DNA Methylation of BDNF and RASA2 Genes Is Associated With Cognitive Function in Postmenopausal Women With Breast Cancer.

OBJECTIVES: To determine associations among DNA methylation of brain-derived neurotrophic factor (BDNF) and RAS p21 protein activator 2 (RASA2) genes with processing speed and perceived cognitive function. SAMPLE & SETTING: This was a cross-sectional, secondary analysis of baseline data from a randomized controlled trial, the Exercise Program in Cancer and Cognition Study. METHODS & VARIABLES: Data included M values for DNA methylation of the BDNF and RASA2 genes; processing speed, objectively measured using the Grooved Pegboard and Digit Vigilance Test scores; and perceived cognitive function, self-reported using the Patient Assessment of Own Functioning Inventory. Regression analysis was conducted. RESULTS: Greater methylation of cg21291635 of the BDNF gene (p = 0.01) and cg20247102 of the RASA2 gene (p = 0.013) were associated with poorer processing speed, whereas greater methylation of cg20108357 of the BDNF gene (p < 0.001) and cg00567892 of the RASA2 gene (p = 0.019) were associated with better perceived cognitive function. IMPLICATIONS FOR NURSING: Gene methylation variations were demonstrated, suggesting the genes' potential roles and two possible distinct mechanisms of cognitive function in cancer. .

Association Between Genes in the Nuclear Factor E2-Related Factor 2 Antioxidative Response Elements Pathway and Cancer-Related Fatigue in Women With Early-Stage Breast Cancer.

OBJECTIVES: To explore genes in the nuclear factor E2-related factor 2 antioxidative response elements (Nrf2-ARE) signaling pathway using a multiomics approach for associations with variability of cancer-related fatigue (CRF) in postmenopausal women with early-stage hormone receptor-positive breast cancer. SAMPLE & SETTING: Postmenopausal women (N = 116) with early-stage hormone receptor-positive breast cancer were recruited from western Pennsylvania. METHODS & VARIABLES: Candidate genes from the Nrf2-ARE pathway were investigated for associations with CRF occurrence and severity. Associations were evaluated using logistic regression for occurrence and linear regression for severity. RESULTS: The rs2706110 TT genotype in NFE2L2 was associated with a 3.5-fold increase in odds of CRF occurrence. The cytosine-phosphate-guanine (CpG) site cg22820568 in PRDX1 was associated with CRF occurrence and severity. IMPLICATIONS FOR NURSING: Biomarkers based on Nrf2-ARE genes may help to identify women at increased risk for more severe CRF and to develop targeted interventions.

The Effects of High-Intensity Interval Training and Moderate Alcohol Consumption on Cognitive Performance-A Multidisciplinary Intervention in Young Healthy Adults.

BACKGROUND: The main purpose of this study was to determine the effects of a high-intensity interval training (HIIT) intervention in the context of moderate alcohol consumption on cognitive performance in healthy young adults. METHODS: We conducted a 10-week HIIT program along with four types of beverages with/without alcohol content. A total of 75 healthy adults (18-40 years old; 46% female) were allocated to either a control Non-Training group or an HIIT program group (2 days/week). Using block randomization, participants in the HIIT group were further allocated to an HIIT-Alcohol group (alcohol beer or sparkling water with vodka added, 5.4%) or an HIIT-NonAlcohol group (sparkling water or non-alcohol beer, 0.0%). The control group was instructed to maintain an active lifestyle but did not undergo any regular training. A comprehensive neuropsychological battery was used to evaluate cognitive performance (i.e., memory, working memory, processing speed, inhibitory control, and verbal fluency). Changes from baseline to week 10 were included in the main analyses. RESULTS: All groups improved in all neuropsychological measures (all p ≤ 0.001), independent of sex and alcohol consumption, with no statistical differences between groups (all p > 0.05). Furthermore, larger increases in maximal oxygen uptake were associated with greater improvements in processing speed, inhibitory control, and verbal fluency (all p < 0.050). CONCLUSIONS: Although the improvements found in cognitive performance cannot be attributed to the HIIT intervention, no significant impairments in cognitive functions were noted due to moderate alcohol intake. Furthermore, our results confirmed that exercise-induced physical fitness improvements were associated with cognitive performance enhancements in young healthy adults.

Effects of aerobic exercise on neurocognitive function in postmenopausal women receiving endocrine therapy for breast cancer: The Exercise Program in Cancer and Cognition randomized controlled trial.

Objective: The Exercise Program in Cancer and Cognition (EPICC) Study was a randomized controlled trial (RCT) designed to determine whether six months of moderate-intensity aerobic exercise improves neurocognitive function in women with breast cancer (BC) receiving endocrine therapy (ET). Methods: Postmenopausal women with hormone receptor+, early-stage BC, within two years post-primary therapy were randomized to the exercise intervention (six months, ≥150 minutes of moderate-intensity aerobic exercise/week) or usual care control condition. Outcomes were assessed at pre-randomization and after intervention completion. Groups were compared using linear mixed-effects modeling. Results: Participants (N=153) were X ¯ = 62.09 ± 8.27 years old, with stage I BC (64.1%) and a median of 4.7 months post-diagnosis. We found a group-by-time interaction (p=0.041) and a trend for the main effect of time (p=0.11) for processing speed with improved performance in the exercise group and no change in the controls. Similar main effects of time were observed for learning and memory (p=0.024) and working memory (p=0.01). Better intervention adherence was associated with improved processing speed (p=0.017). Conclusions: Six months of moderate-intensity aerobic exercise improves processing speed in postmenopausal women with BC receiving ET who initiate exercise within two years of completing primary therapy (surgery +/- chemotherapy). This is the first large-scale study to examine the effects of aerobic exercise on neurocognitive function in women with BC. Additional research is needed to address the long-term effects of aerobic exercise on cognitive function.

Human dopaminergic system in the exercise-cognition link.

While the dopaminergic system is important for cognitive processes, it is also sensitive to the influence of physical activity (PA). We summarize current evidence on whether PA-related changes in the human dopaminergic system are associated with alterations in cognitive performance, discuss recent advances, and highlight challenges and opportunities for future research.

Weakness Thresholds Are Differentially Linked to Cognitive Function by Obesity Status in Older Americans.

Background: Weakness can be operationalized with several thresholds, which in turn, could impact associations with cognitive impairment when considering obesity status. Objective: We examined the associations of absolute, normalized, and collective weakness thresholds on future cognitive impairment by obesity status in older adults. Methods: We performed a secondary data analysis on the 2006-2018 waves of the Health and Retirement Study. A spring-type dynamometer collected handgrip strength (HGS). Males were categorized weak if their HGS was <35.5-kg (absolute), <0.45-kg/kg (body mass normalized), or <1.05-kg/kg/m2 (body mass index (BMI) normalized), while females were defined as weak if their HGS was <20.0-kg, <0.337-kg/kg, or <0.79-kg/kg/m2. The modified Telephone Interview of Cognitive Status examined cognitive function. Persons scoring ≤10 had a cognitive impairment. Obesity was categorized as BMI ≥30 kg/m2. Results: We included 7,532 and 3,584 persons aged ≥65-years living without and with obesity, respectively. Those without obesity but beneath the absolute weakness threshold had 1.54 (95% confidence interval (CI): 1.24-1.91) greater odds for future cognitive impairment. Persons with obesity and beneath each threshold also had greater odds for future cognitive impairment: 1.89 (95% CI: 1.28-2.78) for absolute, 2.17 (95% CI: 1.02-4.62) for body mass normalized, and 1.75 (95% CI: 1.10-2.80) for BMI normalized. Older Americans without obesity but underneath all the weakness thresholds had 1.32 (95% CI: 1.00-1.74) greater odds for impairment in cognitive function, while persons with obesity had 2.76 (95% CI: 1.29-5.93) greater odds. Conclusions: There should be consideration for how body size and different weakness thresholds may influence future cognitive outcomes.

Physical exercise, cognition, and brain health in aging.

Exercise training is an important strategy to counteract cognitive and brain health decline during aging. Evidence from systematic reviews and meta-analyses supports the notion of beneficial effects of exercise in cognitively unimpaired and impaired older individuals. However, the effects are often modest, and likely influenced by moderators such as exercise training parameters, sample characteristics, outcome assessments, and control conditions. Here, we discuss evidence on the impact of exercise on cognitive and brain health outcomes in healthy aging and in individuals with or at risk for cognitive impairment and neurodegeneration. We also review neuroplastic adaptations in response to exercise and their potential neurobiological mechanisms. We conclude by highlighting goals for future studies, including addressing unexplored neurobiological mechanisms and the inclusion of under-represented populations.

Inhibitory control mediates the association between body mass index and math performance in children: A cross-sectional study.

BACKGROUND: Overweight and obesity affect more than 18% of children and adolescents in the world. Obesity-related associations with brain morphology might be associated with reduced efficiency of inhibitory control. This association highlights a possible mechanism by which obesity impacts intelligence and academic achievement. Prior work indicates a mediating effect of inhibitory control on the relationship between body mass index (BMI) and intelligence and academic achievement. However, although obesity is associated with impaired math performance, we do not know whether inhibitory control also mediates the relationship between BMI and math performance. This study tests the hypothesis that inhibitory control statistically mediates the relationship between BMI and math performance. METHODS: 161 children (9 to 13 years old, 80 female) participated in the present study. We evaluated BMI; math performance, in a test composed of 20 arithmetic equations of the type x = (a × b) - c; and inhibitory control through the Flanker test. We carried out Spearman correlation tests, hierarchical multiple linear regression, and tested the confidence of the model where inhibitory control statistically mediates the indirect association between BMI and math performance. Mediation analysis in this cross-sectional study aimed to improve understanding of indirect relationships and offer insights into possible causal connections. RESULTS: Better math performance and lower BMI were associated with greater accuracy on the inhibitory control test and greater accuracy on the inhibitory control test was associated with better performance on math test. We found an indirect association between higher BMI in children and impairments in math performance, that was mediated by inhibitory control (a: -0.008, p = 0.025; b: 7.10, p = 0.0004; c: 0.05, p = 0.592; c': 0.11, p = 0.238; Indirect Effect: -0.0599, 95% CI: -0.13, -0.005). CONCLUSIONS: An indirect association between higher body mass indices in children and impairments in math performance was detected, through the impact that BMI has on inhibitory control.

Sedentary behavior and lifespan brain health.

Higher levels of physical activity are known to benefit aspects of brain health across the lifespan. However, the role of sedentary behavior (SB) is less well understood. In this review we summarize and discuss evidence on the role of SB on brain health (including cognitive performance, structural or functional brain measures, and dementia risk) for different age groups, critically compare assessment approaches to capture SB, and offer insights into emerging opportunities to assess SB via digital technologies. Across the lifespan, specific characteristics of SB (particularly whether they are cognitively active or cognitively passive) potentially act as moderators influencing the associations between SB and specific brain health outcomes. We outline challenges and opportunities for future research aiming to provide more robust empirical evidence on these observations.

The effects of physical activity on white matter microstructure in children with overweight or obesity: The ActiveBrains randomized clinical trial / Los efectos de la actividad física sobre la microestructura de la sustancia blanca en niños con sobrepeso u obesidad: el ensayo clínico aleatorizado ActiveBrains

Background: Emerging research supports the idea that physical activity benefits brain development. However, the body of evidence focused on understanding the effects of physical activity on white matter microstructure during childhood is still in its infancy, and further well-designed randomized clinical trials are needed. Aim: This study aimed: (i) to investigate the effects of a 20-week physical activity intervention on global white matter microstructure in children with overweight or obesity, and (ii) to explore whether the effect of physical activity on white matter microstructure is global or restricted to a particular set of white matter bundles. Methods: In total, 109 children aged 8 to 11 years with overweight or obesity were randomized and allocated to either the physical activity program or the control group. Data were collected from November 2014 to June 2016, with diffusion tensor imaging (DTI) data processing and analyses conducted between June 2017 and November 2021. Images were pre-processed using the Functional Magnetic Resonance Imaging (MRI) of the Brain´s Software Library (FSL) and white matter properties were explored by probabilistic fiber tractography and tract-based spatial statistics (TBSS). Results: Intention-to-treat analyses were performed for all children who completed the pre-test and post-test DTI assessment, with good quality DTI data (N = 89). Of them, 83 children (10.06±1.11 years, 39 % girls, intervention group=44) met the per-protocol criteria (attended at least 70 % of the recommended sessions). Our probabilistic fiber tractography analysis did not show any effects in terms of global and tract-specific fractional anisotropy (FA) and mean diffusivity (MD) in the per-protocol or intention-to-treat analyses. Additionally, we did not observe any effects on the voxel-wise DTI parameters (i.e., FA and MD) using the most restricted TBSS approach (i.e., per protocol analyses and p-corrected image with a statistical...(AU)

Dose-response effects of exercise on mental health in community-dwelling older adults: Exploration of genetic moderators / Efectos dosis-respuesta del ejercicio sobre la salud mental en adultos mayores que viven en la comunidad: exploración de moderadores genéticos

Background/Objective: (1) Examine the role of exercise intensity on mental health symptoms in a community-based sample of older adults. (2) Explore the moderating role of genetic variation in brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) on the effects of exercise on mental health symptoms. Method: This study is a secondary analysis of a three-arm randomized controlled trial, comparing the effects of 6 months of high-intensity aerobic training vs. moderate-intensity aerobic training vs. a no-contact control group on mental health symptoms assessed using the Depression, Anxiety, and Stress Scale (DASS). The BDNF Val66Met polymorphism and APOE ε4 carrier status were explored as genetic moderators of exercise effects on mental health symptoms. Results: The exercise intervention did not influence mental health symptoms. The BDNF Val66Met polymorphism did not moderate intervention effects on mental health symptoms. APOE ε4 carrier status moderated the effect of intervention group on perceived stress over 6 months, such that APOE ε4 carriers, but not non-carriers, in the high-intensity aerobic training group showed a decline in perceived stress over 6 months. Conclusions: APOE ε4 carrier status may modify the benefits of high-intensity exercise on perceived stress such that APOE ε4 carriers show a greater decline in stress as a result of exercise relative to non-APOE ε4 carriers.(AU)

Dose-response effects of exercise on mental health in community-dwelling older adults: Exploration of genetic moderators.

Background/Objective: (1) Examine the role of exercise intensity on mental health symptoms in a community-based sample of older adults. (2) Explore the moderating role of genetic variation in brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) on the effects of exercise on mental health symptoms. Method: This study is a secondary analysis of a three-arm randomized controlled trial, comparing the effects of 6 months of high-intensity aerobic training vs. moderate-intensity aerobic training vs. a no-contact control group on mental health symptoms assessed using the Depression, Anxiety, and Stress Scale (DASS). The BDNF Val66Met polymorphism and APOE ε4 carrier status were explored as genetic moderators of exercise effects on mental health symptoms. Results: The exercise intervention did not influence mental health symptoms. The BDNF Val66Met polymorphism did not moderate intervention effects on mental health symptoms. APOE ε4 carrier status moderated the effect of intervention group on perceived stress over 6 months, such that APOE ε4 carriers, but not non-carriers, in the high-intensity aerobic training group showed a decline in perceived stress over 6 months. Conclusions: APOE ε4 carrier status may modify the benefits of high-intensity exercise on perceived stress such that APOE ε4 carriers show a greater decline in stress as a result of exercise relative to non-APOE ε4 carriers.

A retrospective analysis of serious adverse events and deaths in U.S.-based lifestyle clinical trials for cognitive health.

Objective: This retrospective analysis examined serious adverse events (SAEs) and deaths in U.S. lifestyle clinical trials aimed at enhancing cognitive health in older adults. Methods: Data was gathered from trials completed between January 1, 2000, and July 19, 2023, via ClinicalTrials.gov's API. Results: Among these trials, 76% did not report results. The remaining studies fell into four intervention categories: Cognitive/Behavioral, Exercise/Movement, Diet/Supplement, and Multi-modal. When considering all trial types collectively, the findings suggest that lifestyle clinical trials are generally safe. There was no significant increase in the relative risk of experiencing an SAE in the intervention group compared to the control group. However, in terms of relative risk of death, an increase of 28% was observed in the intervention compared to the control, which was statistically significant (X2 (1, N = 36), p < 0.00688). Nevertheless, this increase did not surpass age-adjusted U.S. mortality rates. Assessing the data by intervention type, Diet/Supplement, and Multi-modal trials displayed an elevated relative risk of SAEs in the intervention. Diet/Supplement trials had a 16% increase (X2 (1, N = 2), p < 0.0263), and Multi-modal trials had a 365% increase (X2 (1, N = 5), p < 0.000213). Diet/Supplement trials also showed a 67% increased risk of death (X2 (1, N = 2), p < 0.000197). Conclusions: These findings should be cautiously considered due to the low rate of reporting, but underscore the significance of reporting clinical trial results, enhancing transparency, and facilitating more accurate safety assessments in cognitive aging and lifestyle interventions for older adults.

Emerging methods for measuring physical activity using accelerometry in children and adolescents with neuromotor disorders: a narrative review.

BACKGROUND: Children and adolescents with neuromotor disorders need regular physical activity to maintain optimal health and functional independence throughout their development. To this end, reliable measures of physical activity are integral to both assessing habitual physical activity and testing the efficacy of the many interventions designed to increase physical activity in these children. Wearable accelerometers have been used for children with neuromotor disorders for decades; however, studies most often use disorder-specific cut points to categorize physical activity intensity, which lack generalizability to a free-living environment. No reviews of accelerometer data processing methods have discussed the novel use of machine learning techniques for monitoring physical activity in children with neuromotor disorders. METHODS: In this narrative review, we discuss traditional measures of physical activity (including questionnaires and objective accelerometry measures), the limitations of standard analysis for accelerometry in this unique population, and the potential benefits of applying machine learning approaches. We also provide recommendations for using machine learning approaches to monitor physical activity. CONCLUSIONS: While wearable accelerometers provided a much-needed method to quantify physical activity, standard cut point analyses have limitations in children with neuromotor disorders. Machine learning models are a more robust method of analyzing accelerometer data in pediatric neuromotor disorders and using these methods over disorder-specific cut points is likely to improve accuracy of classifying both type and intensity of physical activity. Notably, there remains a critical need for further development of classifiers for children with more severe motor impairments, preschool aged children, and children in hospital settings.

Early morning physical activity is associated with healthier white matter microstructure and happier children: the ActiveBrains project.

The background of this study is to examine the associations of individual and combined early morning patterns (i.e., active commuting to school, physical activity before school, having breakfast and good sleep) with white matter microstructure (WMM) and, whether the associated white mater microstructure outcomes were related to mental health outcomes in children with overweight or obesity. 103 children with overweight or obesity (10.0 ± 1.1 years old, 42 girls) from the ActiveBrains project participated in this cross-sectional study. Early morning patterns and mental health indicators (i.e., self-esteem, optimism, positive and negative affect, stress, depression and anxiety) were self-reported by the children using validated questionnaires. WMM was assessed by magnetic resonance imaging using diffusion tensor imaging. When examined independently, early morning patterns were not related with WMM (all P > 0.05). However, the combination of early morning patterns was related with WMM (P < 0.05). Specifically, physically active early morning patterns (i.e., active commuting to school and physical activity before school) were associated with global fractional anisotropy (FA) (ß = 0.298, P = 0.013) and global radial diffusivity (RD) (ß = - 0.272, P = 0.021), as well as with tract-specific FA (ß = 0.314, P = 0.004) and RD (ß = - 0.234, P = 0.032) in the superior longitudinal fasciculus (SLF). Furthermore, combined physically active early morning pattern-associated global (i.e., FA and RD) and tract-specific (i.e., FA and RD in the SLF) WMM indicators were positively associated with happiness (ß absolute value range from 0.252 to 0.298, all P < 0.05). A combination of physically active early morning patterns may positively relate to white matter microstructure in children with overweight or obesity, and, in turn, happiness.

Aerobic exercise training effects on hippocampal volume in healthy older individuals: a meta-analysis of randomized controlled trials.

We conducted a meta-analysis of randomized controlled trials investigating the effects of aerobic exercise training (AET) lasting ≥ 4 weeks on hippocampal volume and cardiorespiratory fitness (CRF) in cognitively unimpaired, healthy older individuals. Random-effects robust variance estimation models were used to test differences between AET and controls, while meta-regressions tested associations between CRF and hippocampal volume changes. We included eight studies (N = 554) delivering fully supervised AET for 3 to 12 months (M = 7.8, SD = 4.5) with an average AET volume of 129.85 min/week (SD = 45.5) at moderate-to-vigorous intensity. There were no significant effects of AET on hippocampal volume (SMD = 0.10, 95% CI - 0.01 to 0.21, p = 0.073), but AET moderately improved CRF (SMD = 0.30, 95% CI 0.12 to 0.48, p = 0.005). Improvement in CRF was not associated with changes in hippocampal volume (bSE = 0.05, SE = 0.51, p = 0.923). From the limited number of studies, AET does not seem to impact hippocampal volume in cognitively unimpaired, healthy older individuals. Notable methodological limitations across investigations might mask the lack of effects.

Data-driven MRI analysis reveals fitness-related functional change in default mode network and cognition following an exercise intervention.

Previous research has indicated that cardiorespiratory fitness (CRF) is structurally and functionally neuroprotective in older adults. However, questions remain regarding the mechanistic role of CRF on cognitive and brain health. The purposes of this study were to investigate if higher pre-intervention CRF was associated with greater change in functional brain connectivity during an exercise intervention and to determine if the magnitude of change in connectivity was related to better post-intervention cognitive performance. The sample included low-active older adults (n = 139) who completed a 6-month exercise intervention and underwent neuropsychological testing, functional neuroimaging, and CRF testing before and after the intervention. A data-driven multi-voxel pattern analysis was performed on resting-state MRI scans to determine changes in whole-brain patterns of connectivity from pre- to post-intervention as a function of pre-intervention CRF. Results revealed a positive correlation between pre-intervention CRF and changes in functional connectivity in the precentral gyrus. Using the precentral gyrus as a seed, analyses indicated that CRF-related connectivity changes within the precentral gyrus were derived from increased correlation strength within clusters located in the Dorsal Attention Network (DAN) and increased anti-correlation strength within clusters located in the Default Mode Network (DMN). Exploratory analysis demonstrated that connectivity change between the precentral gyrus seed and DMN clusters were associated with improved post-intervention performance on perceptual speed tasks. These findings suggest that in a sample of low-active and mostly lower-fit older adults, even subtle individual differences in CRF may influence the relationship between functional connectivity and aspects of cognition following a 6-month exercise intervention.

Physical activity and brain amyloid beta: A longitudinal analysis of cognitively unimpaired older adults.

INTRODUCTION: The current study evaluated the relationship between habitual physical activity (PA) levels and brain amyloid beta (Aß) over 15 years in a cohort of cognitively unimpaired older adults. METHODS: PA and Aß measures were collected over multiple timepoints from 731 cognitively unimpaired older adults participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Aging. Regression modeling examined cross-sectional and longitudinal relationships between PA and brain Aß. Moderation analyses examined apolipoprotein E (APOE) ε4 carriage impact on the PA-Aß relationship. RESULTS: PA was not associated with brain Aß at baseline (ß = -0.001, p = 0.72) or over time (ß = -0.26, p = 0.24). APOE ε4 status did not moderate the PA-Aß relationship over time (ß = 0.12, p = 0.73). Brain Aß levels did not predict PA trajectory (ß = -54.26, p = 0.59). DISCUSSION: Our study did not identify a relationship between habitual PA and brain Aß levels. HIGHLIGHTS: Physical activity levels did not predict brain amyloid beta (Aß) levels over time in cognitively unimpaired older adults (≥60 years of age). Apolipoprotein E (APOE) ε4 carrier status did not moderate the physical activity-brain Aß relationship over time. Physical activity trajectories were not impacted by brain Aß levels.

Physical activity and amyloid beta in middle-aged and older adults: A systematic review and meta-analysis.

BACKGROUND: One of the pathological hallmarks distinguishing Alzheimer's disease from other dementias is the accumulation of amyloid beta (Aß). Higher physical activity is associated with decreased dementia risk, and one potential path could be through Aß levels modulation. We aimed to explore the relationship between physical activity and Aß in middle-aged and older adults. METHODS: A systematic search of PubMed, Web of Science, PsycINFO, Cochrane Central Register of Controlled Trials, and SPORTDiscus was performed from inception to April 28, 2022. Studies were eligible if they included physical activity and Aß data in adults aged 45 years or older. Multi-level meta-analyses of intervention and observational studies were performed to examine the role of physical activity in modulating Aß levels. RESULTS: In total, 37 articles were included (8 randomized controlled trials, 3 non-randomized controlled trials, 4 prospective longitudinal studies, and 22 cross-sectional studies). The overall effect size of physical activity interventions on changes in blood Aß was medium (pooled standardized mean difference = -0.69, 95% confidence interval (95%CI): -1.41 to 0.03; I2 = 74.6%). However, these results were not statistically significant, and there were not enough studies to explore the effects of physical activity on cerebrospinal fluid (CSF) and brain Aß. Data from observational studies were examined based on measurements of Aß in the brain using positron emission tomography scans, CSF, and blood. Higher physical activity was positively associated with Aß only in the CSF (Estimate r = 0.12; 95%CI: 0.05-0.18; I2 = 38.00%). CONCLUSION: Physical activity might moderately reduce blood Aß in middle-aged and older adults. However, results were only near statistical significance and might be interpreted with caution given the methodological limitations observed in some of the included studies. In observational studies, higher levels of physical activity were positively associated with Aß only in CSF. Therefore, further research is needed to understand the modulating role of physical activity in the brain, CSF, and blood Aß, as well as its implication for cognitive health.