Beatriz Fernandez-Gamez

This study examined the associations between 24‐h movement behaviors and cognitive function in cognitively unimpaired older adults, and whether Alzheimer's disease brain signatures, including gray matter mean diffusivity (GMMD) and thickness/volume signatures, moderated these associations. A total of 91 participants were enrolled in the AGUEDA trial (NCT05186090), with 89 included in this cross‐sectional analysis (mean age = 71.61 ± 3.85 years; 56.2% females). Moderate‐to‐vigorous physical activity (MVPA), light physical activity (LPA), sedentary behavior (SB), and sleep were objectively assessed using 9‐day wrist‐worn accelerometry. Cognitive function was assessed across attention/inhibitory control, episodic memory, processing speed, visuospatial processing, and working memory. Thickness/volume and GMMD signatures were derived from cortical and hippocampal regions. Compositional linear regression models (CoDA) examined associations, adjusting for age, sex, and education, and tested interactions between movement behaviors and Alzheimer's disease brain signatures. No direct associations were observed between 24‐h movement behaviors and cognitive domains (all p > 0.05). However, GMMD signature, but not thickness/volume signature, moderated several movement behavior‐cognition associations. Moderation was most evident for episodic memory, with significant interactions for MVPA, LPA, and sleep, while LPA exhibited the broadest pattern of moderation across cognitive domains, interacting with attention/inhibitory control, episodic memory, processing speed, and working memory (all p for interaction ≤ 0.04). In conclusion, the associations between 24‐h movement behaviors and cognitive function may depend on microstructural brain integrity (i.e., GMMD). These findings highlight the importance of considering Alzheimer's disease‐related brain signatures when investigating lifestyle–cognition associations and support a more personalized approach to promoting cognitive health in older adults. Future prospective longitudinal studies and CoDA interventional trials are needed to establish temporal precedence and evaluate whether targeted time reallocations can actively attenuate cognitive trajectories across distinct microstructural vulnerability profiles. Trial Registration: NCT05186090

Background: Coronary artery disease (CAD) increases the risk of cognitive impairment, dementia, and brain structural alterations. This heart-brain connection suggests that exercise-induced cardiovascular responses may influence brain regions vulnerable to Alzheimer's disease (AD), the most common cause of dementia. This study aimed to examine the effects of 12-weeks of either high-intensity interval training (HIIT) plus resistance training (RT) or HIIT alone on AD brain signatures in individuals with CAD, to explore moderating factors, and to assess associations between changes in AD brain signatures and cognition and physical fitness. Methods: This secondary analysis of a single-site, three-arm, single-blinded randomized controlled trial included 105 individuals with CAD (50-75 years; 21% female) randomly allocated to HIIT+RT, HIIT, or usual care (UC) groups. T1- and diffusion-weighted magnetic resonance imaging were acquired before and after the 12-week intervention. Primary outcomes were thickness/volume and gray matter mean diffusivity (GMMD) signatures, derived from seven cortical regions and the hippocampus. Moderators included age, sex, education, and baseline AD brain signatures. Results: For the thickness/volume signature, no between-group differences in changes were observed between HIIT+RT and UC (+0.13 standardized mean difference [SMD]; 95% CI, -0.07 to 0.33) or between HIIT and UC (-0.1 SMD; 95% CI, -0.3 to 0.1); however, a small but significant between-group difference in change was found between HIIT+RT and HIIT, in favor of HIIT+RT (+0.23 SMD; 95% CI, 0.03 to 0.42). For the GMMD signature, no significant between-group differences in changes were found between HIIT+RT and UC (+0.08 SMD; 95% CI, -0.18 to 0.34), HIIT and UC (+0.1 SMD; 95% CI, -0.16 to 0.36), or HIIT+RT and HIIT (-0.02 SMD; 95% CI, -0.28 to 0.23). No moderation effects were identified, and no associations were observed between changes in AD brain signatures and cognition or physical fitness. Conclusion: A 12-week HIIT+RT intervention was more effective than HIIT alone in increasing the thickness/volume signature in individuals with CAD, yet no differences were observed compared to UC and the interventions did not affect the GMMD signature. These findings suggest that the intra-session inclusion of RT with HIIT may enhance AD-related brain macrostructure in individuals with CAD more than just HIIT training.

Background: Brain imaging markers may help detect early cognitive decline and Alzheimer’s disease (AD). Although exercise-related effects on AD-specific brain signatures remain unclear. Objective: To examine the effects of a 24-week resistance exercise (RE) program on AD brain signatures in cognitively unimpaired older adults, to explore potential moderators and to assess associations with cognition, including mediation effects. Methods: This secondary analysis of a single-site, two-arm, single-blinded randomized controlled trial included 90 participants (72 ± 4 years; 58% female) randomly assigned by a blind external researcher to an RE group (3 sessions/week, 60 min/session, n = 46) or a wait-list control group (CG, n = 44). T1- and diffusion-weighted MRI were acquired at baseline and post-intervention. Primary outcomes were thickness/volume and grey matter mean diffusivity (GMMD) signatures, derived from cortical and hippocampal regions. Moderators included age, sex, education, multimorbidity, apolipoprotein E ϵ4 status, amyloid beta (Aβ) status and baseline AD brain signatures. Secondary outcomes included cognitive function. Outcome measures and analyses were conducted by staff blinded to intervention assignment. Results: Compared with the CG, the RE group showed a reduction in the thickness/volume signature (−0.23 standardized mean difference [SMD]; 95% CI, −0.43 to −0.02), but no effect on the GMMD signature (0.08 SMD; 95% CI, −0.13 to 0.29). Aβ-status moderated the effect, as Aβ-positive participants in the RE group showed a larger reduction in the thickness/volume signature than those in the CG (−0.64 SMD; 95% CI, −1.09 to −0.18), whereas no effect was observed in Aβ-negative participants. Thickness/volume and GMMD reductions were associated with improvements in executive function and attentional/inhibitory control, respectively. Changes in AD signatures did not mediate cognitive outcomes. Conclusion: Our findings suggest that reductions in the macrostructural AD signature following a 24-week RE program may reflect adaptive, rather than detrimental, brain changes, particularly in Aβ-positive older adults, as these changes were associated with improved executive function. Trial registration: Registered on Clinicaltrials.gov (Identifier: NCT05186090).

Age and coronary artery disease (CAD) are known risk factors for cognitive decline and dementia, in which cerebral blood flow (CBF) has as a key role. Cardiorespiratory fitness (CRF) has shown consistent links with brain health and dementia, though its association with CBF and whether it differs depending on age or disease status remains limited. The main aim of this study was to examine the association of CRF, assessed through the six-minute walk test (6MWT) and peak oxygen uptake (VO₂peak), with CBF in cognitively normal older adults and individuals with CAD. We hypothesized that CRF will be positively associated with global and regional CBF. Seventy-nine cognitively normal older adults from the AGUEDA trial and 84 individuals with CAD from the Heart-Brain trial were included in this cross-sectional analysis. Participants underwent 6MWT, and a 3D arterial spin labelling magnetic resonance imaging scan to assess global and regional CBF. In the Heart-Brain project, participants additionally conducted a cardiopulmonary exercise test from which VO ₂ peak was determined. In the Heart-Brain sample, after adjusting for age, sex, education, mean arterial pressure and APOE4, CRF was positively associated with global CBF (6MWT: β=0.26, P=0.04; VO ₂ peak: β=0.33, P=0.02). At a regional level, CRF was positively associated with CBF in the posterior cingulate cortex (6MWT: β=0.26, P=0.04; VO ₂ peak: β=0.31, P=0.02), the anterior cingulate cortex (6MWT: β=0.29, P=0.02), the precuneus (6MWT: β=0.28, P=0.02; VO ₂ peak: β=0.32, P=0.01) and the hippocampus (VO ₂ peak: β=0.29, P=0.03). No significant associations were observed in the AGUEDA sample (all P>0.05). When adding body mass index (BMI) to the models, the associations were no longer statistically significant in either sample. The association between VO ₂ peak and CBF was significantly mediated (i.e. indirect effect) by BMI (Indirect effect: β=0.250 (95% CI 0.02;0.486), percentage of mediation=72.67%). CRF was positively associated with CBF in individuals with CAD, but not in cognitively normal older adults. Interestingly, the association of CRF with CBF was largely explained and mediated by BMI. Further studies are warranted to clarify the role of CRF and BMI in relation to CBF, the mechanisms involved and the implications for dementia risk prevention in older adults and individuals with CAD.

INTRODUCTION: The Active Gains in Brain Using Exercise During Aging (AGUEDA) trial examined the effects of a 24 week resistance exercise (RE) intervention on executive function (EF) and other cognitive domains in cognitively normal older adults. METHODS: Ninety participants (mean age, 71.8 years; 57.8% female) were randomized to an RE or control group. At baseline and 24 weeks, EF and other cognitive domains were assessed. RESULTS: The RE group showed significant improvements in overall EF (standardized mean difference [SMD] = 0.39, 95% confidence interval = 0.14, 0.65), with no significant between‐group difference (SMD = 0.13, p = 0.37). The RE group showed a significant improvement in attentional/inhibitory control (SMD = 0.43, p < 0.001) compared to the control group, while no effects were observed in other domains (all p > 0.12). Moderation by age, education, and subjective cognitive decline was observed. DISCUSSION: Although no overall EF benefit was observed, RE improved attentional/inhibitory control in cognitively normal older adults. RE may yield greater benefits in vulnerable subgroups. CLINICAL TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT05186090). Highlights: Cognitive effects of resistance exercise (RE) may vary across different cognitive domains in cognitively healthy older adults. Twenty‐four week RE produced selective improvements in attention/inhibitory control. RE did not improve executive function (EF), or other cognitive domains (episodic memory, processing speed, visuospatial processing, and working memory). RE improved muscular strength, which were associated with gains in EF, episodic memory and working memory. There is value in personalized exercise interventions tailored to individual risk populations, such as those with higher subjective cognitive decline.

Aims: Patients with coronary artery disease (CAD) are at risk of accelerated cognitive decline. We aimed to explore how different cardiorespiratory fitness (CRF) indicators associate with brain structure and cognitive function in these patients. Methods and results: We studied 105 stable CAD patients (62.1 ± 6.6 years, 21% female), using baseline data from the randomized controlled Heart–Brain trial. Time-to-exhaustion (TTE), peak oxygen uptake (VO2peak), ventilatory anaerobic threshold (VAT), oxygen uptake efficiency slope (OUES), peak O2-pulse, and 60-s heart rate recovery (HRrec) were determined from cardiopulmonary exercise tests. From magnetic resonance imaging, we extracted brain volumes [total-, grey-, and white matter volumes (TBV, GMV, and WMV)] and hippocampal volume (HV), and calculated the difference between estimated and chronological brain age (brainPAD). Episodic memory, processing speed, working memory, executive function/attentional control, and general cognition were evaluated. TTE, VO2peak, and OUES were positively associated with TBV (βstd range 0.15–0.19, P < 0.05) and HV (βstd range 0.23–0.36, P < 0.05). Higher OUES, HRrec, and O2-pulse were associated with lower brainPAD (βstd −0.23 to −0.32, P < 0.05). Higher VAT was associated with better working memory (βstd = 0.26, P = 0.023), and higher OUES with better executive function/attentional control (βstd = 0.20, P = 0.021). Hippocampal atrophy was more prevalent in lower vs. middle/upper VO2peak tertile (P = 0.001). Conclusion: In CAD patients, both maximal and submaximal CRF indicators were associated with larger brain volumes, with stronger region-specific association with HV, and younger physiological appearance of the brain, while associations with cognitive functions were fewer and weaker. Our findings support CRF as a biomarker of structural brain health in CAD patients.

Introduction: Alzheimer's disease (AD) is a leading cause of disability worldwide. Alterations in cerebral blood flow (CBF) and AD blood biomarkers are fundamental at early stages of AD. Exercise shows promise in delaying physiological changes, but its mechanisms for enhancing brain health remain unclear. flADex aims to examine the acute effects of different exercise types on CBF and blood biomarkers in older adults. This protocol describes the methodology and rationale of flADex. Methods: flADex is a counterbalanced crossover trial in 20 older adults, aged 68–83 years old, with negative brain amyloid status (< 12 centiloid) who are APOEε4 noncarriers. Participants will complete a 30‐min session of each condition in a randomized order: (i) moderate‐intensity aerobic exercise (60%–70% age‐predicted maximal heart rate), (ii) moderate‐intensity resistance exercise (rating of perceived exertion: 4–6 points out of 10), and (iii) resting condition. Changes in CBF are the primary outcome and will be assessed by magnetic resonance imaging using pseudo‐continuous arterial spin labeling at pre‐ and at 3 timepoints post‐condition (starting at 20, 27, 34 min). Secondary outcomes are biomarkers of AD pathology and neurodegeneration (Aβ42, Aβ40, p‐tau217, p‐tau181, BD‐tau, GFAP, NfL) and growth factors (BDNF, IGF‐1), measured through blood samples collected at pre‐ and post‐condition (at 3, 50, 70 min). Moreover, cognitive outcomes and mood status will be measured pre‐ and post‐condition. Conclusion: flADex will highlight the acute effects of different exercise types on CBF and biomarkers before beta‐amyloid accumulation. Acute effects on CBF dynamics and blood biomarkers are expected to be greater with aerobic than resistance exercise when compared to resting. CBF is expected to vary by brain region, and biomarkers to fluctuate dynamically postexercise. This will provide critical insights into exercise's impact on vascular and molecular pathways associated with AD pathology and potential recommendations for standardized blood sampling to enhance diagnostic accuracy.

Objective To examine the effects of a 24-week resistance exercise (RE) program on Alzheimer’s disease (AD) brain signatures in cognitively normal older adults; and to identify moderating factors, assess the association between AD brain signatures changes and cognitive outcomes, including mediation by AD brain signatures Methods Ninety participants (72±4 years, 58% female) were randomized to a RE group (3 sessions/week, 60 min/session, n=46) or a wait-list control group (CG, n=44). T1- and diffusion-weighted MRI (3T) were acquired pre- and post-intervention. AD thickness/volume and gray matter mean diffusivity (GMMD) signatures were derived from cortical and hippocampal regions. Baseline adjusted mixed models tested intervention effects. Moderators included age, sex, education, APOE4 status, amyloid beta (Aβ) status, and baseline AD signatures. Associations with cognition and possible mediators were explored. Results The RE group showed reduction in the AD thickness/volume signature (−0.23 standardized mean difference [SMD]; 95% CI, −0.43 to −0.02), but no effect on the AD GMMD signature (0.08 SMD; 95% CI, −0.13 to 0.29) vs CG. Aβ status moderated the effect, with Aβ-positive participants in the RE group showing a larger reduction in AD thickness/volume signature compared to the CG (−0.64 SMD; 95% CI, −1.09 to −0.18), whereas no effect was found in Aβ-negative participants. AD thickness/volume signature reductions were associated with better executive function, and AD GMMD signature reductions with attentional/inhibitory control improvements. Changes in AD signatures did not mediate changes in cognition. Conclusion A 24-week RE intervention reduced AD thickness/volume signature, especially in Aβ-positive participants, and was linked to improved executive function. No effects were observed on the AD GMMD signature. These findings suggest RE may support brain health by delaying structural changes characteristic of preclinical stages of AD. Further research is needed to replicate and confirm these results.

Objective The AGUEDA trial examined the effects of a 24-week resistance exercise (RE) intervention on executive function (EF) and other cognitive domains in cognitively normal older adults. Method Ninety participants (71.75 ± 3.96 years, 57.8% female) were randomized to an RE group (n = 46) or a control group (n = 44). The RE group performed 180 minutes/week of supervised training, while the control group maintained usual activities. EF and other cognitive domains (e.g., attentional/inhibitory control, episodic memory, processing speed, visuospatial processing, and working memory) were assessed at baseline, and 24 weeks. Intervention effects were analyzed using intention-to-treat (ITT) and per-protocol (PP) approaches, with exploratory subgroup analyses based on sociodemographic and AD-related characteristics. Results EF composite score improved in both groups, with no significant between-group differences (standardized mean difference (SMD) = 0.13, p = 0.37). In addition, the RE group showed significant improvements in attentional/inhibitory control compared to the control group (SMD = 0.43, p < 0.001), while the rest of cognitive domains showed no significant differences (p > 0.05). Subgroup analyses revealed greater EF benefits for the oldest adults, those with lower educational levels, and individuals with higher subjective cognitive decline (SCD) at baseline. RE had an effect on knee extension strength (SMD = 0.25, p = 0.02), which was positively correlated with better EF (r = 0.38, p = 0.0005) and improved episodic memory (r = 0.31, p = 0.008). Conclusion The 24-week AGUEDA intervention revealed no significant differences in EF or other cognitive domains after 24 weeks. However, participants in the RE group demonstrated significantly greater improvements in attentional/inhibitory control compared to the control group. Moreover, our findings support the notion that RE can yield greater benefits in the more vulnerable subgroups, such as the oldest participants, those with SCD or fewer years of education. Although the mediation analysis did not find significant indirect effects, lower body muscular strength improvements were positively correlated with better EF and episodic memory, highlighting the potential role of strength in cognitive health.