Marcos Olvera-Rojas

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

Objective: To analyze the associations between cardiorespiratory fitness (CRF) indicators and cardiovascular health, assessed through the Life’s Essential 8 (LE8) score, in individuals with coronary artery disease (CAD). Patients and methods: This cross-sectional study included individuals (aged 50-75 years) with stable CAD were enrolled in the Heart-Brain randomized controlled trial ( NCT06214624 ) from April 2022 to June 2024. Participants underwent a cardiopulmonary exercise test until volitional exhaustion. CRF indicators included peak oxygen consumption (VO _2peak ), time to exhaustion (TTE), ventilatory anaerobic threshold (VAT), peak oxygen pulse, 60-s heart rate recovery (HRrec) and oxygen uptake efficiency slope (OUES). LE8 score (range 0-100) was calculated as the unweighted average of 8 variables: physical activity, sleep, diet, nicotine exposure, glucose, lipids, body mass index, and blood pressure, as defined by the American Heart Association. We used linear regression models adjusted for sex, age, and education. Results: 102 individuals were included (21 females). VO _2peak (β _std =0.67, P <.001) and TTE (β _std =0.64, P <.001) showed strong positive associations with LE8 total score, followed by VAT (β _std =0.43, P <.001) and HRrec (β _std =0.26, P =.01). No associations were found for OUES (β _std =-0.08, P =.54) and peak oxygen pulse (β _std =-0.05, P =.72). Conclusion: Maximal and submaximal indicators of CRF were positively associated with LE8 in individuals with CAD, yet maximal indicators showed the strongest associations. Notably, TTE demonstrated a similar strength of association with LE8 as VO _2peak . These findings have important clinical and research implications as they support TTE as a simpler (than the gold-standard VO _2peak ), yet informative, marker of cardiovascular health in individuals with CAD. Clinical trials registration number: NCT06214624, https://clinicaltrials.gov/study/NCT06214624 Abstract presentation: Preliminary results of this study were previously presented as an abstract at the “XI EXERNET Symposium (Salud y bienestar a través del ejercicio: abordajes innovadores en la Red EXERNET), Seville, Spain, October 24–25, 2025”.

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.

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.

We examined whether a 24-week resistance training program influenced brain amyloid-β (Aβ) and Alzheimer’s Disease (AD)-related blood-based biomarkers. Ninety cognitively normal, physically inactive older adults aged 65–80 years were randomly allocated to a 24-week resistance training program (three ∼60-min supervised sessions/week) or a wait-list control group. Primary analyses assessed exercise-induced changes in brain Aβ (Centiloid values) and plasma ptau217/Aβ1-42 IPMS ratio. Secondary analyses examined ptau217/Aβ42 SIMOA ratio, ptau217, ptau181 and Aβ42/40, as well as potential interactions with sex, age, education, apolipoprotein ε4 ( APOE4 ) status, amyloid PET-positivity, and comorbidities. The intervention produced no significant differences on brain Aβ or AD-related blood-based biomarkers (p>0.05) compared to the control group. However, the ptau217/Aβ1–42 IPMS ratio showed a small, non-significant increase in the control group (SMD = 0.162; 95% CI: −0.159 to 0.483) while remaining stable in the exercise group (SMD = 0.01; 95% CI: −0.291 to 0.310) with a similar trend for ptau217/Aβ42 SIMOA. Moderator analyses indicated differential responses by amyloid PET-positivity and APOE4 status on brain Aβ (p for interactionAPOE4 carriers and amyloid PET–positive individuals in the control group, whereas those allocated to the exercise intervention reduced their levels. The specificity observed within our subgroups suggests that resistance exercise may serve as a targeted intervention to modulate AD pathophysiology, raising new questions regarding its broader role in the delay of the disease in vulnerable populations.

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.

Alzheimer´s Disease (AD) and neurodegenerative blood-based biomarkers (BBMs) are transitioning from research settings to clinical practice, where accurate interpretation is critical for their appropriate use. Particularly, the limited alignment between AD pathology and metrics of cognitive performance suggest unappreciated factors of resilience or inter-individual variability that could be influencing clinical utility and interpretation of these measures. Ninety-one cognitively normal older adults from the AGUEDA trial (NCT05186090) (71.8 ± 3.9 years; 58% females) were cross-sectionally examined for plasma Aβ42/40 SIMOA, BD-tau, GFAP, NfL, ptau217, ptau181, ptau217/Aβ1-42 IPMS and ptau217/Aβ42 SIMOA. We evaluated BBMs classification accuracies for brain amyloid-beta and examined their associations with cognitive outcomes. We then examined whether selected individual characteristics impact BBMs. Ptau217 and ptau217/Aβ42 measured by both IPMS and SIMOA exhibited strong predictive accuracy for PET Aβ positivity (AUC > 0.8) with the inclusion of some individual characteristics lowering their accuracy. Episodic memory showed a positive association with BD-tau (r = 0.29; p = 0.018), attentional/inhibitory control correlated positively with ptau217/Aβ42 SIMOA (r = 0.26; p = 0.041) and processing speed was negatively linked to GFAP (r = -0.21; p = 0.047). Age, creatinine, depressive symptoms, comorbidities and sex were associated with BD-tau, GFAP, NfL, and ptau217/Aβ42 (both IPMS and SIMOA), with standardized β values ranging from -0.27 to 0.62 (all p < 0.05). These results highlight the utility of ptau217 and ptau217/Aβ42 ratios in identifying brain amyloid pathology in cognitively normal older adults. BBMs could be used complementarily to support differential diagnosis and better understand the origins of cognitive deficits.

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.

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 remains 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 that will include 20 older adults aged 68 to 83 years old with negative brain amyloid status (WO2020193500A1 and patent applications # 2450702-2, #63/693,956, # 63/679,361, and 63/672,952 .