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.

Plasma amyloid-β (Aβ) peptides, alone or in ratio with p-tau217, show strong potential as Alzheimer’s disease biomarkers. While immunoprecipitation-mass spectrometry (IP-MS) is the preferred method for plasma Aβ quantification, current assays are resource- and time-intensive. Here, we developed a streamlined IP-MS method using a cost-effective instrument that significantly improved the efficiency of an original assay by incorporating a single immunoprecipitation step, an optimized buffer system, and approximately 75

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.

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.

BACKGROUND: Many autistic people seek therapy for mental health concerns or to improve emotional wellbeing. Unfortunately, there is limited guidance for providers on the most effective approach to improve mental health for autistic people. Therapies that target emotion dysregulation may be clinically effective and parsimonious. However, it remains unclear if emotion dysregulation interventions that were not developed for autism are effective or if interventions developed for autistic clients may confer additional benefits in terms of effectiveness and ease of implementation by community clinicians. The Emotion Awareness and Skills Enhancement (EASE) Program was developed to target emotion dysregulation specifically in autism, and has been shown to be efficacious for autistic youth and young adults in a standard clinical trial conducted in a research setting. METHODS: In this Hybrid Type 1 comparative effectiveness randomized controlled trial, we examine clinical impact and implementation outcomes across two treatments. The target intervention is a mindfulness-based curriculum developed for autistic clients (EASE) compared to the child, adolescent, and adult Unified Protocols (UP), established interventions rooted in cognitive-behavioral therapy that were not developed for autistic clients. This research is based on a community-driven, advisory model, including two community partner groups that provide input on project implementation. Providers are community clinicians at mental health agencies in Pennsylvania and Alabama, with randomization by agency. Clients include autistic individuals aged 10 to 30 years, with a target sample size of 400. Data are collected at pre-, mid-, post-, and 3 months following therapy. The primary aim is to test comparative effectiveness. The secondary aim is to evaluate the feasibility, benefits, harms, and implementation outcomes. A third exploratory aim focuses on moderators of outcome. EASE is hypothesized to outperform UP. The primary outcomes are client emotion dysregulation and provider-rated acceptability and feasibility of implementation. Secondary outcomes include responder status determined by a condition-naive interviewer, questionnaires of mental health, quality of life, and client satisfaction, and coder-rated therapeutic alliance. Qualitative data on feasibility and implementation outcomes is collected from clients, providers, and agency leaders. DISCUSSION: Findings will inform clinical decision-making and hopefully help increase access to evidence-based mental healthcare for autistic individuals. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov ID NCT06158581. It was first registered on 11/27/23.

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.

Different tasks of episodic memory (EM) are only moderately correlated with each other. Furthermore, various EM tasks exhibit disproportional relationships with the hippocampus. This study examined the covariance structure of EM tasks and assessed whether this structure relates differently to hippocampal volume (HV) in a sample of 648 cognitively unimpaired older adults (mean age = 69.88). A confirmatory factor analysis (CFA) and linear regression models were used to test the associations between the observed factors of EM and HV. A model with three first-order subfactors (immediate verbal recall, delayed verbal recall, and visuospatial) derived from a second-order EM domain factor satisfied model fit (χ2 p value ≥ 0.05, CFI > 0.90, RMSEA < 0.08, SRMR < 0.08). Total, left, and right HV explained a similar amount of variance in all EM subfactors. CA1, CA3, subiculum, and entorhinal cortex volume were associated with all subfactors, while CA2 and dentate gyrus volume were not associated with EM. These results suggest that EM tasks are measuring the same construct, but different complex processes contribute to EM. Furthermore, HV accounted for a small portion of the variance in EM, suggesting that HV might not be a useful marker of EM in cognitively unimpaired older adults. Finally, this study provides evidence that various hippocampal subfield volumes may not be purely associated with any one aspect of EM processing.

Lower lifetime estrogen exposure is associated with age- and Alzheimer’s-related reductions in brain volume, while estrogen-based therapies are associated with larger volume. We investigated associations between hormone-based medication use and structural neuroimaging markers, hypothesizing that hormone-based therapies would be associated with larger brain volumes. We investigated baseline associations in Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE), a multi-site, randomized exercise trial. We report structural data from magnetic resonance imaging. We processed the T1-MPRAGE using SPM12 and CAT12 software, adjusting for total intracranial volume. We focused on regions related to Alzheimer’s disease and higher concentrations of estrogen-beta receptors, dominant in the hippocampus. In 459 women (ages 65-80), we evaluated associations between retrospective recall of hormone-based medication use (birth control, menopausal hormone therapy) and brain volumes accounting for age, education, SES, and APOE4 carrier status. Birth control use (average start age 22) was associated with larger right parahippocampal volume (β = 0.100, p = 0.034). APOE4 carriers had smaller volumes in estrogen-beta-receptor regions (β=-0.096, p = 0.045). APOE4 carriers using birth control had smaller volumes than non-carriers using birth control (β=-.242, p=.028). Younger age when starting menopausal hormone-therapy was associated with greater white matter volume (β=-0.150, p = 0.037). These cross-sectional findings support the critical window hypothesis, i.e., timing of estrogen exposure is important for healthy brain aging. Our study uniquely links estrogen exposure in early adulthood to later-life brain structure. Future research should investigate mechanisms by which APOE4 may moderate estrogen’s influence on brain aging. Findings have clinical implications for estrogen therapies throughout the lifespan.

Poor sleep is associated with worse cognitive function in older adults. However, nuanced associations between sleep and cognition might be masked by the multidimensional nature of sleep which requires multiple approaches (e.g., self-report and actigraphy) to gain meaningful insight. We investigated associations of sleep with cognition and hypothesized that the most consistent association would be between self-reported sleep duration and actigraphy-measured wake after sleep onset (WASO). We utilized baseline data from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise study. Cognitively unimpaired older adults (n=589, aged 65–80) completed a comprehensive cognitive assessment with generation of five domain-specific cognitive composite scores. Sleep was measured via the Pittsburgh Sleep Quality Index (PSQI) and 24-h actigraphy (GT9X Link). Greater actigraphy WASO and shorter self-reported sleep duration were associated with poorer performance in all five cognitive domains (β[range: WASO] = −0.14 to −0.19, all p<0.05; β[range: duration] = 0.08–0.15, all p<0.05). Shorter actigraphy sleep duration was also associated with poorer EF/attentional control (β=0.09, p=0.020) and processing speed (β=0.10, p=0.013). Actigraphy and self-reported sleep were more strongly associated with episodic memory in older (74 years) and younger (66 years) individuals, respectively. Actigraphy-derived WASO was consistently and robustly associated with cognitive performance. Additionally, our results suggest that self-reported sleep duration provides insight into sleep behaviors related to brain health (e.g., long periods of still wakefulness), beyond actigraphy-measured sleep duration. Thus, both self-report and actigraphy measures of sleep provide critical and unique information for interpreting relationships with cognitive performance.

Aging is associated with heightened systemic inflammation, decline in selective aspects of cognition, and an increase in white matter lesions (WMLs). Both WMLs and systemic inflammation have been related to cognition. However, it is not clear how they interdependently relate to cognitive aging. In this study we examined whether WMLs mediate the relation between markers of systemic inflammation and cognition in late adulthood. Baseline data from the randomized clinical trial “Investigating Gains in Neurocognition in an Intervention Trial of Exercise” (IGNITE) were used, which included 598 healthy older adults (mean age=69.9±3.75 years). Interleukin 6 (IL-6) and Tumor Necrosis Factor Alpha (TNF-α) were included as markers of systemic inflammation. A confirmatory factor analysis of cognitive performance resulted in factors measuring episodic memory (EM), processing speed (PS), working memory (WM), attentional control (AC), and visuospatial function (VF). WML volumes were computed from FLAIR and T1 scans using UBO detector. Mediation models were run with age, sex, years of education, and study site included as covariates. Higher levels of IL-6 were associated with more WMLs (b = 0.12, p < 0.001) as well as lower scores on all cognitive factors (all p < 0.03). In contrast, higher levels of TNF- α were associated with more WMLs (b = 0.10, p < 0.05) but not with any of the cognitive measures (all p > 0.3). More WMLs were associated with poorer PS, WM, AC, and VF (all p < 0.03), but not EM (all p > 0.05). Further, associations between IL-6 and measures of PS, WM, AC, and VF were statistically mediated by WMLs (all b = -0.01, all p < 0.05). These findings suggest that markers of systemic inflammation might lead to poorer cognitive performance by impacting WMLs. The differences between IL-6 and TNF-α with cognition highlight the need for more research to understand how different cytokine pathways relate to cognition. Our results are important for building a mechanistic framework to understand the interplay between inflammation, WMLs, and cognition and could inform the development of targeted interventions focusing on regulating cytokines to support brain health and cognitive aging.

INTRODUCTION:Age-related cognitive decline occurs, in part, due to diminishing white matter integrity. Higher cardiorespiratory fitness (CRF) is associated with better cognitive performance, but the neurobiological mechanisms underlying this association remain uncertain. Previous magnetic resonance imaging (MRI) studies have suggested that CRF-related changes in white matter microstructure might prevent or slow age-related cognitive decline, but have been limited by small sample sizes and methodological limitations. Specifically, most prior studies used tensor-based diffusion-weighted MRI metrics, which are insensitive to complex white matter architectures, including crossing fibers. METHODS:Here, we leveraged a novel analysis framework capable of resolving individual fiber populations at the within-voxel level-fixel-based analysis (FBA)-to analyze three metrics of white matter organization from diffusion-weighted MRI scans: fiber density (FD), fiber cross-section (FC), and their combined measure (FDC). Using a cross-sectional sample of 636 cognitively unimpaired older adults aged 65 to 80 years (mean age = 69.8 years; 71% female), we hypothesized that FBA metrics would be associated with CRF and that this variation in FBA metrics would mediate associations between CRF and cognitive performance. RESULTS:In whole-brain analyses, higher CRF was associated with greater FD, FC, and FDC. Furthermore, these FBA-derived metrics statistically mediated the relationship between CRF and cognitive performance in the domains of visuospatial abilities, processing speed, working memory, and executive function/attentional control, but not episodic memory. DISCUSSION:These findings highlight the potential for CRF in the preservation of multiple aspects of cognition as a function of white matter micro- and macro-structural properties. Our results provide novel insights into the neurobiological mechanisms of fitness-related cognitive resilience. Highlights:Higher cardiorespiratory fitness (CRF) is linked to better white matter integrity in older adults.Fixel-based analysis reveals CRF associations with fiber density and cross-section.White matter properties mediate CRF effects on cognition, excluding episodic memory.Findings suggest CRF supports cognitive resilience via white matter organization.

BACKGROUND:Midlife lifestyle factors, including physical activity, are associated with late-life brain health, yet the role of aerobic exercise on structural brain health in early and mid-adulthood remains poorly understood. This study aimed to examine the effect of aerobic exercise on structural brain age and to explore potential mediators. METHODS:In a single-blind, 12-month randomized clinical trial, 130 healthy participants aged 26-58 years were randomized into a moderate-to-vigorous intensity aerobic exercise group or a usual-care control group. The exercise group attended two supervised 60-min sessions per week in a laboratory setting plus engaged in home-based exercise to achieve 150 min of exercise per week. Brain-predicted age difference (brain-PAD) and cardiorespiratory fitness (CRF) were assessed at baseline and 12 months. Both intention-to-treat (ITT) and completers analyses (including participants who completed post-intervention assessments) were performed. RESULTS:The 130 participants (67.7% female) had an age of 41.28 ± 9.93 years (mean ± SD). At baseline, higher CRF (peak oxygen uptake, VO2peak) was associated with smaller brain-PAD (β = -0.309, p = 0.012). After the intervention, the exercise group showed a decrease in brain-PAD (estimated mean difference (EMD) = -0.60; 95% confidence interval (95%CI): -1.15 to -0.04; p = 0.034) compared to the control group (EMD = 0.35; 95%CI: -0.21 to 0.92; p = 0.217); time × group interaction (between-group difference (BGD) = -0.95; 95%CI: -1.72 to -0.17; p = 0.019). VO2peak improved in the exercise group (EMD = 1.60; 95%CI: 0.29-2.90; p = 0.017) compared to the control group (EMD = -0.78; 95%CI: -2.17 to 0.60; p = 0.265); time × group interaction (BGD = 2.38; 95%CI: 0.52-4.25; p = 0.015). Body composition, blood pressure, and brain-derived neurotrophic factor levels were unaffected. None of the proposed pathways statistically mediated the effect of exercise on brain-PAD. The results from completers were similar. CONCLUSION:Engaging in 12 months of moderate-to-vigorous exercise reduced brain-PAD in early-to-midlife adults. The pathways by which these effects occur remain unknown.