% reduction in aggregated Aβ (albeit not significant) and reduced soluble Aβ₄₀, whereas Wolf et al. [269] used an 11-month protocol starting with 10-week-old mice and saw no effects. This could be due to different models being used (Tg2576 and APP-23, respectively), but may also indicate that beginning an exercise regime later in life can still provide protective benefits, though this has yet to be confirmed in humans.

Nearly all studies utilizing a forced running protocol showed a reduction in Aβ [114 , 267], while most [169 , 268], but not all [112, 118, 269–271 , 112, 118, 269–271] voluntary running protocols induced positive effects. This indicates that voluntary wheel running is not the best intervention for reducing Aβ pathology in rodents, as it may not be inducing sufficient stress to induce change. Interestingly, Yuede et al. used both forced and voluntary interventions for 16 weeks, and found that while neither group showed changes in soluble Aβ, only the voluntary running group exhibited Aβ plaque reductions [268]. Therefore, it is not definite that forced exercise interventions are better for reducing Aβ levels, and many other methodological considerations, such as mouse model, must be considered. Taken together, most studies, both forced and voluntary, indicate that exercise interventions are beneficial for AD by broadly reducing Aβ load and improving cognition in rodents.

The reduction of Aβ via exercise is likely due to either changes in AβPP processing or changes in the clearance and/or degradation of Aβ. BACE-1 has been a prime target regarding AβPP processing, as it is a key enzyme involved in forming toxic oligomers of Aβ [272]. Evidence from animal studies have demonstrated that exercise may reduce or prevent the increase of BACE-1 [116 , 273], although other studies have been unable to replicate this finding [118, 267]. Alternatively, Yu et al. [116] showed that in an induced-AD rat model, ADAM17 is increased. This enzyme is part of the α-secretase pathway of processing AβPP, forming non-toxic species of amyloid and consequently reduces toxic Aβ generation [274].

Improved Aβ clearance may also be responsible for the central Aβ reductions observed in animal studies. Herring et al. [263] actively checked for efflux of Aβ across the blood-brain barrier and found exercise enhanced efflux, but the underlying mechanisms responsible for the results were not determined. As previously discussed, low Aβ₄₂ levels in plasma are associated with cognitive decline [275] and enhanced efflux from the CNS is critical, as Aβ can be metabolized in the periphery. Other groups have also found that Aβ degrading enzymes such as NEP or LRP-1, which are important in Aβ metabolism, are enhanced through exercise, leading to a reduction in central Aβ [257 , 276]. Multiple mechanisms are likely altered regarding AβPP processing, clearance, and degradation due to exercise, yet it remains elusive as to exactly how these changes are initiated and whether certain types or intensities of exercise favor Aβ reduction mechanisms.

Exercise and Aβ in humans

Observational and exercise intervention studies in humans have shown inconsistent results when investigating Aβ or cognition (Table 2). Studies using cross-sectional designs, where physical activity levels are subjectively reported via questionnaire, are split between positive [277 –281] or no effect [282 –284] on Aβ levels. Furthermore, the two studies examining cognition found no benefit of exercise [282, 284]. An advantage of this design is that it allows for a larger sample, but self-reported statistics are hard to validate and give little indication of exercise intensity or general lifestyle practices.

Table 2

Effect of exercise on Aβ levels in humans. 7/13 show a positive effect on Aβ levels. 3/6 show a positive effect on cognition

Subjects /age/cognition	Methods	Effect on Aβ	Effect on cognition	Reference/year
69 subjects (75% f), 55–88, cognitively normal	Cross sectional questionnaire	Decreased PIB binding, increased CSF Aβ₄₂	Not tested	[277] 2010
165 subjects, 45–88, cognitively normal	Cross sectional questionnaire	Reduced Aβ in ApoE4 carriers. Increased CSF Aβ₄₂	Not tested	[278] 2013
546 subjects, 60–95, cognitively normal	Cross sectional questionnaire	Decreased PIB binding in ApoE4 carriers, improvement Aβ_40 :42 ratio	Not tested	[279] 2013
317 subjects, 40–65, cognitively normal	Cross sectional questionnaire	Reduced age-related PIB binding	Not tested	[280] 2014
515 subjects, 70–93, cognitively normal/MCI	Cross sectional questionnaire	No effect	No effect	[282] 2012
65 subjects, mean 76, cognitively normal	Cross sectional questionnaire	No effect	Not tested	[283] 2012
268 subjects, >70, cognitively normal/MCI	Cross sectional questionnaire	No effect	No effect	[284] 2015
33 subjects, 55–85, MCI	RCT. 45–60 min, 4x p/w for 6 months	No effect	Improved executive function in women but not memory function	[285] 2010
28 subjects, 57–83, cognitively normal, glucose impairment or overweight	RCT. 45-60 min, 4x p/w for 6 months	Reduced CSF Aβ₄₂ (trend, p = 0.07)	Improved executive but not memory function	[286] 2010
53 subjects, >60, mild AD	RCT. 60 min, 3x pw for 4 months.	No effect	Not tested	[287] 2016
65 subjects, >90, cognitively normal	RCT. 45 min, 3x p/w for 2 months	No effect	No effect	[288] 2015
25 subjects (90% f), >70, cognitively normal	RCT. 60 min 3x p/w for 4 months with exercise or cognitive/ exercise combo	Improvement in Aβ_40 :42 ratio in both tasks	Recall, visuospatial, verbal fluency, and attention improved in combo task group	[289] 2015
85 subjects, 51–74, cognitively normal	Activity measured for 1 week with accelerometer	Increased CSF Aβ₄₂ with moderate activity	Not tested	[281] 2018

Human studies where participants undergo an exercise intervention have found limited benefit of exercise on AD pathology or cognitive functioning [285 –289]. The longest trials (6 months) are from Baker et al. using MCI patients and cognitively normal adults (55–85 years) [285], or glucose intolerant adults (57-83 years) [286]. These studies had patients exercising for 45–60 minutes 4x per week and found improved executive function in women with MCI and glucose intolerant adults, but neither studies found overall benefits on Aβ levels or memory function. Similar studies with interventions lasting two and three months also saw no effect of exercise on Aβ levels, but the patient groups included mild AD [287] or nonagenarians [288]. Utilizing these patient populations may be limiting the benefits of exercise interventions as exercise is not potent enough to combat established pathology. One study exclusively using cognitively sound and healthy adults (over 65) found that 3 months of exercise (aerobic, strength, and stretching) improved the CSF Aβ_42 :40 ratio and cognitive functions [289], although it should be taken into account that the study had a small sample size (n = 13), and larger trials need to be conducted to confirm these results.

Overall, both cross sectional and intervention trials, mostly using cognitively normal participants, have shown mixed results on the effect of exercise on Aβ (Table 2). Notably, most studies including MCI, mild AD, or very old participants, exhibit no benefit of exercise on Aβ or cognition [282 , 288]. Exercise interventions may not be sufficient to counteract the severity of the disease once cognitive and functional deficits are apparent, as is the case with MCI or mild AD patients.

Cognitive reserve and BDNF

The improvements in cognitive functions from exercise reported by many studies may not be due to changes in Aβ pathology. Instead, exercise may be improving cognitive or brain reserves. Cognitive reserve involves the brain actively attempting to compensate for damage by using alternative neural pathways [290]. Brain reserve is a more passive function that involves stimulating neurogenesis and promoting plasticity to be more resistant to pathology [290]. Lifestyle factors, such as exercise, may be boosting these reserves, causing increased tolerance to AD pathology [291]. Brain-derived neurotrophic factor (BDNF) is likely vital in mediating these reserves, a hypothesis supported by the fact that people with high brain BDNF expression experience slower cognitive decline than those with low BDNF in both healthy and AD populations [292].

Exercise has long been known to enhance BDNF production, and it may be responsible for mediating the benefits from exercise such as improved neurogenesis, learning, and cognition [293, 294]. At a fundamental level, BDNF is vital for neuronal plasticity, long-term potentiation, and for the encoding of memories [295 –297]. Physiological changes such as increased hippocampal neurogenesis and volume can be induced by exercise, and both these effects are mediated by BDNF [298, 299]. Exercise may be raising BDNF levels through the FNDC5 membrane protein, which is elevated post-exercise and stimulates BDNF expression [300]. A recent study demonstrated that FNDC5 is downregulated in AD patients, and FNDC5 knock-out mice become cognitively impaired, which can be rescued by raising FNDC5 expression [301]. Taken together, exercise can increase BDNF levels in the brain and the cognitive and pathological improvements resulting from exercise may be due to BDNF-mediated neuroprotection, rather than as a direct effect on Aβ or tau.

Exercise and tau in animals

The number of exercise studies examining changes in tau in animals are limited (Table 3), but like Aβ, there is evidence to suggest a beneficial effect of exercise on tau. Exercise can reduce tau phosphorylation, and therefore activity, at multiple locations within tau [302 –304]. Cognitive function is improved on the Morris water maze [304] and Y-maze [305] post-exercise. One study using the THY22 model found that a 9-month physical activity intervention reduced pathological tau species in the hippocampus, although the total amount of tau was unchanged [305]. This was corroborated by another investigation using the 3xTG model found that P-tau levels were reduced in the cortex and hippocampus from exercise [113]. Conversely, a study using TgCRND8 mice found no improvement in tau pathology, as measured by AT8-positive dystrophic neurites, though it is important to note that the intervention started at an advanced stage (24 months), which may have prevented the possibility for improvement [263]. The duration of exercise interventions may have profound effects on the outcomes of animal studies. For instance, one study reported an increase in tau pathology from exercise after 3 weeks [306] and a 5-month study reported no change in tau but improved cognitive functions [263], whereas a 9-month intervention reduced pathological tau species [305]. This may indicate a long-term intervention is needed to improve tau pathology, however, these studies were performed in different mouse models of AD so further research is needed to confirm if reductions in tau are dependent on the animal model used or length of the intervention.

Table 3

Effect of exercise on tau in rodents. 5/7 show positive effects on tau. 5/5 show positive effects on cognition

Model/sex/age)	Intervention	Effect on tau	Effect on cognition	Reference/year
Mouse (P301S, sex not indicated, 7-8 months)	40 min, 5x p/w for 4 months	Reduced tau phosphorylation (spinal cord, hippo), no change in cortex	Not tested	[302] 2014
Mouse (NSE/hTau23, male and female, 16 months)	60 min, 5x p/w for 4 months	Reduced tau phosphorylation and P-tau (hippo)	Not tested	[303] 2009
Mouse (NSE/hTau23, sex not indicated, 18 months)	30-50 min, 5x p/w for 4 months	Reduced tau phosphorylation (cerebral cortex)	Improvement on MWM	[304] 2015
Mouse (Tg601, female, 19 months)	30 min, 5x p/w for 3 weeks	Increased insoluble tau and C terminus phosphorylation	Not tested	[306] 2015
Mouse (3xTG, female, 12 months)	Ad libitum running for 3 months	Reduced P-tau levels (cortex, hippo)	Improvement on MWM, reduced dementia behavioral symptoms	[113] 2015
Mouse (TgCRND8, female, 7 months)	Ad libitum running for 5 months	No effect	Improved spatial learning and memory	[263] 2016
Mouse (THY22, male, 3 months)	Ad libitum running for 9 months	Total unchanged, pathological species reduced (hippo)	Improvement on Y-maze in THY22, not WT	[305] 2011

The mechanism by which tau pathology is reduced by exercise is likely through the suppression of tau kinases. For example, GSK-3, which mediates tau hyperphosphorylation and Aβ production, stimulates neuroinflammation, and is an inhibitor of hippocampal neurogenesis [307, 308], has been found to be reduced in exercised mice [304]. This study also showed that exercise increased phosphorylation of PI3K/AKT, which are upstream precursors of GSK-3 (which loses its kinase activity when phosphorylated by, e.g., PI3K/AKT). This finding is consistent with another study [303] which found reductions in the MAPK pathway (JNK, ERK, p38 activity), and PKA (a cAMP dependent protein kinase), both of which have been shown to be closely involved in the phosphorylation of tau [309, 310].

Exercise and tau in humans

Very few studies have examined tau pathology in humans and the ones that do are limited in scope (Table 4). In patients with mild AD, exercise appears to have no effect on tau pathology [287]. Similar results were observed with an intervention including cognitively normal participants [281]. Finally, one study found a reduced AD pathology burden in active people, but the technique used (FDDNP-PET imaging) measures both Aβ and tau and cannot distinguish the two [311].

Table 4

Effect of exercise on tau in humans. 2/3 show a positive effect on tau

Subjects/age/cognition	Methods	Effect on Tau	Effect on cognition	Reference/year
44 subjects, 40–85, cognitively normal	Cross sectional questionnaire	Tau/Aβ reduced in MCI patients^*	Not tested	[311] 2016
53 subjects, >60, mild AD	60 min, 3x pw, 3 months.	No change	Not tested	[287] 2016
85 subjects, 51–74, cognitively normal	PA measured for 1 week with accelerometer	Tau unchanged. Improved Aβ/tau profile	Not tested	[281] 2018

^*Methodology cannot distinguish between tau and Aβ.

Altogether, exercise tends to have a positive effect on Aβ levels in animals and coincides with an improvement in cognition. Similar results are found for tau, but this area has been considerably less explored. The mechanisms driving these effects are elusive and additional in vivo studies are needed to unravel these, particularly for tau. In humans, exercise could have a beneficial effect on AD pathology, although relative to the animals, the data is limited and mixed, so further research using long-term exercise interventions examining both Aβ and tau pathology is needed to make firm conclusions [312].

DISCUSSION

With aging populations and no disease-modifying treatments available, AD has already become one of the major global medical problems of the 21^st century. Based on the current failures of Aβ reduction treatments, it is likely that there will not be a single-target treatment for AD. Moreover, AD often has mixed pathologies with other diseases, as almost half of probable AD cases have AD pathology combined with cerebral infarcts and/or Lewy bodies [313], adding further complexity to the pharmacological treatment of the disease.

Substantial progress has been made in our understanding of AD pathology, and our understanding of the etiology of AD has illuminated the possibility of non-pharmacological interventions to prevent or delay AD. As approximately a third of all AD cases can be directly attributed to modifiable risk factors, a push towards altering lifestyle may have profound benefits on the outcome for an aging population [9]. AD rarely develops independently of other modifiable risk factors, and this understanding has led to the recognition of lifestyle factors that contribute to pathologies driving disease development. Exercise is one of these lifestyle factors and there is a growing evidence-based foundation supporting its protective role against AD (Fig. 2). The biological data discussed in this review are now being bolstered by large-scale multidomain human trials which include exercise as a component. Completed studies such as the FINGER trial, which produced promising results [314], has led to the development of similar trials being prepared in the USA, Australia, China, and Singapore [315]. Additionally, accessibility to the internet has led to digital solutions that can provide a scalable framework for remote multidomain lifestyle interventions [316]. The FINGER studies provide evidence that exercise, in combination with interventions targeting diet, vascular health, and cognitive training, can improve cognition in at-risk adults. Moreover, exercise interventions may still provide cognitive benefits to those with established MCI [285], and multidomain intervention studies using MCI and AD populations would be invaluable in reducing the global burden of dementia. There is, however, considerable research to be done to understand how exercise can influence AD biomarkers.

Fig.2

Biological pathways modified by exercise that encourage healthy aging and decrease the risk of AD. The effects of exercise are wide reaching and can affect oxidative stress, inflammation, organ health, and directly influence AD pathology. NEP, neprilysin; IDE, insulin-degrading enzyme; BDNF, brain-derived neurotrophic factor; AβPP, amyloid-beta protein precursor; Aβ, amyloid-beta.

To begin, epidemiological studies provide a large-scale foundation to build on, but cannot eliminate all bias/confounders or provide mechanistic details, therefore animal and human clinical studies are needed. However, there is often a disparity between the human and animal data. This is likely due to animal studies lasting considerably longer than human studies in terms of lifespan (e.g., the longest human Aβ intervention is approximately 0.6% of lifetime, whereas in mice this can be up to 50%, see Tables 1–4), demonstrating the need for longer human intervention studies. Next, as the first neuropathological signs of AD can begin decades before onset [10 –12], efforts to identify at-risk individuals at an early stage and performing longer studies beginning earlier in life will be needed to determine the effectiveness of lifestyle interventions in humans [77].

The underlying mechanisms by which exercise might affect the development or progression of AD include OS, inflammation, systemic health, and direct interaction with Aβ and tau. First, a reduction in OS may help prevent lipid, protein, and DNA damage. Reduced OS can be a result of diminished free radical production or a boost in antioxidant enzymes such as SOD and glutathione, both of which have been demonstrated in animal studies through exercise interventions.

Second, exercise may aid in the prevention of age-associated chronic inflammation. By reducing the expression of inflammatory molecules such as IL-6, TNF-α, and IL-1β, exercise helps prevent immune cell mediated damage and further exacerbation of OS. This also creates a more favorable environment for proper immune functioning, further contributing to the degradation of Aβ.

Third, exercise assists in preventing metabolic dysfunction and maintaining the health of the heart, liver, and kidneys, which may reduce risk for cognitive decline. Improved cardiovascular health may contribute to increased CBF, in turn promoting the efflux of Aβ into the periphery for degradation. Alternatively, reducing hypertension prevents blood vessel damage in the brain, which can contribute to AD, though the evidence for these mechanisms are inconclusive. Exercise can help prevent metabolic dysfunctions associated with AD, including hyperinsulinemia, hyperglycemia, and dyslipidemia, which seem to be risk factors for AD themselves, but also have strong relationships with CVD and T2DM. The benefits provided by exercise on metabolism are short-lived, and exercise regularity is critical for maintaining metabolic health. The liver and kidney are directly responsible for a large amount of Aβ clearance, so it is vital that attention be paid to their health by preventing fatty liver disease or kidney dysfunction. The evidence for the role of the liver and kidney in AD is sorely lacking and further research is needed to elucidate how influential peripheral organs are involved in AD pathology.

Finally, exercise may influence AD pathology through mechanisms that directly affect Aβ or tau. This includes reduced expression of AβPP and BACE-1 to lower toxic Aβ production or the upregulation of NEP or IDE to increase Aβ degradation, among others. Few studies have explored exercise-induced changes in tau pathology, but animal evidence indicates that lower expression of tau kinases such as GSK-3 and the MAPK pathway contribute to reductions in pathology. Moreover, improvements in cognitive or brain reserve from exercise may assist in the prevention of cognitive decline seen in many animal studies as it increases the pathological threshold needed to induce symptoms [290, 291]. However, all these effects are yet to be confirmed in humans.

These four mechanisms will often occur concurrently. For example, exercising will improve one’s cardiovascular health, which could alone reduce risk of AD, but simultaneous reduction in adiposity will mean reduced inflammation and coincide with less immune-mediated OS, possibly followed by reduced Aβ aggregation. This synergy makes isolation and identification of a single mechanism of action difficult when studying the effects of exercise on AD. Understanding individual mechanisms of action remains important in unraveling the role of exercise in AD pathology, at the same time, holistic approaches are also needed to gain insight into how a lifestyle behavior such as exercise can alter the course of AD.

The growing data from animal studies warrants further research in humans. Importantly, the vast majority of human studies remain focused on aerobic exercise, which ignores the multimodal nature of physical exercise, including strength training, flexibility, balance training, and combinations thereof. It is likely that the mechanisms between exercise modalities will overlap, and that the substantial benefits of exercise are more strongly tied to frequency and intensity than a specific modality [18, 317]. Nevertheless, understanding the biology of non-aerobic exercise is necessary to further demonstrate the categorical value of exercise as a preventative intervention.

In conclusion, exercise provides a non-invasive way of influencing multiple mechanisms that have been shown to alter AD pathology. Exercise alone will not be sufficient to prevent AD, but it serves as a foundation for non-pharmacological lifestyle interventions. In combination with exercise interventions, targeting modifiable risk factors such as diet, smoking, sleep, and cognitive engagement [33] provide a multidomain approach that may delay the onset of AD symptomatology. Such multidomain non-pharmacological interventions may additionally serve as the foundation for combination therapies including pharmacological treatment, which may further reduce risk and delay symptom onset.

Footnotes

ACKNOWLEDGMENTS

The authors would like to acknowledge Ben Weisman for his help with the visuals represented in this article. They would also like to thank Theodore (Teshie) Bronk for his feedback during the development process.

Authors’ disclosures available online ().

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