BACKGROUND:Although many studies support a neuroprotective role for estrogens and other ovarian hormones in women, findings across imaging studies remain mixed. Few studies have explored both early- and midlife- hormone exposures simultaneously or incorporated whole-brain, voxel-wise approaches. This study examined the effects of early- and midlife exposure to ovarian hormones- via hormonal birth control (BC), menopausal hormone therapy (MHT)- and their timing on brain health in older women. We also studied the relationship of age of menopause (i.e., greater endogenous exposure to ovarian hormones) to brain health in older adulthood. METHODS:We analyzed baseline data from 459 women (ages 65-80) in the multi-site IGNITE study, a 12-month randomized aerobic exercise study. We examined retrospective self-report of BC and MHT use in relation to structural MRI metrics using voxel-based morphometry (VBM) for gray matter volume and surface-based morphometry (SBM) for cortical thickness. FINDINGS:BC use compared to no BC use was associated with greater gray matter volume in temporal, occipital, and frontal regions in older adulthood. Longer BC duration was linked to larger fusiform gyrus volume. Combined BC and MHT use compared to no use was associated with greater volume in parietal and temporal areas and thicker cortex in the posterior cingulate and temporal gyri. Later menopause onset correlated with greater posterior cortical thickness. No associations were found for MHT timing or BC start age. INTERPRETATIONS:Both endogenous and exogenous lifetime exposure to ovarian hormones were associated with structural brain measures generally consistent with preserved brain aging. These findings highlight the importance of exposure timing in women's brain health and AD risk prevention.

Background:Sedentary behavior is highly prevalent following traumatic brain injury (TBI) and compounds existing risks for cardiovascular, neurodegenerative, and affective disorders. The cognitive and behavioral sequelae of TBI, including impaired decision-making, blunted reward processing, and cognitive fatigue, create particular barriers to adopting and maintaining an active lifestyle. Effective behavior change interventions targeting physical activity in community-dwelling TBI survivors remain scarce. Here, we evaluated the feasibility, compliance, and preliminary efficacy of a 12-week remotely delivered walking intervention combining planning, reminders, and monetary micro-incentives. Methods:Fifty-six community-dwelling adults aged 40-80 years with a mild-to-moderate TBI diagnosed between 3 months and 15 years prior were randomized to either a planning, reminders, and micro-incentives intervention (n=23) or a health advice control condition (n=25). Participants wore a Fitbit Inspire 3 continuously throughout the study. Intervention participants completed weekly phone calls to plan five 30-minute walks for the following week, received daily text message or email reminders on planned walk days, and earned small incentives (redeemed for money at the end of the study) upon walk completion. Control participants received weekly health education calls. Feasibility was operationalized as recruitment, retention, and adverse event rates. Compliance was assessed via phone call completion rates and Fitbit wear time. Efficacy outcomes included weekly walk counts, walking duration, and step counts. Modifiers and exploratory outcome measures included environmental and psychosocial variables. Results:Forty-eight participants completed the study (retention rate: 84.2%), with high phone call compliance in both groups (intervention: 98.4%; control: 98.1%). Intervention participants completed more walks than controls from week 1 onward (aIRR = 5.33, 95% CI: 2.27-12.5), with the group difference growing over time (interaction aIRR = 1.09 per week, 95% CI: 1.01-1.17). The intervention group also walked significantly longer at week 1 (b = 62.14 min, 95% CI: 1.05-123.23), with the difference growing over time. Similarly, the intervention group accumulated significantly more steps during walks at week 1 (b = 4,779 steps, 95% CI: 45.50-9,513.00). Baseline intrinsic motivation increased the probability of walking on any given day and those who on average walked for >150 minutes per week saw higher improvement in their perceived cognitive abilities (b = 4.21, 95% CI: 0.15, 8.27). Conclusions:Remotely delivered, multicomponent walking interventions consisting of planning, reminders, and micro-incentives are possible candidate programs to fill a gap in community-based healthcare for individuals living with lifelong consequences of TBI. With high retention and compliance, and strong preliminary efficacy of the intervention these findings provide compelling support for a larger, fully powered trial prior to implementation in a clinical setting.

Motor learning is central to human adaptive behaviour. This study explored behavioural and neural changes during acquisition of a complex visuomotor skill (soccer juggling). We recruited 111 participants, assigning them to a 10-week juggling intervention group or a non-training control group. Using MRI and graph theory, we analysed white matter network changes at pre-test (T0), mid-term (T1), and post-test (T2). Results indicated that, relative to the control group, the intervention group exhibited a significant increase in global efficiency and a significant decrease in the shortest path length of the white matter network during the later learning stage (T1-T2). Conversely, during the early learning stage (T0-T1), the intervention group demonstrated no significant changes in global efficiency and shortest path length. Furthermore, the control group demonstrated a significant decrease in nodal efficiency of ORBmid.L at T0-T2 and T1-T2, whereas the intervention group showed no significant changes in this marker. Additionally, the intervention group demonstrated increased nodal degree centrality in SPG.R at T0-T1 and T0-T2, whereas controls exhibited significant declines. These findings demonstrate that extended soccer juggling training drives changes in network topology involving frontal and parietal white matter regions, particularly during late-stage skill consolidation. The study advances current knowledge by identifying temporally distinct phases of neuroplasticity, emphasising the critical role of sustained practice in optimising brain network efficiency for complex motor skill mastery.

Positive movement experiences (e.g., exergaming) may enhance cognition, but evidence in midlife is limited. In a double-blind RCT, 233 adults (35-64) were randomized to a 10-day cognitive-motor Games intervention (n = 118) or a passive video control (n = 115) across five lab and five home sessions. Dual-task cost was assessed pre- and post-intervention, with engagement (affect, exertion, expectancy) modeled as predictors. Adherence was high (98.3%); exergaming elicited moderate- intensity (Delta M = 18.76 bpm, p < .001). Positive affect predicted reduced dual-task cost in one paradigm (beta = -0.316, p = .025), whereas higher exertion predicted poorer outcomes. Expectancy, baseline activity, and streak predicted improvement, underscoring task-specific affective contributions to cognitive adaptation.

OBJECTIVE:Cognitive decline is common among the oldest-old, particularly in assisted living facilities (ALFs). This pilot randomized controlled trial examined the effects of aerobic, resistance, and mind-body exercises on cognition in ALF residents aged ≥80 years, and the feasibility and safety of exercise programs. METHODS:In a 24-week four-arm trial in one Shanghai ALF, 76 participants (aged 86.8 ± 4.1; 72.4% female) were randomized to aerobic, resistance, mind-body (simplified Tai Chi), or non-exercise control groups. Thirty-minute exercise sessions were delivered three times weekly for 24 weeks. Cognition was assessed at baseline, Week 12, and Week 24 using the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Immediate Story Recall (ISR), Boston Naming Test (BNT), Trail Making Test-A (TMT-A), and Trail Making Test-B (TMTB). Data were analyzed using intention-to-treat baseline-adjusted linear mixed-effects models with Holm-adjusted pairwise contrasts. RESULTS:Recruitment was 65.5%; mean exercise attendance was 90.1%, and no intervention-related serious adverse events occurred. At week 24, aerobic and mind-body groups showed higher MMSE scores than control (aerobic-control Δ = 3.45, 0.92 to 5.99, pHolm = 0.0481; mind-body-control Δ = 3.29, 0.81 to 5.77, pHolm = 0.0492). Mind-body exercise showed higher ISR scores than control (ISR Δ = 9.84, 3.22 to 16.46, pHolm = 0.0234), whereas aerobic exercise showed better TMT-B performance than control (TMT-B Δ = -25.66 s, -41.95 to -9.37, pHolm = 0.0137). MoCA, BNT, and TMT-A differences were not significant after multiple-comparison correction. CONCLUSIONS:These exercise programs were feasible and safe in ALF residents aged ≥80. Aerobic and mind-body exercise improved specific cognitive outcomes, while larger trials are needed to confirm these findings. TRIAL REGISTRATION:This study was registered on Chinese Clinical Trail Registry (ChiCTR2500111703).

Cognitive decline in older adults is a growing global concern, with over 55 million people living with dementia worldwide. Exercise games, which combine physical exercise with cognitive training in an interactive digital environment, represent a promising approach for mitigating this decline in community settings. Here we present a systematic review and meta-analysis examining the cognitive effects of exercise games on community-dwelling older adults, including those with mild cognitive impairment and dementia. Across 10 randomized controlled trials with 690 participants (mean age 74 years), exercise games produced a small but statistically significant overall cognitive benefit compared to control conditions (Hedges' g = 0.135, 95% CI [0.037, 0.229], p = 0.012). Domain-specific analyses revealed memory showing a trend toward improvement (g = 0.179, p = 0.060), while global cognition, executive function, and attention did not reach statistical significance. A single study examining processing speed showed a positive effect, though this finding requires replication. Multicomponent exercise programs incorporating aerobic elements demonstrated numerically larger, though non-significant, effects (g = 0.291, p = 0.138) compared to aerobic-only interventions (g = 0.119, p = 0.142). The evidence base for clinical populations remains limited and inconclusive, with only two studies examining MCI (g = 0.256, p = 0.168) and three studies examining dementia (g = 0.005, p = 0.975), neither showing statistically significant effects. These findings provide preliminary evidence supporting exercise games as a modest, accessible supplementary intervention for cognitive health in community settings, though the small effect sizes and limited evidence in clinical populations indicate that substantially more research with larger samples and standardized protocols is needed to establish efficacy and optimize implementation.Systematic review registrationhttps://doi.org/10.17605/OSF.IO/AM8QT.

Background Cognitive impairments, a prevalent quality-of-life concern in breast cancer (BC), are particularly pronounced in women having undergone adjuvant chemotherapy. These impairments—affecting executive function, attention, and processing speed—are often underdiagnosed, with no established treatments. Exercise is a potential intervention to mitigate cancer-related cognitive impairment (CRCI). Since virtual care delivery is feasible, remotely delivered exercise interventions for CRCI management in patients with BC may be explored. Objective We examined the feasibility of an 8-week remotely delivered combined exercise program (aerobic+resistance training) compared to a stretching and toning active control in postchemotherapy patients with BC. Methods Patients with BC who completed adjuvant chemotherapy within 48 months were recruited across Canada from February to July 2023. The combined exercise group engaged in unsupervised aerobic exercise (30 minutes, thrice per week), supervised group-based resistance training (30 minutes, twice per week via Zoom [Zoom Communications, Inc]), and one recorded class weekly, supplemented with 4 biweekly behavioral counseling sessions. The active control group participated in low-intensity balance and flexibility classes (30 minutes, twice per week live, once per week recorded). Feasibility was assessed via enrollment, adherence, attrition, measurement completion, adverse events, and participant satisfaction; cognitive function, using the National Institutes of Health Toolbox Cognition Battery Remote Administration (V2) at baseline and post intervention. Results Twenty-one participants (mean age 51.6, SD 7.2 years; 11.8, SD 12.9 months since treatment) were randomized to the combined exercise (n=10) or the active control (n=11) group. Final analyses included 18 participants (mean age 51.9, SD 7.4 years; mean months since treatment 12.6, SD 13.5) with 9 participants in each group (51.2% enrollment rate; 14.3% attrition; no adverse events). Measurement completion rates were 85.7% and participants reported high satisfaction with the intervention, indicating minimal burden. Adherence rates for exercise classes were 70.8% in both groups. Adherence to behavioral counseling sessions was 77.5% (combined exercise group only). There were no significant differences in objectively measured cognitive function, but small-to-medium effect size improvements were observed in objectively measured episodic memory (mean difference 5.33, 95% CI –12.5 to 23.2; ηp²=0.03), working memory (mean difference 8.17, 95% CI –4.2 to 20.6; ηp²=0.12), executive function updating (mean difference –394.35, 95% CI –1035.67 to 246.96 ms; ηp²=0.07), and immediate memory and verbal learning (mean difference +3.22, 95% CI –2.0 to 8.5; ηp²=0.12), trending toward the multicomponent exercise group vs the active control group. In contrast, small-to-medium effect size improvements were observed in the Oral Reading Recognition Test (mean difference –9.65, 95% CI –22.9 to 3.5; P=.14; ηp²=0.14) and Picture Vocabulary Test (mean difference –2.48, 95% CI –5.2 to 0.3, P=.07; ηp²=0.20), trending toward the active control group. Conclusions A remotely delivered combined exercise intervention is feasible and may improve CRCI in patients with BC. Larger randomized controlled trials are warranted to confirm its efficacy in enhancing cognitive function and quality of life in this population. Trial Registration ClinicalTrials.gov NCT05704855; https://clinicaltrials.gov/study/NCT05704855

Musical training is associated with improved cognitive and academic performance across development. While specific neural mechanisms have been implicated in these associations, the precise relationship between white matter structure and putative cognitive effects of musical training are unclear. The present study examined the relationships between musical training, cognitive performance, and white matter structure in middle childhood. Using a combination of behavioral assessments and diffusion tensor imaging (DTI) in a sample of 76 preadolescents (38 with musical training and 38 without musical training) between 7-9 years old, cognitive abilities were tested using the Woodcock-Johnson Tests of Cognitive Abilities (WJ III) and the Operation Span Task (OSPAN), while academic achievement was assessed using the Kaufman Test of Educational Achievement (KTEA II). Behavioral results revealed that participants with musical training had higher cognitive scores (F(5, 70) = 2.89, p =.02) and greater academic achievement (F(5, 70) = 4.09, p =.003) compared to those without musical training. DTI results revealed that musical training was associated with higher mode (F(1, 48) = 5.82, p = 0.02) in the right PCG to STGp tract of the arcuate fasciculus (AF), although the relationship was marginally significant following Benjamini-Hochberg correction. Together, these results provide both behavioral and neural evidence for the relationship between musical training and cognition in a sample of preadolescents.

Glutathione (GSH), the brain's primary endogenous antioxidant, is integral to the cerebral antioxidant defense system and essential for maintaining redox homeostasis and neuronal health. Brain GSH levels naturally decrease with age, potentially contributing to cognitive vulnerability through diminished antioxidant capacity. Currently, the relationship between brain GSH and cognitive function in humans remains poorly understood. Using multiple quantum chemical shift imaging, we measured brain GSH levels in 206 cognitively unimpaired older adults (mean age 69.8 ± 3.9 years) and assessed cognitive performance across five core domains: working memory, episodic memory, visuospatial processing, executive function/attentional control, and processing speed. We hypothesized that higher GSH would be associated with better cognitive performance across all five domains, reflecting the putative role of antioxidant capacity in cognitive function. Using multiple regression with age, sex, years of education, and study site as covariates in the model, we found that higher regional brain GSH levels, including frontal and parietal regions, were associated with better working memory ( p  = 0.008), episodic memory ( p  = 0.040), and visuospatial processing ( p  = 0.001), but not with executive function/attentional control or processing speed. These findings highlight the critical neuroprotective role of GSH within the cerebral antioxidant defense system in supporting cognitive health in late adulthood.

Purpose: Physical activity supports cognitive and brain health, however the biological mechanisms underlying these benefits remain unclear. This study investigated changes in salivary alpha-amylase (sAA), a marker of sympathetic nervous system activity, and salivary cortisol (CORT), reflecting hypothalamus-pituitary-adrenal (HPA) axis activity, as candidate mechanisms mediating the effects of acute exercise on brain function, cognition, and academic achievement in children. Methods: In a pre-post randomized crossover design, 104 children (ages 9-10) completed exercise, the Trier Social Stress Test for Children (TSST-C; active control), and seated rest (passive control) conditions, with neuroelectric activity (P3 amplitude and latency), attentional inhibition, and academic achievement as outcomes. Structural equation modeling was performed to examine sAA and CORT as mediators of the relationship between exercise and outcomes. Moderated mediation tested whether the magnitude of the sAA-mediated path varied as a function of pre-intervention baseline CORT. Results: Exercise led to lower sAA than both controls and lower CORT than the TSST-C, controlling for pre-intervention baselines. Post-exercise reductions in sAA mediated reductions in trial-to-trial reaction time variability (SDRT) on incongruent trials, indexing more consistent inhibitory control. Exercise effects on neuroelectric activity (P3 amplitude) varied with baseline CORT. Conclusions: This study is among the first to investigate the biological underpinnings of acute exercise-induced changes in cognition in children using molecular, behavioral, neuroelectric, and academic achievement measures. Findings implicate sAA-indexed sympathetic activity as a candidate mechanism through which acute exercise may support specific aspects of inhibitory control in children, reflected behaviorally as more consistent responding on trials requiring the upregulation of inhibitory control. These findings also suggest that individual differences in baseline HPA axis activity moderate exercise effects on neural markers of attentional inhibition.

This study examined the associations between sedentary behavior (SB) at age 11 and mathematics ability at age 17, and assessed the mediating effect of internalizing and externalizing problems at age 14, using UK Millennium Cohort Study data (N = 3622; 53% male). Self-reported frequency of SB (listening to music, Internet use, reading, and playing games) and parental-reported SB duration (time spent on TV viewing and doing homework) were collected at age 11. Behavioral issues were assessed at age 14 via the Strengths and Difficulties Questionnaire. Mathematics ability was examined at age 17 using the Number Analogies Activity Task. Negative binomial regression and mediation analysis (med4way in Stata) were applied. Among female adolescents, reading, doing homework, and using the Internet were positively associated with mathematics ability. For males, TV viewing was negatively associated with mathematics ability, mediated by internalizing problems. Findings suggest that in children sex-dependent association between SB characteristics and mathematical abilities exists, implying that future initiatives targeting SB may consider leveraging sex-specific interventions.

BACKGROUND AND OBJECTIVES:Maintaining cognitive function despite the presence of Alzheimer disease (AD) pathology is the foundation of cognitive reserve. Although the theory of cognitive reserve is strongly supported by empirical research, the field lacks standardized, validated methods for quantifying cognitive and brain reserve. We tested whether associations between AD pathology and cognitive function were modified by proxy measures of cognitive reserve (years of education, socioeconomic status; SES) and brain reserve (brain-predicted age difference, and a volumetric AD signature). We hypothesized that greater structural brain integrity, higher education, and higher SES would attenuate the association between greater AD pathology and poorer cognitive performance. METHODS:This cross-sectional study analyzed baseline data from a multisite randomized clinical trial, which was conducted at 3 US universities and enrolled cognitively unimpaired, physically inactive, community-dwelling adults. AD pathology was measured via plasma assays for phosphorylated tau (p-tau)-217 in the whole cohort, and PET for β-amyloid (Aβ) in a subset of participants as a secondary analysis. The primary outcome of cognitive function was evaluated by a comprehensive cognitive assessment. SES was measured via the MacArthur Socioeconomic Status Index, and magnetic resonance imaging was used to calculate brain-predicted age difference (brain-PAD) and a volumetric AD signature. Data were analyzed using linear regression models with interaction terms for moderation analyses. RESULTS:A total of 621 participants (aged 69.9 ± 3.8, 71% female) had available data for the main analyses and 355 had PET Centiloid data available. Brain-PAD moderated the association between AD pathology (measured by p-tau217) and multiple cognitive domains, including episodic memory (β = -0.09 [-0.16 to -0.02]), processing speed (β = -0.08 [-0.15 to -0.01]), working memory (β = -0.10 [-0.18 to -0.03]), and executive function/attentional control (β = -0.08 [-0.15 to -0.01]). Specifically, the negative association of greater AD pathology with poorer cognition was weakest in individuals with younger appearing brains. A latent SES score also moderated the relationship between p-tau217 and episodic memory (β = 0.08 [0.01-0.16]), but this did not survive correction for multiple comparisons. Neither years of education nor the volumetric AD signature moderated pathology-cognition associations. DISCUSSION:These results support the hypothesis that higher cognitive and brain reserve may help buffer the cognitive consequences of AD pathology. Strategies to increase both cognitive and brain reserve could help to boost resilience against emerging AD pathology; however, longitudinal studies are needed to confirm these conclusions.

Objectives:This study examined whether peripheral biological pathways including inflammation, insulin resistance, and arterial stiffness, partially explain the link between cardiorespiratory fitness (CRF) and cognitive function in older adults. Methods:In a cross-sectional sample of cognitively unimpaired older adults (N = 648, 71% female, M age = 69.88 ± 3.75 years), participants completed a comprehensive cognitive battery assessing executive function (EF)/Attentional control, episodic memory, processing speed, working memory, and visuospatial abilities. CRF was measured using a maximal graded exercise test performed on a motorized treadmill. Peripheral biomarkers included low-grade systemic inflammation (Interleukin-6; IL-6), insulin resistance (Homeostatic Model Assessment for Insulin Resistance; HOMA-IR) and arterial stiffness (carotid-femoral pulse wave velocity; cfPWV). Parallel mediation models, adjusted for age, sex, APOE4 carriage, body fat percentage, study site and years of education, tested whether these biomarkers statistically mediated associations between CRF and cognitive performance. Results:IL-6 emerged as a consistent significant mediator of the relationship between CRF and EF, episodic memory, visuospatial processing and working memory. HOMA-IR statistically mediated the association between CRF and both EF and processing speed. In contrast, cfPWV did not statistically mediate an association between CRF and performance in any cognitive domain. Conclusion:These findings suggest that low-grade systemic inflammation broadly mediates the relationship between CRF and cognitive function, while metabolic pathways show more domain-specific associations. Together, these results highlight the need for understanding the plural, yet distinct, biological mechanisms by which higher CRF relates to better cognitive performance, with the goal of identifying potential targets for interventions aimed at preserving cognitive health in older adulthood.

OBJECTIVES:The study investigates sex differences in how cardiorespiratory fitness (CRF) and accelerometry-based physical activity (PA) relate to depressive symptoms in community-dwelling older adults. We hypothesized that the relationship between higher CRF and PA levels with lower depressive symptoms would be more prominent in women relative to men. METHODS:Participants included 648 community-dwelling adults aged 65-80 (71% women [n = 461]; mean age [SD] = 69.88 [3.75]) without evidence of clinical depression (Geriatric Depression Scale score <9). CRF was assessed using a graded exercise test, and PA (light PA, moderate-to-vigorous PA [MVPA]) was assessed using a 7-day actigraphy protocol. Subsyndromal depressive symptoms were evaluated using the Hospital Anxiety and Depression Scale. Multiple linear regression analyses were performed to examine the relationships between CRF, light PA, MVPA, and depressive symptoms, adjusting for age, sex, years of education, body mass index, and anxiety symptoms, and to evaluate the moderating role of sex. RESULTS:Higher CRF and greater amounts of MVPA and light PA were associated with fewer depressive symptoms (β = -0.12, p = .010; β = -0.09, p = .021; and β = -0.13, p < .001, respectively) within the overall sample. However, moderation analysis by sex revealed that higher CRF was associated with fewer depressive symptoms only among female participants (β = -0.19, p < .001). Sex moderation effects were not observed for light PA or MVPA. DISCUSSION:These findings suggest CRF is a key physiological correlate of subsyndromal depressive symptoms in late life, particularly for women. Understanding sex-specific responses to PA may inform tailored prevention and intervention strategies targeting mood symptoms prior to full clinical expression of depression. CLINICAL TRIAL REGISTRATION NUMBER:NCT02875301.

INTRODUCTION:Subjective cognitive concerns frequently diverge from objective cognitive performance in cognitively unimpaired (CU) older adults, yet the neurobiological basis of this mismatch remains unclear. METHODS:In 648 participants from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE), we defined four profiles by integrating subjective and objective cognitive status. We examined associations with plasma neurofilament light chain (NfL), phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), a magnetic resonance imaging-based volumetric Alzheimer's disease (AD) signature reflecting atrophy, and brain-predicted age difference (brain-PAD). RESULTS:Joint profiles were differentially associated with NfL (P = 0.0427) and brain-PAD (P = 0.0296). Follow-up contrasts further indicated higher NfL and lower volumetric AD signature in the concordant lower functioning profile, and higher brain-PAD in discordant profiles. p-tau217 and GFAP did not differ across profiles. DISCUSSION:Joint subjective-objective cognitive profiles may capture biologically meaningful heterogeneity relevant to neurodegeneration and brain aging in older adults. TRIAL REGISTRATION:ClinicalTrials.gov: NCT02875301.

INTRODUCTION:Physical activity (PA) and cardiorespiratory fitness (CRF) are associated with reduced risk of cognitive decline and dementia, yet their relationships with dementia-related pathophysiology remain unclear. In a community-dwelling older adult cohort, we examined associations between objectively measured PA, CRF, biomarkers of Alzheimer's disease (AD)-related pathology, and cognition. METHODS:Participants (n = 648, 71% female, age 69.88 ± 3.75) completed a comprehensive cognitive evaluation, objective assessments of moderate-to-vigorous PA (MVPA) and CRF (VO2peak), and AD-related brain (positron emission tomography [PET] amyloid beta [Aβ]) and blood biomarkers (Aβ1-42/1-40, phosphorylated tau [p-tau]217, p-tau181, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]). RESULTS:Greater MVPA (β = -0.107; p = 0.013) and CRF (β = -0.114; p = 0.027) were associated with lower NfL, but not Aβ PET, p-tau217, Aβ1-42/1-40, or GFAP. Aβ positivity moderated the CRF-NfL relationship, with higher CRF linked to lower NfL specifically among Aβ-positive individuals. NfL mediated relationships between MVPA, CRF, and cognitive performance in select domains. DISCUSSION:Neuroprotective benefits of PA may be conferred through mechanisms influencing neurodegeneration, particularly among those with emerging AD pathology.

The development of Alzheimer's disease (AD) involves accumulation of brain pathology; however, some individuals appear to maintain cognitive and day-to-day function in the presence of neuropathology better than others. One likely contributor to this resilience is the maintenance of structural brain integrity to a greater extent than expected based on age-related norms, i.e., a younger ‘brain age’. In this study we examined whether brain age moderated the association between AD-related blood biomarkers and cognitive function. We utilized baseline data from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE) study. Cognitively unimpaired older adults ( n  = 648, aged 69.9±3.8, 71% female) completed a comprehensive cognitive assessment and an MRI scan where T1-weighted images were used to calculate brain age using brainageR. The difference between chronological age and brain age was used to calculate the brain-predicted age difference ( brain-PAD ). Assays were completed for plasma-based biomarkers phosphorylated tau ( p -tau) 217 and neurofilament light (NfL) measured on the SIMOA platform. After covarying for age, sex, site, BMI, image quality and education, brain-PAD moderated the association of p -tau217 with episodic memory (β=-0.09, SE  = 0.04, p  = .017), processing speed (β=-0.07, SE  = 0.04, p  = .046), working memory (β=-0.10, SE  = 0.04, p  = .005), and executive function/attentional control (β=-0.08, SE  = 0.04, p  = .035), but not visuospatial processing. The direction of these interactions was such that the association between higher p -tau217 and poorer cognitive performance was strongest in those with higher brain-PAD (i.e., accelerated brain aging). We do not find evidence of a significant moderation effect of brain-PAD on the association between NfL and cognitive performance in any domain (all p >.05). Our results suggest that maintenance of structural brain integrity (slower brain aging) may help protect against cognitive deficits in the face of AD pathology (i.e., p -tau217) in cognitively unimpaired individuals. These results provide support for the concept of brain maintenance, however, should be further tested in samples across the AD trajectory (i.e., mild cognitive impairment and AD). Understanding these mechanisms could inform strategies to promote resilience and delay AD-related cognitive decline in aging populations

The free radical theory of aging posits that oxidative stress is a key mechanism underlying aging and the onset and progression of neurodegeneration, leading to dementia and Alzheimer's disease (AD). Brain tissue undergoing oxidative stress is reflected by lower levels of brain glutathione (GSH), the major antioxidant in the brain, which provides a first line of defense against free radicals that are known to cause cellular damage, impaired cell function and eventual cell death. Brain GSH levels are depleted in individuals with mild cognitive impairment and AD, as GSH is consumed in this protective process. GSH levels are also tied to AD neuropathology, amyloid-β and tau, as well as with bioenergetics and mitochondrial function, all features underscoring aging and dementia. However, there remains a poor understanding of how GSH relates to different cognitive domains, especially in cognitively unimpaired older adults. We predicted that higher levels of GSH would reflect elevated antioxidant defenses and relate to better cognitive function. We employed MR spectroscopy (MRS) with advanced multiple quantum chemical shift imaging technique to map GSH levels in the human brain. Older adults ( n  = 206, 63 M, 143 F; age 69.8±3.9 years) from three geographical regions (Kansas City, Pittsburgh, Boston) underwent MR scans and a battery of cognitive testing for working memory, episodic memory, visuospatial processing, attentional control, and processing speed. A multiple regression model was used to evaluate the association between brain GSH and cognitive performance in each domain. Brain GSH levels were correlated positively with working memory ( p  = 0.019), episodic memory ( p  = 0.030), and visuospatial processing ( p  = 0.003), adjusted for sex, age and years of education. However, neither attentional control ( p  = 0.54) nor processing speed ( p  = 0.90) were significantly associated with brain GSH levels. Overall higher brain GSH levels were linked to better episodic memory, working memory, and visuospatial performance in older adults. Our findings contribute to our understanding of the potential role of antioxidant defenses in brain aging, suggesting that enhancing brain GSH levels may constitute a route for improving cognitive function in older adults.

INTRODUCTION Poor sleep is associated with neurodegenerative disease, but mechanisms are unclear. Greater volume of the choroid plexus (ChP), a brain structure supporting neurotoxic waste clearance, is linked to neurodegeneration and cognitive decline. We tested whether poor sleep promotes neurodegeneration and cognitive deficits via ChP dysfunction.METHODS Baseline magnetic resonance imaging (MRI) -derived ChP, hippocampal, ventricular, and gray matter volumes from 635 cognitively unimpaired older adults were analyzed. Sleep was measured with the Pittsburgh Sleep Quality Index and accelerometry. Confirmatory factor analysis generated cognitive domain scores.RESULTS Poorer self-reported sleep quality was associated with greater ChP volume, while accelerometry measures were not. Greater ChP volume was associated with smaller hippocampi and gray matter, and larger ventricles. ChP mediated relationships between sleep quality and hippocampal and ventricular volumes. Gray matter mediated associations between ChP and cognitive domains.DISCUSSION Altered ChP morphology may link poor sleep to neurodegeneration and cognitive decline in older adults.

The association between cognitive training and exercise motivation remains unclear, particularly when the training is not explicitly focused on modifying goal content. Our study investigated the impact of such training on exercise-related decision-making skills among a sample of low-active adults (N = 233; Mage = 46.7 years) who completed the Exercise Motivation Inventory-2 (EMI2) at baseline and one-month follow-up. Latent profile analyses (LPA) were used to identify participants’ motivational profiles at each time point, and longitudinal tests of profile similarity and latent transition analyses (LTA) assessed the replicability of these profiles and the stability of participants’ profile membership over time. Our results revealed four profiles, which were replicated over time: Weakly Motivated, Moderately Motivated with Fitness Orientation, Moderately Motivated with Psychological Well-being Orientation, and Strongly Motivated. Membership to these profiles was not influenced by participants demographic characteristics, and only minimally by baseline Fitbit steps and cardiorespiratory fitness. The first two profiles displayed fewer months (over a period of 12 months post-intervention) meeting physical activity guidelines, whereas the latter two showed higher levels of adherence. The Strongly Motivated profile was the least stable but most influenced by the cognitive training intervention, whereas the Moderately Motivated with Fitness Orientation was more stable but similarly influenced by the intervention. These findings highlight the potential of a multimodal cognitive training in influencing exercise motivation and behavior, providing practical implications for tailoring interventions to specific motivational profiles. Future research should investigate the specific types of cognitive training most effective for enhancing exercise motivation and adherence.