Physical exercise_cognition_and brain health in aging

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<p>Trends in</p><p>Review</p><p>Physical exercise, cognition, and brain health</p><p>in aging</p><p>Neurosciences</p><p>Nárlon C. Boa Sorte Silva1,2,3, Cindy K. Barha4,5, Kirk I. Erickson6,7, Arthur F. Kramer8,9, and</p><p>Teresa Liu-Ambrose1,2,3,*</p><p>Highlights</p><p>Exercise training is among the main</p><p>strategies that have been proposed to</p><p>promote cognitive and brain health</p><p>outcomes in older individuals with and</p><p>without cognitive impairment.</p><p>The effects of exercise on cognition are</p><p>mediated, in part, by structural and func-</p><p>tional adaptations in the brain, including</p><p>changes in gray matter volumes and</p><p>white matter microstructural integrity.</p><p>Muscular contractions during exercise</p><p>produce a category of cytokines referred</p><p>Exercise training is an important strategy to counteract cognitive and brain health</p><p>decline during aging. Evidence from systematic reviews and meta-analyses</p><p>supports the notion of beneficial effects of exercise in cognitively unimpaired and</p><p>impaired older individuals. However, the effects are often modest, and likely in-</p><p>fluenced by moderators such as exercise training parameters, sample characteris-</p><p>tics, outcome assessments, and control conditions. Here, we discuss evidence on</p><p>the impact of exercise on cognitive and brain health outcomes in healthy aging and</p><p>in individuals with or at risk for cognitive impairment and neurodegeneration. We</p><p>also review neuroplastic adaptations in response to exercise and their potential</p><p>neurobiological mechanisms. We conclude by highlighting goals for future studies,</p><p>including addressing unexplored neurobiological mechanisms and the inclusion of</p><p>under-represented populations.</p><p>to as myokines, which represent a</p><p>potential molecular pathway mediating</p><p>neuroplastic adaptations and associated</p><p>cognitive improvements in response to</p><p>exercise.</p><p>Understanding the ideal combination of</p><p>exercise training parameters across</p><p>populations and life stages could lead</p><p>to interventions that promote greater</p><p>effects on cognitive and brain health</p><p>outcomes.</p><p>1Djavad Mowafaghian Centre for Brain</p><p>Health, Faculty of Medicine, University of</p><p>British Columbia, Vancouver, British</p><p>Columbia, Canada</p><p>2Department of Physical Therapy,</p><p>Faculty of Medicine, University of British</p><p>Columbia, Vancouver, British Columbia,</p><p>Canada</p><p>3Centre for Aging SMART at Vancouver</p><p>Coastal Health, Vancouver Coastal</p><p>Health Research Institute, Vancouver,</p><p>British Columbia, Canada</p><p>4Faculty of Kinesiology, University of</p><p>Calgary, Calgary, Alberta, Canada</p><p>5Department of Cell Biology and</p><p>Anatomy, Hotchkiss Brain Institute,</p><p>Calgary, Alberta, Canada</p><p>6Department of Psychology, University</p><p>of Pittsburgh, Pittsburgh, PA, USA</p><p>7AdventHealth Research Institute,</p><p>Neuroscience, Orlando, FL, USA</p><p>Can physical activity help support brain health and prevent cognitive decline</p><p>during aging?</p><p>Epidemiological studies show that higher physical activity levels are associated with better cogni-</p><p>tion during aging [1] and lower dementia risk [2]. These effects are mediated by changes in brain</p><p>structure and function, including slower graymatter atrophy rates [3], preservedwhitematter struc-</p><p>tural integrity [4,5], maintenance of functional connectivity of brain networks [6], and greater synap-</p><p>tic integrity [7]. Despite this correlational evidence, a central question is whether increasing one’s</p><p>physical activity levels can causally confer benefits to cognitive and brain health outcomes and re-</p><p>duce dementia risk. In this review we discuss evidence from meta-analyses and randomized con-</p><p>trolled trials (RCTs) regarding the impact of exercise on cognitive and brain health outcomes in</p><p>older individuals (Box 1). We also review findings on neuroplastic adaptations associated with</p><p>exercise, and the potential neurobiological mechanisms underlying the effects of exercise on</p><p>cognition and brain health outcomes. We focus primarily on human studies, and the review is orga-</p><p>nized under four main pillars to contextualize the evidence: the ‘what’, ‘who’, ‘when’, and ‘how’ of</p><p>exercise (Figure 1). We also highlight current knowledge gaps and future directions for the field.</p><p>Exercise and its impact on cognitive outcomes</p><p>What is exercise?</p><p>Exercise is a form of physical activity which requires planning, structure, and repetition with the</p><p>goal of improving or maintaining physical fitness [8]. Exercise training includes prescription</p><p>parameters such as type, frequency, intensity, and session duration (Box 2).</p><p>Exercise effects on cognition</p><p>We next outline briefly the main impact of exercise on cognition across commonly defined samples</p><p>within normal and pathological aging (Box 1). In the context of healthy aging, exercise has been</p><p>shown to improve global cognition and domain-specific functions with overall modest effect</p><p>402 Trends in Neurosciences, June 2024, Vol. 47, No. 6 https://doi.org/10.1016/j.tins.2024.04.004</p><p>© 2024 Published by Elsevier Ltd.</p><p>https://doi.org/10.1016/j.tins.2024.04.004</p><p>http://crossmark.crossref.org/dialog/?doi=10.1016/j.tins.2024.04.004&domain=pdf</p><p>CellPress logo</p><p>8Center for Cognitive and Brain Health,</p><p>Northeastern University, Boston, MA,</p><p>USA</p><p>9Beckman Institute, University of Illinois</p><p>Urbana-Champaign, Champaign, IL,</p><p>USA</p><p>*Correspondence:</p><p>teresa.ambrose@ubc.ca (T. Liu-Ambrose).</p><p>Box 1. Overview of key stages of cognitive decline in older individuals</p><p>A generally accepted view of cognitive decline, which has been widely applied in the exercise literature, is that it comprises</p><p>a syndrome wherein individuals may fall along a continuum of preclinical, prodromal, or dementia stages [62,159]. These</p><p>stages are outlined as follows:</p><p>• The preclinical stage includes those without overt cognitive impairment but whomay decline with increasing age or pa-</p><p>thology accumulation. This may include individuals with subjective cognitive decline who do not present objective im-</p><p>pairment but self-report declines in cognitive performance [160].</p><p>• Mild cognitive impairment is the prodromal stage in which individuals have lower cognitive performance compared with</p><p>age-, sex-, and education-adjusted controls [161].</p><p>• The dementia stage is hallmarked by severe cognitive impairment and the loss of independence [62,162]. Alzheimer’s</p><p>disease, vascular, Lewy Body [33], and mixed dementias [39] are the most common dementia types.</p><p>Trends in Neurosciences</p><p>sizes [9–14] (but see also [15]). Executive functions and memory have been overwhelmingly</p><p>targeted in RCTs of exercise [12] because these domains are significantly impacted by age-</p><p>related neurodegenerative processes [16]. Executive functions, in particular, consistently</p><p>improve following exercise [11,14]. These findings suggest exercise-specific neuroplastic adapta-</p><p>tions in cortical regions supporting executive functions, most notably the prefrontal cortex [17–19].</p><p>Such improvements have important implications for healthy aging given the central role of executive</p><p>functions in commanding behaviors relevant to functional independence [20], which deteriorate</p><p>with aging, sometimes accompanied by neuropathology accumulation [21]. Memory impairment,</p><p>especially hippocampus-dependent episodic memory, is a common feature of normal and patho-</p><p>logical aging (e.g., Alzheimer’s disease) [16,22].Whereas it has been reported that exercise imparts</p><p>modest yet positive effects on episodic memory [23], this effect is not consistently found across</p><p>meta-analyses [14,24]. These contrasting findings likely reflect how memory is assessed and</p><p>classified across studies [25]. Therefore, despite findings of exercise-driven neuroplasticity in the</p><p>hippocampus in the context of healthy aging [26], evidence for memory improvements remains</p><p>unclear [11,23].</p><p>Individuals with mild cognitive impairment (MCI) are at greater risk for dementia compared with</p><p>their cognitively unimpaired counterparts (Box 1) [27]. Exercise interventions in this population</p><p>may attenuate underlying neuropathology and clinical progression [27]. Meta-analyses report</p><p>an overall positive yet modest effect of exercise on global cognition and domain-specific functions</p><p>[28,29]. 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logo</p><p>Trends in Neurosciences</p><p>164. Borg, G. (1982) Psychophysical bases of perceived exertion.</p><p>Med. Sci. Sports Exerc. 14, 377–381</p><p>165. Simonsson, E. et al. (2023) Effects of controlled supramaximal</p><p>high-intensity interval training on cardiorespiratory fitness and</p><p>global cognitive function in older adults: the Umeå HIT Study – a</p><p>randomized controlled trial. J. Gerontol.: Series A 78, 1581–1590</p><p>166. Brown, B.M. et al. (2021) High-intensity exercise and cognitive</p><p>function in cognitively normal older adults: a pilot randomised</p><p>clinical trial. Alzheimers Res. Ther. 13, 33</p><p>167. Frost, N.J. et al. (2021) A randomized controlled trial of high-</p><p>intensity exercise and executive functioning in cognitively</p><p>normal older adults. Am. J. Geriatr. Psychiatr. 29, 129–140</p><p>Trends in Neurosciences, June 2024, Vol. 47, No. 6 417</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0820</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0820</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0825</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0825</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0825</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0825</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0830</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0830</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0830</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0835</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0835</p><p>http://refhub.elsevier.com/S0166-2236(24)00062-6/rf0835</p><p>CellPress logo</p><p>Physical exercise, cognition, and brain health in aging</p><p>Can physical activity help support brain health and prevent cognitive decline during aging?</p><p>Exercise and its impact on cognitive outcomes</p><p>What is exercise?</p><p>Exercise effects on cognition</p><p>The ‘what’: exercise prescription parameters and cognition in older individuals</p><p>The ‘who’: exercise in individuals at risk of cognitive impairment and neurodegenerative diseases</p><p>Non-communicable chronic conditions</p><p>Cerebral small vessel disease</p><p>Prodromal stage of Alzheimer’s disease</p><p>The ‘when’: critical windows to utilize exercise for cognitive and brain health outcomes</p><p>The ‘how’: neurobiological mechanisms of the impact of exercise on cognitive and brain health outcomes</p><p>Exercise and gray matter structural changes</p><p>Exercise effects on white matter structure and brain function outcomes</p><p>A future outlook for clarifying the effects of exercise on cognitive and brain health outcomes in aging</p><p>Limitations and knowledge gaps in relation to population trials</p><p>Understanding the relationship between cognitive changes and neurobiological adaptations</p><p>Underexplored mechanisms of exercise effects on brain health</p><p>Potential genetic moderators</p><p>Increasing participant diversity and inclusion in exercise population studies</p><p>Concluding remarks</p><p>Acknowledgments</p><p>Declaration of interests</p><p>References</p><p>and delayed memory recall</p><p>[28], attention, and executive functions [31]. The extent to which these effects slow progression of</p><p>clinical symptoms and prevent conversion to dementia remains to be fully explored. The clinical</p><p>profiles of individuals with MCI are often heterogeneous [27], and the underlying neuropathology</p><p>(e.g., β-amyloid deposition, white matter hyperintensities burden) [32] is not well characterized in</p><p>exercise trials. Thus, it is unclear whether exercise has selective effects in mitigating progression</p><p>of underlying neuropathology (e.g., via β-amyloid clearance), promotes cognitive enhancement</p><p>via neuroplastic adaptations in healthy tissue (e.g., new synapses), or both.</p><p>Progression in neuropathological burden leads to a dementia diagnosis in approximately 15% of</p><p>individuals with MCI [27]. Alzheimer’s disease is the most prevalent dementia type, followed by</p><p>vascular dementia (Box 1) [33]. Slowing dementia progression would have an immense societal</p><p>impact [33]. Meta-analyses report a small positive effect of exercise on global cognition [34].</p><p>Effects on specific cognitive domains remain equivocal [34], although improvements in executive</p><p>functions have been observed [35]. Notably, some meta-analyses have not found an effect on</p><p>cognitive outcomes in this population [36–38]. Equivocal results may be due to varying inclusion</p><p>criteria across meta-analyses [37,38] and the way in which types and stages of dementia are</p><p>assessed [35]. Heterogeneity in brain structure and function among individuals with dementia</p><p>[39] could contribute to interindividual variability in responsiveness to exercise; thus, the potential</p><p>Trends in Neurosciences, June 2024, Vol. 47, No. 6 403</p><p>CellPress logo</p><p>TrendsTrends inin NeurosciencesNeurosciences</p><p>Figure 1. The effects of exercise on cognitive and brain health outcomes in older individuals. The schematic is</p><p>organized along four pillars: the ‘what’, ‘who’, ‘when’, and ‘how’ of exercise. ‘What’ refers to the different types of</p><p>exercise training. ‘Who’ refers to population of older individuals known to benefit from exercise training, as well as</p><p>subgroups for whom training would likely result in effective prevention (e.g., prodromal Alzheimer’s disease, cerebral small</p><p>vessel disease, and non-communicable chronic conditions). ‘When’ refers to life stageswherein exercise interventions should</p><p>be assessed or implemented. ‘How’ refers to known neurobiological adaptions driven by exercise which are thought to</p><p>underlie exercise-induced effects on cognition across populations. The ‘Next Steps’ section outlines recommendations</p><p>and knowledge gaps to be addressed in future research, including investigation of upregulation of myokines in response</p><p>to exercise as a potential molecular pathway mediating neuroplastic adaptations and cognitive changes.</p><p>Trends in Neurosciences</p><p>benefits of exercise may not be as easily detectable in heterogeneous samples. Better characteriza-</p><p>tion of participants – including assessing neuropathology load and genetic phenotypes – could</p><p>reduce variability and unveil stronger effects of exercise in neurobiological and cognitive</p><p>endpoints [40,41].</p><p>The ‘what’: exercise prescription parameters and cognition in older individuals</p><p>Each type of exercise (e.g., aerobic or resistance training) impacts specific physiological</p><p>pathways and potentially elicits differential effects on cognitive and brain health outcomes [42]. In cog-</p><p>nitively unimpaired individuals, different types of exercise – such as aerobic, resistance, or multicom-</p><p>ponent training –were reported to lead to improvements in global cognition without clear differences</p><p>404 Trends in Neurosciences, June 2024, Vol. 47, No. 6</p><p>Image of Figure 1</p><p>CellPress logo</p><p>Box 2. Exercise training prescription parameters</p><p>In RCTs of exercise, training parameters include type, frequency, intensity, and session duration. These parameters are</p><p>defined as follows:</p><p>• Type: refers to distinct exercise modalities characterized by the expected physiological effect of training [163]. These</p><p>chiefly include aerobic, resistance, and multicomponent training. Aerobic training targets changes in cardiorespiratory</p><p>fitness and includes activities such as walking, running, and cycling. Resistance training targets changes in muscular</p><p>strength, power, or endurance and includes activities such as weightlifting and body weight exercises. Multicompo-</p><p>nent training combines both aerobic training and resistance training or any combination of other forms of exercise train-</p><p>ing (e.g., balance and flexibility) for overall physical fitness benefits.</p><p>• Frequency: denotes how often exercise training is performed and is commonly measured as the number of exercise</p><p>sessions prescribed per week [163].</p><p>• Intensity: the targeted level of exertion during exercise training [163,164]. Aerobic training intensity is typically assessed</p><p>via achieved percentage of maximum heart rate or maximal oxygen uptake (VO2max). Resistance training intensity can</p><p>be measured using the percentage of repetition maximum achieved (%RM) or number of repetitions of a given exer-</p><p>cise. For both aerobic and resistance training, intensity can also be assessed indirectly via rate of perceived exertion.</p><p>• Session duration: the amount time of exercise training is performed, usually measured asminutes or hours per exercise</p><p>session [163].</p><p>Trends in Neurosciences</p><p>between exercise types [9,10]. However, in those living with MCI, interventions which incorporate el-</p><p>ements of resistance training are more efficacious in improving global cognition and domain-specific</p><p>functions [31,35], with notable effects on executive functions, memory [35], and attention [31,35].</p><p>Whether these effects are also evident in individuals living with dementia is still equivocal [34].</p><p>Exercise frequency, intensity, and session duration are also key parameters in exercise prescription</p><p>(Box 2). In humans, evidence from RCTs that systematically manipulate exercise parameters</p><p>is scarce. Findings assessing the influence of these parameters are almost exclusively based</p><p>on meta-analytic studies [9,10,12,34] and may be influenced by differences in how exercise</p><p>parameters are categorized and analyzed (Box 3). Thus, the current data do not provide a clear</p><p>understanding of whether training parameters influence exercise-induced neurobiological and</p><p>cognitive changes (Box 3). This conclusion underscores the need for RCTs focused onmodulating</p><p>training parameters. Outcomes from such RCTs will allow better understanding of what exercise</p><p>prescription (i.e., type of exercise, how often, how intense, and for how long) is ideal to exert greater</p><p>improvements on cognitive and brain health outcomes.</p><p>The ‘who’: exercise in individuals at risk of cognitive impairment and</p><p>neurodegenerative diseases</p><p>In the previous sections we summarized the effects of exercise in cognitively unimpaired and</p><p>impaired individuals. Here, we complement these discussions by reviewing how exercise may</p><p>impact individuals with health conditions which increase their risk of cognitive impairment and</p><p>neurodegenerative diseases.</p><p>Non-communicable chronic conditions</p><p>Diabetes and hypertension are highly prevalent in middle-aged and older individuals [43,44] and</p><p>are significant risk factors for cognitive impairment [33]. Accumulating evidence from meta-</p><p>analyses indicates that exercise improves global cognition in older individuals living with type</p><p>2 diabetes [45,46], and data from one RCT also showed improvements in memory [47]. Reducing</p><p>blood pressure is an effective strategy to mitigate cognitive impairment and promote brain health</p><p>[48]. Exercise is highly efficacious in reducing blood pressure levels [49]; however, its effects on</p><p>cognitive and brain health outcomes in individuals with hypertension remains largely unexplored.</p><p>While no effects of aerobic exercise on cognitive outcomes were found in one RCT on individuals</p><p>with mild hypertension [50], improvements in hippocampal cerebral blood flow after aerobic</p><p>training was reported in individuals with hypertension</p><p>with genetic risk for Alzheimer’s disease</p><p>Trends in Neurosciences, June 2024, Vol. 47, No. 6 405</p><p>CellPress logo</p><p>Box 3. Influence of exercise parameters on cognition in aging individuals</p><p>Modulation of key training parameters is thought influence the robustness and magnitude of exercise effects. A summary</p><p>of the literature on the topic follows:</p><p>• Frequency: one meta-analysis showed three sessions/week of aerobic training improved episodic memory in individ-</p><p>uals without dementia, whereas one or two sessions/week or four to seven sessions/week had no statistically signif-</p><p>icant effect [23]. By contrast, another meta-analysis in individuals with any type of cognitive impairment showed that</p><p>more than four sessions/week of exercise improved cognitive outcomes [11]. Several meta-analyses report no</p><p>moderating effect of frequency [9,10,12,23,34]. In sum, evidence is still equivocal regarding the effect of exercise fre-</p><p>quency on cognition.</p><p>• Intensity: according to one meta-analysis, moderate- or high-intensity exercise benefits cognitive outcomes compared</p><p>with low-intensity exercise [10]. However, a moderating effect of intensity has not been consistently found</p><p>[11,12,23,34]. The discrepancies may result, in part, from the fact that not all RCTs comprehensively report data on in-</p><p>tensity monitoring, adherence, and fidelity. Data from RCTs directly comparing different exercise intensities show</p><p>mixed effects [165–167]. One RCT showed that high-intensity aerobic training improved working memory versus mod-</p><p>erate-intensity training [165], but others found no differences between high- or moderate-intensity aerobic training</p><p>on cognition [166,167].</p><p>• Session duration: exercise sessions lasting >90 min (versus 30 or 60 min/session) improved cognitive outcomes in</p><p>a meta-analysis of cognitively unimpaired individuals [12]; however, these effects were observed only in interventions</p><p>lasting longer than 22 weeks. A meta-analysis reported 45–60 min/session improved cognitive outcomes versus <45</p><p>min/session or >60 min/session durations [10]. In individuals with any type of cognitive impairment, session duration <30</p><p>min/session improved cognitive outcomes versus 30–45 min/session or >45 min/session [11]. Despite this, several other</p><p>meta-analyses have not reported moderating effects of session duration [9,10,12,23,34].</p><p>These findings do not present a clear picture of whether training parameters influence cognition. As evidence fromRCTs directly</p><p>modulating exercise parameters is scarce, current interpretations of how frequency, intensity, and session duration influence out-</p><p>comes rely on meta-analytic evidence. Notably, parameters are likely interdependent, and the effect of manipulating one param-</p><p>eter (e.g., increasing intensity) should be considered in the context of how itmay impact others (e.g., shortening session duration).</p><p>Modulating exercise parameters can also influence adherence to training protocol, limiting potential for observing intervention ef-</p><p>fects. Thus, modulation of training parameters at the RCT level in future research would more clearly indicate whether exercise</p><p>has dose-dependent effects on cognitive and brain health outcomes.</p><p>Trends in Neurosciences</p><p>[51]. These promising findings suggest that reducing the burden of diabetes or hypertension via</p><p>exercise could reduce dementia risk [33]. Importantly, hypertension and diabetes play a substantial</p><p>role in the etiology of cerebral small vessel disease [52] and influence Alzheimer’s disease neuropa-</p><p>thology [53,54]. Exercise could aid in preventing onset of downstream neuropathological</p><p>processes underlying these neurodegenerative conditions in individuals with hypertension</p><p>and diabetes [52].</p><p>Below we discuss how exercise could also be a strategy to manage pathology burden and ben-</p><p>efit cognition in individuals already living with cerebral small vessel disease or early Alzheimer’s</p><p>disease neuropathology.</p><p>Cerebral small vessel disease</p><p>Cerebral small vessel disease is a leading cause of vascular cognitive impairment and dementia</p><p>[39,52,55]. The disease is characterized by vascular-related damage in the brain, especially</p><p>white matter hyperintensities [56]. One RCT showed that aerobic training improved global cogni-</p><p>tion in this population [57]. Training-induced cardiorespiratory fitness in this RCT correlated with</p><p>maintenance of cortical thickness, which predicted improvements in executive functions [58].</p><p>This RCT also showed aerobic training improved neural activation measured via task-based func-</p><p>tional magnetic resonance imaging (fMRI) in cortical regions associated with executive functions</p><p>[59]. Research on other types of exercise in cerebral small vessel disease is scarce. Preliminary</p><p>findings suggest that resistance training slows progression of white matter hyperintensities in</p><p>cognitively unimpaired individuals [60,61]. This indicates that exercise can be a disease-</p><p>modifying approach in this population; however, larger RCTs emphasizing MRI-based neuro-</p><p>pathological markers and cognitive outcomes are needed.</p><p>406 Trends in Neurosciences, June 2024, Vol. 47, No. 6</p><p>CellPress logo</p><p>Trends in Neurosciences</p><p>Prodromal stage of Alzheimer’s disease</p><p>Alzheimer’s disease is characterized by a long prodromal stage with gradual accumulation of</p><p>neural-impairing β-amyloid plaques and tau neurofibrillary tangles [62]. β-Amyloid clearance</p><p>has been the main target for treatment of Alzheimer’s disease [63]. In animal models, exercise</p><p>was shown to reduce β-amyloid aggregates [64,65], mitigating cognitive dysfunction [66].</p><p>Targeting Alzheimer’s disease neuropathology in the prodromal stage of the disease could</p><p>offer better prospects for prevention [67] as β-amyloid accumulation often starts decades before</p><p>disease diagnosis [62]. The impact of exercise on β-amyloid accumulation in older individuals</p><p>is still unclear [68,69]. Two RCTs showed no effects of aerobic training on positron emission</p><p>tomography (PET)-measured β-amyloid burden or cognition [68,69]. However, aerobic training</p><p>slowed hippocampal atrophy in participants with higher β-amyloid load [68], suggesting a poten-</p><p>tial benefit of exercise in those with greater Alzheimer’s disease biomarker burden. Additional</p><p>RCTs evaluating the effect of other types of exercise on β-amyloid are needed [70]. It would be</p><p>valuable to assess the impact of resistance training, considering that there is a neurobiological</p><p>basis from animal models for resistance training-driven reduction of β-amyloid aggregates [64].</p><p>A major obstacle in the field has been the need to use costly (PET) or invasive (cerebrospinal</p><p>fluid) biomarkers limited to specialized medical centers [71]. Recent developments in blood-</p><p>based biomarkers for Alzheimer’s disease could allow for more cost-effective assays to screen</p><p>eligible high-risk individuals in the prodromal disease stages (although access to highly specialized</p><p>equipment may be limited in some settings) [71,72]. Considering this, future RCTs could feasibly</p><p>test the efficacy of exercise on biomarkers of Alzheimer’s disease neuropathology.</p><p>The ‘when’: critical windows to utilize exercise for cognitive and brain health</p><p>outcomes</p><p>Most RCTs of exercise and brain health have focused on late adulthood [12] with little research in</p><p>midlife (e.g., 40–59 years). Midlife represents a critical period during which accumulation of</p><p>cardiovascular risk factors are strongly associated with cognitive impairment and brain health</p><p>outcomes later in life [33,73–76]. Neuropathological markers of Alzheimer’s disease also start</p><p>to accumulate in this stage of life (e.g., β-amyloid deposition) [67,77]. In females, midlife com-</p><p>prises a critical window due in part to perimenopause. Perimenopause has been argued to</p><p>negatively impact brain health [78,79] and contribute to female’s greater lifetime risk for dementia</p><p>[80,81]. Compared with age-matched males, females may experience widespread changes in</p><p>brain structure and function during perimenopause [81,82]. These changes include reductions in</p><p>cerebral glucose metabolism and</p><p>gray and white matter volumes, as well as greater β-amyloid</p><p>and tau deposition [78,83,84]. There is also evidence from an observational study in 2124 females</p><p>suggesting declines in episodic memory and processing speed across perimenopause [85].</p><p>Although these declines resolve for some females later in the postmenopause period [81,83],</p><p>many individuals experience persisting symptoms and are at increased risk of long-term cognitive</p><p>impairment [81]. Mechanisms underlying these declines remain unclear, but plausible explanations</p><p>involve changes in ovarian hormone secretion, including 17β-estradiol [78,79]. In the brain, 17β-</p><p>estradiol has neuroprotective effects, including inhibition of β-amyloid formation and reduction of</p><p>oxidative cell damage [86–88]. It is thus conceivable that dysregulation of 17β-estradiol during</p><p>perimenopause could underlie major changes in brain physiology and contribute to accelerating</p><p>cognitive decline [81].</p><p>In this context, preventive interventions implemented in midlife could exert clinically meaningful</p><p>short- and long-term protective effects. One RCT with individuals aged 50–70 years showed</p><p>positive effects of aerobic training on executive functions and attention/processing speed tasks</p><p>[89]. Aerobic training also improved executive functions and increased prefrontal cortex thickness</p><p>in an RCT with individuals aged 20–67 years [90]. The effect of other types of exercise is unclear.</p><p>Trends in Neurosciences, June 2024, Vol. 47, No. 6 407</p><p>CellPress logo</p><p>Trends in Neurosciences</p><p>We are also unaware of any RCTs that have investigated the impact of exercise on cognitive</p><p>outcomes during perimenopause. Nonetheless, the emerging evidence supports the positive</p><p>effects of exercise on cognition and cortical gray matter in midlife [89,90], which brings about the</p><p>notion that neuroplasticity earlier in life could offset cognitive impairment as individuals age. This is</p><p>aligned with the concept of building cognitive and brain reserve in this stage of life to alleviate the</p><p>impact of age- and pathology-related neurodegeneration in older adulthood [91]. Support for</p><p>this hypothesis is needed in forthcoming research, including in perimenopausal females.</p><p>The ‘how’: neurobiological mechanisms of the impact of exercise on cognitive</p><p>and brain health outcomes</p><p>Previous reviews have comprehensively summarized potential molecular mechanisms underlying</p><p>exercise effects on cognition [42,92,93]. Here, we focus on MRI measures which are more</p><p>commonly implemented in RCTs to help elucidate how exercise impacts cognition in humans.</p><p>Exercise and gray matter structural changes</p><p>Assessing the impact of exercise on cerebral gray matter via MRI has been central in RCTs.</p><p>Among key measures of brain health, gray matter changes can offer important insights into</p><p>neurogenerative processes [94]. A foundational study in mice showed that voluntary aerobic</p><p>training enhanced hippocampal neurogenesis, long-term potentiation, and learning [95]. These</p><p>effects likely result from exercise upregulation of neurotrophic factors such as brain-derived</p><p>neurotrophic factor (BDNF) [96]. In humans, one RCT in cognitively unimpaired older individuals</p><p>showed aerobic training increased hippocampal volume, which correlated with increased</p><p>BDNF [26]; however, this effect has not been consistently observed [97]. Notably, meta-</p><p>analyses examining exercise across the lifespan and in clinical samples show positive effects</p><p>on the hippocampus [98,99]. For instance, one RCT found that aerobic training increased hippo-</p><p>campal volume in females with MCI [100]. Clinical samples may thus be more sensitive to</p><p>exercise-induced increases in hippocampal neuroplasticity. Evidence in individuals living with</p><p>dementia, however, is less clear [101]. Aerobic training also increased whole-brain and regional</p><p>(e.g., frontal, temporal, and cingulate) gray matter volumes in the cortex of cognitively unimpaired</p><p>individuals [18]. These global effects are thought to reflect neurobiological adaptations, including</p><p>synaptogenesis, axonal sprouting, dendritic branching/arborization, and angiogenesis [42].</p><p>Research is needed to assess the impact of other exercise types on the hippocampus and other</p><p>gray matter structures [102,103]. Resistance training is known to influence neurotrophic factors</p><p>such as insulin-like growth factor I [104] and BDNF [96,104,105], both of which facilitate</p><p>neuroplasticity and hippocampal neurogenesis [93]. However, there is inconclusive evidence that</p><p>resistance training impacts whole-brain or regional gray matter volume [100,102,103,106–108].</p><p>This may reflect the limited number of studies measuring the impact of resistance training on</p><p>MRI markers of brain health in older individuals [102].</p><p>Exercise effects on white matter structure and brain function outcomes</p><p>Despite promising results from individual RCTs [18,26], findings frommeta-analyses suggest that</p><p>the effects of exercise on gray matter structure in humans may be limited [97,102,109]. Study of</p><p>alternative mechanisms could help elucidate how exercise induces cognitive improvements. Cur-</p><p>rent literature suggests the role of exercise in enhancing white matter integrity and myelination, as</p><p>well as gray matter changes related to neurovascular function, network functional connectivity,</p><p>and neuronal efficiency [13].</p><p>One RCT of dance-based aerobic training increased white matter integrity in the fornix [110] and</p><p>improved a proxy measure of myelin content in the whole-brain white matter and genu of the</p><p>408 Trends in Neurosciences, June 2024, Vol. 47, No. 6</p><p>CellPress logo</p><p>Trends in Neurosciences</p><p>corpus callosum [111]. Similar findings have been reported in white matter volume in the corpus</p><p>callosum, frontal, and parietal regions [112]. Another RCT showed that resistance training slowed</p><p>down white matter atrophy [106] and reduced white matter hyperintensities progression [60].</p><p>Aerobic training increased neuronal activation measured via fMRI in regions of the prefrontal</p><p>and parietal cortices during an executive function task [19]. Another RCT showed that aerobic</p><p>training increased resting-state functional connectivity measured via fMRI between regions</p><p>involved in the default mode network and frontal executive network [113]. Resistance training</p><p>has been shown to benefit neuronal efficiency during an executive function task paradigm in</p><p>older females [114]. Effects were observed both in the left insula extending into lateral orbital</p><p>frontal cortex and left middle temporal gyrus [114]. Resistance training also imparted functional</p><p>plasticity during an associative memory task paradigm in older females living with MCI [115].</p><p>These effects were observed in the right frontal pole, right lingual, and right occipital-fusiform</p><p>gyri. Notably, most of this evidence regarding the impact of exercise on brain structural and</p><p>functional outcomes comes from RCTs in cognitively unimpaired individuals and those with</p><p>MCI. Evidence in individuals living with dementia and those with non-communicable chronic</p><p>conditions or in early stages of neurodegenerative diseases is very limited [116,117]. This under-</p><p>scores the need for further focused research.</p><p>A future outlook for clarifying the effects of exercise on cognitive and brain health</p><p>outcomes in aging</p><p>Limitations and knowledge gaps in relation to population trials</p><p>Exercise trials to date show large variation in critical elements like training parameters, adherence</p><p>and fidelity, sample characteristics, outcome assessments, and control/comparator conditions</p><p>[9,10,12,34]. These sources of variability can contribute to divergent findings and modest effect</p><p>sizes observed on cognitive [15,109] and brain health measures [68,97,102,109,118,119].</p><p>Of particular interest, the choice of control conditions may be a key driver of these modest effect</p><p>sizes [10,15]. Meta-analyses show that the effect of exercise on cognition is larger when com-</p><p>pared with no-contact controls (e.g., wait-list) and smaller when compared with education</p><p>(e.g., health education sessions) or active (e.g., stretch)</p><p>controls [10,15]. This suggests that no-</p><p>contact controls fail to account for key confounders of exercise known to influence brain health,</p><p>such as increased socialization, increased physical activity due to travel requirements to the</p><p>research/exercise center, and perceived benefit. Therefore, inclusion of no-contact controls could</p><p>inflate the effect size of exercise and contribute to greater heterogeneity across investigations, as</p><p>well as influence the interpretation of potential mediators, moderators, andmechanisms associated</p><p>with cognitive and neuroplastic adaptations. Teasing out the effects of confounders would allow</p><p>better measurement of the effects of exercise and inform the design of more effective interventions.</p><p>As such, we recommend that future trials should avoid using no-contact control conditions.</p><p>Importantly, the modest effects of exercise observed to date may also reflect our still evolving</p><p>knowledge of how the four pillars outlined in this review (i.e., ‘what’, ‘who’, ‘when’, and ‘how’)</p><p>influence exercise efficacy for cognition. A better understanding of these pillars will provide the</p><p>foundation for prescribing tailored exercise interventions with potential to elicit greater benefits</p><p>for cognitive and brain health outcomes. A comprehensive Phase 3 clinical trial designed to</p><p>assess the effect of exercise dose parameters is currently under way [120]. The trial will evaluate</p><p>the impact of moderate- to- vigorous aerobic training administered at different doses (225 min/</p><p>week versus 150min/week) compared with an active control group (150min/week) on cognition,</p><p>blood-based biomarkers, and key neuroimaging measures (PET, MRI) among other outcomes in</p><p>cognitively unimpaired older individuals [120]. Two ongoing large RCTs employ a factorial design</p><p>to directly assess what type of exercise is more efficacious for improving cognitive and brain</p><p>Trends in Neurosciences, June 2024, Vol. 47, No. 6 409</p><p>CellPress logo</p><p>Trends in Neurosciences</p><p>health outcomes [121,122]. Both RCTs have similar designs and will investigate the effects of</p><p>either aerobic training, resistance training, or both compared with active controls in cognitively</p><p>unimpaired individuals [122] or in those living with MCI [121]. These trials will help address</p><p>some of the major limitations in the current literature [120–122].</p><p>Ongoing and future RCTs should also carefully consider the influence of biological sex and gender</p><p>on exercise effects. There are differences between males and females in the incidence and preva-</p><p>lence of cognitive impairment and dementia [80]. Thus, biological sex may influence the effects of</p><p>exercise as suggested by moderation effects in several meta-analyses [12,14,123]. For example,</p><p>sex-based differences on the effects of exercise have been observed in executive functions and</p><p>visuospatial functions favoring females, and word fluency favoring males [14]. By contrast, a</p><p>meta-analysis combining data from younger and older individuals found that females benefitted</p><p>less than males [12]. These results are limited by the fact that meta-analyses are unable to assess</p><p>disaggregated effects between sexes. Future RCTs should be designed to assess sex-specific</p><p>effects by recruiting equal numbers of males and females or randomize stratified by sex, and report</p><p>disaggregated results. AnRCT powered to assess sex differences is currently ongoing andwill help</p><p>clarify current findings [121]. Furthermore, research on the influence of gender and brain health is</p><p>underdeveloped [80,124]. Gender comprises one’s self-identity, which may be influenced by</p><p>personal choices as well as sociocultural, environmental, and behavioral factors [125]. To our</p><p>knowledge, no study has investigated the influence of gender on the effects of exercise on cogni-</p><p>tive and brain health outcomes. Therefore, there is a need for future research on the effects of</p><p>exercise that considers gender and biological sex in study design and analyses [124].</p><p>Understanding the relationship between cognitive changes and neurobiological adaptations</p><p>It is still unclear whether and how exercise-induced neuroplasticity translates into better cogni-</p><p>tion. Onemeta-analysis found that exercise had a positive overall effect on several neurobiological</p><p>markers, but these improvements did not correlate with cognition [13]. Critically, RCTs have not</p><p>been designed with neuroimaging markers of brain health as the primary outcome, thus most are</p><p>underpowered for these analyses. This, along with methodological differences, might reflect</p><p>divergent findings in the literature, especially regarding the effects of exercise on gray matter</p><p>volume changes [97,99,102]. Beyond these limitations, it is also plausible that gray matter</p><p>changes after exercise follow an expansion–renormalization model for neuroplastic adaptations</p><p>[126,127]. This model postulates that volumetric brain changes induced by training could result</p><p>from an initial increase in gray matter structure reflecting processes like synaptogenesis, glial</p><p>cell proliferation, dendritic arborization, and angiogenesis [126,127]. This initial growth, however,</p><p>would be followed by a selective pruning, leading to a renormalization of gray matter structure</p><p>either partially or entirely to baseline levels [126,127]. Considering that the neuroplastic adaptions</p><p>would reflect tissue efficiency, this renormalization would accompany continued improvement or</p><p>maintenance of cognition [126,127] and gray matter tissue that is typically deteriorating in older</p><p>individuals [98,99]. Whether this model applies to exercise and is affected by age- or</p><p>pathology-related changes in the brain remains poorly understood. Another possibility could be</p><p>a differential time course of behavioral and brain health outcomes, such that some of the struc-</p><p>tural and functional adaptations might precede cognitive changes that result from exercise.</p><p>These hypotheses need further investigation.</p><p>Underexplored mechanisms of exercise effects on brain health</p><p>Current knowledge of molecular and cellular mechanisms underlying the impact of exercise on</p><p>brain health is still rudimentary, especially in the context of older individuals. Emerging evidence</p><p>points to exercise-induced secretion of cytokines in skeletal muscles as an area requiring further</p><p>investigation. Muscular contractions during exercise produce and secrete a category of cytokines</p><p>410 Trends in Neurosciences, June 2024, Vol. 47, No. 6</p><p>CellPress logo</p><p>Trends in Neurosciences</p><p>referred to as myokines [128]. These myokines are synthesized by myocytes and released into</p><p>the bloodstream and are thought to mediate crosstalk between the muscles and other organs,</p><p>including the brain [129]. For example, irisin is a myokine produced during exercise which crosses</p><p>the blood–brain barrier and stimulates BDNF expression in primary cortical neurons and the</p><p>hippocampus, hence promoting downstream processes such as synaptic plasticity and neuronal</p><p>differentiation [130,131]. Exercise-induced irisin secretion plays a substantial role in rescuing</p><p>synaptic plasticity and memory performance in animal models of Alzheimer’s disease [132].</p><p>Cathepsin B is another myokine that passes through the blood–brain barrier and enhances</p><p>BDNF production, which could then promote neuroplasticity, memory, and learning [129].</p><p>Thus, it is plausible that myokine signaling underlies the benefits of exercise on the brain. Notably,</p><p>evidence shows that physical activity and exercise promote the myokine response, while physical</p><p>inactivity impairs the response [133].</p><p>Potential genetic moderators</p><p>The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease</p><p>[134] and maymoderate exercise effects on cognition [135]. It has been postulated that APOE ε4</p><p>carriers experience greater cognitive improvement from exercise versus non-carriers [135]. A</p><p>current model proposes that exercise ameliorates APOE ε4-related neural-impairing processes</p><p>like poor β-amyloid degradation, downregulation of neurotrophic factors (e.g., BDNF), neuro-</p><p>inflammation,</p><p>and impaired glucose metabolism [136]. Although evidence to support this</p><p>model is still equivocal [137], a small RCT of aerobic training in people with Alzheimer’s disease</p><p>revealed that executive functions improved to a greater extent in APOE ε4 carriers versus controls</p><p>without changes in non-carriers [41]. APOE ε4 carriers also showed greater post-intervention</p><p>upregulation of BDNF measured using neuron-derived extracellular vesicles in plasma, implicating</p><p>BDNF signaling as a pathway for cognitive improvements [40]. By contrast, another RCT in younger</p><p>adults reported that only APOE ε4 non-carriers improved executive functions after aerobic training</p><p>[90]. This contrast could be explained by age and clinical diagnoses across investigations</p><p>[40,41,90], with exercise likely favoring older APOE ε4 carriers with cognitive impairment. Future</p><p>work is needed to consolidate these findings.</p><p>The BDNF Val66Met single-nucleotide polymorphism is associated with cognitive and brain</p><p>health outcomes [138–140]. Higher physical activity is associated with larger hippocampal and</p><p>temporal lobe volumes in BDNF Val/Val homozygotes, while the opposite association is observed</p><p>in Met carriers [141]. Carrying the Val66Met polymorphism is thought to reduce mature BDNF</p><p>secretion in response to exercise, thereby limiting neuroplasticity and cognitive improvements</p><p>[140,142]. Evidence from RCTs assessing the moderating effect of Val66Met is still unclear due to</p><p>the limited number of studies and small samples sizes [140]. While some RCTs report no</p><p>moderating effects [143–145], one RCT reported that aerobic training improved executive functions</p><p>in female Val/Val carriers versus controls, but had the opposite effect in male Val/Val carriers and</p><p>femaleMet carriers [142]. This preliminary evidence underscores the relevance of the Val66Met poly-</p><p>morphism in influencing the effect of exercise on cognitive and brain health outcomes.</p><p>Genotyping in future RCTs will allow for a greater understanding of the intricate relationship</p><p>between genetic factors and neurobiological response to exercise. Notably, understanding</p><p>gene–gene interactions will be particularly relevant, as the BDNF Val66Met polymorphism, for</p><p>instance, interacts with APOE ε4 allele to influence brain health [146,147].</p><p>Increasing participant diversity and inclusion in exercise population studies</p><p>Race and ethnicity play a significant role in dementia risk. This is especially evident in the context</p><p>of countries with large racial and ethnic diversity like in the United States [148,149], where African</p><p>Trends in Neurosciences, June 2024, Vol. 47, No. 6 411</p><p>CellPress logo</p><p>Trends in Neurosciences</p><p>Outstanding questions</p><p>Can exercise training offset long-term</p><p>cognitive impairment and reduce the</p><p>risk of dementia?</p><p>Are there specific combinations of</p><p>exercise parameters (i.e., type, fre-</p><p>quency, intensity, and duration) that</p><p>would confer the greatest benefits to</p><p>cognitive and brain health outcomes</p><p>in late adulthood?</p><p>Can exercise training confer benefits to</p><p>cognitive and brain health outcomes in</p><p>midlife, and if so, are such potential</p><p>benefits also reflected at older ages?</p><p>Can exercise training confer benefits to</p><p>cognitive and brain health outcomes in</p><p>individuals living with chronic conditions</p><p>which are related to dementia risk</p><p>(e.g., diabetes and hypertension)?</p><p>Considering that sex, gender, race/</p><p>ethnicity, and socioeconomic status</p><p>influence risk of cognitive impairment</p><p>and dementia, would these factors also</p><p>moderate the effects of exercise on</p><p>cognitive and brain health outcomes?</p><p>Can exercise training mitigate</p><p>accumulation of Alzheimer’s disease</p><p>pathology in prodromal stages of</p><p>the disease and slow progression</p><p>of disease-related neurogenerative</p><p>processes?</p><p>Does exercise affect cognition in</p><p>individuals with cognitive impairment</p><p>via selective effects on underlying</p><p>neuropathology (e.g., via β-amyloid</p><p>clearance), via neuroplastic adaptations</p><p>in healthy tissue (e.g., new synapses),</p><p>or both?</p><p>Are exercise-induced neuroplastic</p><p>adaptations associated with improve-</p><p>ments in global cognition and domain-</p><p>specific functions?</p><p>What is the ideal timeframe to measure</p><p>neuroplastic adaptations after exercise</p><p>in older individuals?</p><p>Does the effect of exercise on gray</p><p>matter structure follow an expansion–</p><p>renormalization model for neuroplastic</p><p>adaptations?</p><p>Are APOE ε4 and BDNF Val66Met</p><p>moderators of the effects of exercise on</p><p>cognitive and brain health outcomes?</p><p>Americans/Blacks and Latinxs show higher dementia rates than non-Hispanic Whites [148,149].</p><p>This might be explained by socioeconomic, cultural, and lifestyle factors uniquely interacting with</p><p>neuropathology (e.g., β-amyloid) and driving cognitive impairment across different groups</p><p>[150–152]. Despite this different risk profile, there is little research investigating the impact of</p><p>exercise in these populations [33]. The racial and ethnic makeup of previous exercise RCTs is</p><p>often unclear, andwe are unaware of anymeta-analyses assessing themoderating role of these fac-</p><p>tors on the impact of exercise on cognitive and brain health outcomes. One small RCT in African</p><p>Americans found no benefits of a combined physical activity, resistance training, and balance inter-</p><p>vention on global cognition and domain-specific functions [153]. A pilot RCT of a dance-based</p><p>program showed modest improvements on inhibition in African American females [154]. Evi-</p><p>dence from larger trials which also include other racial and ethnic groups is warranted.</p><p>Socioeconomic status may also be an important moderator of the effects of exercise on cognitive</p><p>and brain health outcomes [155]. Individuals with low socioeconomic status (e.g., low income</p><p>and education) are at greater risk for cognitive impairment and dementia compared with their</p><p>high socioeconomic status counterparts [156]. Lifestyle factors such as lower levels of physical</p><p>activity in those with low socioeconomic status might contribute to the heightened risk for cogni-</p><p>tive impairment and dementia [157,158]. We are unaware of any RCTs assessing the influence of</p><p>socioeconomic status on the effects of exercise on cognitive and brain health outcomes. How-</p><p>ever, we speculate that individuals with low socioeconomic status might be underrepresented</p><p>in exercise RCTs, as they may have less access to the resources facilitating participation in</p><p>these studies. This possibility requires rigorous assessment, and strategies for more balanced</p><p>representation across socioeconomic status groups might be needed in designing future</p><p>exercise RTCs.</p><p>Concluding remarks</p><p>The cumulative evidence discussed in earlier sections suggests that exercise benefits cognition in</p><p>older individuals. However, the observed effects are small overall, and this is likely due to high var-</p><p>iation in training parameters across RCTs and high interindividual variability in response to exer-</p><p>cise. To reap greater benefits of exercise on cognitive and brain health outcomes, better</p><p>understanding is required of moderators, mediators, interaction effects, and contextual factors</p><p>(see Outstanding questions). This evidence will lead to more precise exercise recommendations</p><p>for individuals with similar characteristics.</p><p>Thus, there is a need for interdisciplinary research efforts to advance our understanding of ‘what’</p><p>(e.g., type of exercise) should be recommended, ‘for whom’ (e.g., female versus male), and</p><p>‘when’ (e.g., midlife versus later life). All three of these will need to be informed by prerequisite</p><p>knowledge regarding ‘how’ exercise benefits cognitive and brain health.</p><p>Specifically, it remains undetermined whether exercise counteracts neurodegeneration in</p><p>individuals with chronic health conditions that increase the risk of cognitive impairment and</p><p>dementia. In this regard, evidence suggests that exercise is a potential strategy to prevent</p><p>or manage cerebral small vessel disease, a leading cause of vascular dementia strongly</p><p>associated with diabetes and hypertension. Anchored on evidence from animal studies,</p><p>exercise may also counteract accumulation of Alzheimer’s</p><p>disease pathology markers early</p><p>in the course of the disease and slow Alzheimer’s disease progression. Beyond investigating</p><p>the impact of exercise in late adulthood, exercise trials targeting middle-aged individuals,</p><p>including perimenopausal females, could also offer insights regarding the influence of exer-</p><p>cise on cognitive and brain outcomes, reserve, and the long-term risk of cognitive impairment</p><p>and dementia.</p><p>412 Trends in Neurosciences, June 2024, Vol. 47, No. 6</p><p>CellPress logo</p><p>Trends in Neurosciences</p><p>Is exercise-induced myokine secretion</p><p>a key pathway by which exercise pro-</p><p>motes neuroplastic adaptations and</p><p>cognitive improvements?</p><p>With regard to mechanisms, many of the studies to date have focused on gray matter structural</p><p>changes. The overall evidence suggests exercise, especially aerobic training, may impact gray</p><p>matter structures including the hippocampus. However, these effects have not been consistently</p><p>demonstrated. Emerging evidence postulates that exercise may have additional neuroplastic</p><p>effects such as enhancing white matter integrity and myelination as well as improving neurovascular</p><p>function, neuronal connectivity and activation. An important knowledge gap is whether or how</p><p>neuroplastic effects translate into cognitive improvements, and which molecular pathways underlie</p><p>neuroplasticity. Exercise-induced secretion of myokines like irisin and cathepsin B are potential</p><p>molecular candidates for future research on this topic.</p><p>Key moderators of exercise effects on cognition and brain health outcomes remain understudied.</p><p>Some evidence suggests that biological sex modulates the effects of exercise, but little is known</p><p>about the role of factors such as gender, race/ethnicity, and socioeconomic status. APOE ε4 and</p><p>BDNF Val66Met are among the relevant genetic factors influencing cognition, but their role in</p><p>moderating exercise efficacy for cognitive and brain health outcomes remains elusive.</p><p>Finally, it is currently unknown whether exercise can elicit long-term, sustained benefits to cogni-</p><p>tion, and whether acquired gains require continuous training. Evidence from large ongoing RCTs</p><p>will help address some of themajor limitations in the current literature and help clarify the effects of</p><p>exercise on cognitive and brain health outcomes.</p><p>Acknowledgments</p><p>N.C.B.S.S. was funded with fellowship awards from the Canadian Institutes of Health Research, Michael Smith Health</p><p>Research BC, Canadians for Leading Edge Alzheimer Research, and StrokeCog. C.K.B. is a Tier II Canada Research Chair</p><p>in Neuroscience, Brain Health, and Exercise. K.I.E. was supported by research grants from the National Institutes of Health</p><p>(R35 AG072307, R01 AG053952, R01 AG060741). A.F.K. was supported by research grants from the National Institutes of</p><p>Health (R01 AG053952). T.L.A. is a Tier I Canada Research Chair in Healthy Aging.</p><p>Declaration of interests</p><p>The authors declare no competing interests in relation to this work.</p><p>References</p><p>1. Yaffe, K. et al. 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