Interplay of Large Neutral Amino Acids, Metabolic Syndrome, and Apolipoprotein E ε4 on Brain Integrity at Midlife.

INTRODUCTION: Large neutral amino acids (LNAAs) tryptophan and phenylalanine have been implicated in the pathogenesis of neurodegenerative diseases. Given limited research on the effects of LNAA on brain health across different life stages, vascular risk, and genetic backgrounds, our study aimed to explore the interaction of LNAA levels, metabolic syndrome (MetS), and the presence of the apolipoprotein E ε4 (ApoE ε4) allele brain integrity at midlife. METHODS: Sixty-eight adults aged 40-61 underwent a health assessment to calculate the number of MetS components, quantify LNAA, measure white matter hyperintensity (WMH) volume, and genotype ApoE ε4. Multivariate linear regression analyses were performed to test the joint effect of LNAA, MetS, and ApoE ε4 on WMH while adjusting for sex, age, and education. RESULTS: Significant 3-way interactions were observed between serum tryptophan (ß = 0.042, SE = 0.018, p < 0.05) and phenylalanine (ß = 0.044, SE = 0.013, p < 0.01) levels, number of MetS components, and ApoE ε4 alleles status on WMH volume. Neither individual LNAA levels nor MetS components alone predicted WMH volume. CONCLUSIONS: The study highlights significant 3-way interactions between LNAA, MetS, and genetic risk factors in the pathology of WMH, particularly in individuals genetically predisposed to Alzheimer's disease. These interactions suggest differential impacts of LNAA on WMH volume dependent on both genetic and metabolic factors. Results emphasize the need for personalized metabolic and genetic profile assessments in neurodegenerative disease management.

Age exacerbates the negative effect of depression on executive functioning in racial and ethnic minorities.

Age and depression may interact to produce a "double jeopardy" for cognitive impairment, and executive functioning, in cognitively unimpaired aging. Few studies have considered middle age or the ethnoracial diversity of subjects, despite evidence of more severe cognitive outcomes in historically minoritized people. In this pilot study, we investigated the impact of age on depression-related cognitive impairment and the underlying brain volumes in middle-aged non-Hispanic White adults (116), and Hispanic and Black adults (60), with a total number of 176 adults. The result shows a significant interaction between age and depression for executive functioning, specifically for middle-aged Hispanic and Black adults, but not non-Hispanic White adults. Prefrontal cortex volumes, which were reduced in the Black and Hispanic compared to the non-Hispanic White adults, partially mediated the relationship between depression level and executive functioning, across age and ethnoracial group. Collectively, these results suggest that the negative impact of depression on executive functioning and Prefrontal cortex volumes integrity may be exacerbated by age and that historically minoritized people may be particularly sensitive to this double jeopardy.

Large Neutral Amino Acids Moderate the Effects of Metabolic Syndrome on Cognitive Performance in Middle-Aged Adults.

INTRODUCTION: Two large neutral amino acids (LNAA), tryptophan and tyrosine, are precursors to cerebral neurotransmitters and are involved in cognitive function. Higher levels of LNAA in young adults are associated with improved cognition, although these associations appear to reverse over time. Given that exposure to metabolic syndrome (MetS) may induce premature cognitive aging, the current project aims to fill the gap in the literature by examining the effect of LNAA on cognitive performance in midlife adults with metabolic risks. METHODS: Eighty-eight adults, ages 40-61 years, participated in this cross-sectional study. LNAA metabolites were quantified, MetS components were measured using high-performance liquid chromatography, and MetS components were assessed in the laboratory. Composite verbal memory and executive functioning scores were computed using principal component analysis. We used linear regression models to test the interaction between LNAA and MetS while covarying for sex, age, and education. RESULTS: The kynurenine/tryptophan ratio moderated the relation between MetS and verbal memory, even after adjusting for relevant covariates. Tyrosine metabolites were not significant moderators of the association between MetS and executive functioning. CONCLUSION: Our findings suggest that the detected weaker memory performance in adults with a high number of MetS components may be related to relative tryptophan depletion and possible decreases in serotonin production. Further investigation is warranted to examine the potential role of LNAA in associations between cognitive performance and metabolic risks over time.

Association between Large Neutral Amino Acids and Brain Integrity in Middle-Aged Adults at Metabolic Risk.

This investigation delves into the interplay between large neutral amino acids (LNAA) and metabolic syndrome (MetS) in midlife adults, examining their collective influence on brain structure and cognitive function. While LNAA, such as tryptophan and phenylalanine, are known to bolster cognition in youth, our study hypothesizes a reversal of these benefits in older adults with MetS, potentially signaling premature cognitive aging. Eighty participants between 40-61 years underwent MetS component quantification, LNAA measurement via high-performance liquid chromatography, and brain imaging to evaluate white matter hyperintensity (WMH) volume and medial temporal lobe (MTL) cortical thickness. Our linear regression analysis, adjusting for sex, age, and education, revealed that phenylalanine levels moderated the relationship between MetS and WMH volume (F(6, 69) = 3.134, p < 0.05, R2 = 0.214), suggesting that MetS's cognitive impact may be partly due to phenylalanine catabolism byproducts. However, LNAA metabolites did not significantly modulate the MetS-MTL cortical thickness relationship. The findings suggest that LNAA metabolic dysregulation, marked by elevated levels in the presence of MetS, could correlate with brain structural compromises, particularly in the form of MTL cortical thinning and increased WMH load, detectable in midlife. This nuanced understanding of LNAA's role in cognitive health amid cardiovascular risk factors is pivotal, proposing a potential biomarker for early intervention. Further research is crucial to elucidate the longitudinal influence of LNAA and MetS on brain health, thereby informing strategies to mitigate cognitive decline.

Empirically derived psychosocial-behavioral phenotypes in Black/African American and Hispanic/Latino older adults enrolled in HABS-HD: Associations with AD biomarkers and cognitive outcomes.

INTRODUCTION: Identification of psychosocial-behavioral phenotypes to understand within-group heterogeneity in risk and resiliency to Alzheimer's disease (AD) within Black/African American and Hispanic/Latino older adults is essential for the implementation of precision health approaches. METHODS: A cluster analysis was performed on baseline measures of socioeconomic resources (annual income, social support, occupational complexity) and psychiatric distress (chronic stress, depression, anxiety) for 1220 racially/ethnically minoritized adults enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD). Analyses of covariance adjusting for sociodemographic factors examined phenotype differences in cognition and plasma AD biomarkers. RESULTS: The cluster analysis identified (1) Low Resource/High Distress (n = 256); (2) High Resource/Low Distress (n = 485); and (3) Low Resource/Low Distress (n = 479) phenotypes. The Low Resource/High Distress phenotype displayed poorer cognition and higher plasma neurofilament light chain; differences between the High Resource/Low Distress and Low Resource/Low Distress phenotypes were minimal. DISCUSSION: The identification of psychosocial-behavioral phenotypes within racially/ethnically minoritized older adults is crucial to the development of targeted AD prevention and intervention efforts.

Lower Body Mass Index at Baseline Is Related to Steeper Cognitive Decline in the Alzheimer's Disease Neuroimaging Initiative Cohort.

OBJECTIVE: Midlife obesity is a risk factor for dementia, whereas obesity in older age may be protective of cognition, a phenomenon known as the "obesity paradox." The mechanisms underlying this phenomenon and the relationship between body mass index (BMI) and cognitive function over time remain unclear. METHODS: In 1399 adults with and without mild cognitive impairment (median age 73.6 years) from the Alzheimer's Disease Neuroimaging Initiative, we modeled the effects of baseline BMI on within-person trajectories of cognitive decline using Latent Growth Curve Modeling. We also tested if the effects of BMI on cognitive decline are global or specific to memory, executive function, or language. RESULTS: Higher baseline BMI was associated with better memory ( ßBMI = 0.06, p < .05) and worse executive function ( ßBMI = -0.05, p < .05) and not associated with language. Independent of baseline diagnosis, higher baseline BMI was associated with slower rate of decline in executive function, memory, and language ( ßBMI = 0.13, 0.12, and 0.12, respectively; p < .01). Higher BMI was not associated with the intercept ( ßBMI = 0.04, p = .059) or change ( ßBMI = 0.04, p = .415) in a global cognitive factor. CONCLUSIONS: We found that higher baseline BMI was associated with slower cognitive decline in participants with and without mild cognitive impairment diagnosis. Higher BMI in this context seems to be protective of cognitive function for people at risk for dementia. Our findings also support domain-specific effects of obesity on various cognitive functions rather than a final common pathway.

Fatty Acid-Binding Protein 3 Is a Marker of Neurodegeneration and White Matter Hyperintensity Burden in Mexican American Older Adults.

We examined ethnoracial differences in fatty acid binding protein (FABP)-a family of intracellular lipid carriers-and clarified FABP3 associations with gray and white matter. Relative to Mexican Americans (MAs), FABP3 was higher in Non-Hispanic Whites (NHWS, p < 0.001). Regressions revealed, independent of traditional AD markers, FABP3 was associated with neurodegeneration (B = -0.08, p = 0.003) and WMH burden (B = 0.18, p = 0.03) in MAs, but not in NHWs (ps > 0.18). Findings suggest FABP3 is related to neural health within MAs and highlight its potential as a prognostic marker of brain health in ethnoracially diverse older adults.

An examination of the clinical utility of phonemic fluency in healthy adults and adults with mild cognitive impairment.

The Controlled Oral Word Association Test (COWAT) is a widely utilized measure of phonemic fluency. However, two issues remain: (1) whether demographic, cognitive variables, or version of test administered predict performance; (2) if the test is predictive of Mild Cognitive Impairment (MCI). Recent studies report that item-level analyses such as lexical frequency may be more sensitive to early cognitive change. The purpose of this study was to examine the clinical utility of the COWAT, considering both total correct words and the lexical frequency. Sixty-seven healthy adults and thirty-seven adults with MCI completed neuropsychological testing. Mann-Whitney U tests were used to determine if there was a difference in COWAT performance between groups. Elastic net regression models were used to assess whether variance in total scores/lexical frequencies can be predicted by demographics, test version, or diagnosis; which cognitive tests explained the variance in performance; and how total scores and lexical frequencies compared with other cognitive tests in predicting diagnosis. Overall, individuals with MCI produced fewer and higher frequency words. The variance in total correct words or lexical frequency was not explained by demographics, test version, or diagnosis. Total correct words was a more important predictor of diagnosis than lexical frequency.

Influence of endogenous estrogen on a network model of female brain integrity.

Recent reports document sex differences in midlife brain integrity and metabolic health, such that more relationships are detectable between metabolic syndrome (MetS) components and markers of brain health in females than in males. Midlife is characterized by a rapid decrease in endogenous estrogen levels for women which is thought to increase risk for cardiometabolic disease and neurocognitive decline. Our study used network models, designed to explore the interconnectedness and organization of relationships among many variables at once, to compare the influence of endogenous estrogen and chronological age on a network of brain and metabolic health in order to investigate the utility of estrogen as a biomarker for brain vulnerability. Data were analyzed from 82 females (ages 40-62). Networks consisted of known biomarkers of risk for late-life cognitive decline: the five components of MetS; Brain-predicted age difference calculated on gray and white matter volume; white matter hyperintensities; Default Mode Network functional connectivity; cerebral concentrations of N-acetyl aspartate, glutamate and myo-inositol; and serum concentrations of estradiol. A second network replaced estradiol with chronological age. Expected influence (EI) of estradiol on the network was -1.190, relative to chronological age at -0.524, indicating that estradiol had a stronger expected influence over the network than age. A negative expected influence indicates that higher levels of estradiol would be expected to decrease the number of relationships in the model, which is thought to indicate lower risk. Overall, levels of estradiol appear more influential than chronological age at midlife for relationships between brain integrity and metabolic health.

Network Modeling Sex Differences in Brain Integrity and Metabolic Health.

Hypothesis-driven studies have demonstrated that sex moderates many of the relationships between brain health and cardiometabolic disease, which impacts risk for later-life cognitive decline. In the present study, we sought to further our understanding of the associations between multiple markers of brain integrity and cardiovascular risk in a midlife sample of 266 individuals by using network analysis, a technique specifically designed to examine complex associations among multiple systems at once. Separate network models were constructed for male and female participants to investigate sex differences in the biomarkers of interest, selected based on evidence linking them with risk for late-life cognitive decline: all components of metabolic syndrome (obesity, hypertension, dyslipidemia, and hyperglycemia); neuroimaging-derived brain-predicted age minus chronological age; ratio of white matter hyperintensities to whole brain volume; seed-based resting state functional connectivity in the Default Mode Network, and ratios of N-acetyl aspartate, glutamate and myo-inositol to creatine, measured through proton magnetic resonance spectroscopy. Males had a sparse network (87.2% edges = 0) relative to females (69.2% edges = 0), indicating fewer relationships between measures of cardiometabolic risk and brain integrity. The edges in the female network provide meaningful information about potential mechanisms between brain integrity and cardiometabolic health. Additionally, Apolipoprotein ϵ4 (ApoE ϵ4) status and waist circumference emerged as central nodes in the female model. Our study demonstrates that network analysis is a promising technique for examining relationships between risk factors for cognitive decline in a midlife population and that investigating sex differences may help optimize risk prediction and tailor individualized treatments in the future.

Metabolic syndrome components moderate the association between executive function and functional connectivity in the default mode network.

Middle aged individuals with Metabolic Syndrome are at high risk for cognitive decline. Dyssynchrony in the resting state Default Mode Network is one early indicator of brain vulnerability. We set out to explore the relationship between default mode resting state functional connectivity and cognitive performance in both memory and executive domains at midlife in the presence of Metabolic Syndrome components. Seed-based Correlation Analyses were performed between the seed voxel in the posterior cingulate cortex and the medial prefrontal cortex on 200 participants (ages 40-61). Executive domain scores were significantly predicted by the interaction between number of Metabolic Syndrome components and resting state connectivity in the Default Mode Network (p = .004) such that connectivity was negatively related to executive function at higher numbers of Metabolic Syndrome components. Results were not significant for memory. Our findings indicate that clusters of cardiovascular disease risk factors alter functional relationships in the brain and highlights the need to continue exploring how compensatory techniques might operate to support cognitive performance at midlife.

Metabolic Syndrome and Cognitive Function in Midlife.

OBJECTIVE: Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors associated with cognitive decline. We investigated the relationship between MetS and cognition in middle-aged adults. We hypothesized that higher numbers of MetS components will relate to poorer performance on executive function (EF) tasks as frontal lobe regions critical to EF are particularly vulnerable to cardiovascular disease. METHODS: 197 adults (ages 40-60) participated. MetS was evaluated using established criteria. Composite scores for cognitive domains were computed as follows: Global cognitive function (subtests from the Wechsler Abbreviated Scale of Intelligence, 2nd Edition), EF (Stroop Color Word, Digit Span Backward, and Trails A and B), and memory (California Verbal Learning Test, 2 Edition). RESULTS: Higher number of MetS components was related to weaker EF-F(4, 191) = 3.94, p = .004, MetS components ß = -.14, p = .044. A similar relationship was detected for tests of memory-F(4, 192) = 7.86, p < .001, MetS components ß = -.15, p = .032. Diagnosis of MetS was not significantly associated with EF domain score (ß = -.05, p = .506) but was significantly associated with memory scores-F(4, 189) = 8.81, p < .001, MetS diagnosis ß = -.19, p = .006. CONCLUSIONS: Our findings support prior research linking MetS components at midlife to executive dysfunction and demonstrate that MetS, and its components are also associated with poorer memory function. This suggests that cognitive vulnerability can be detected at midlife. Interventions for MetS at midlife could alter cognitive outcomes.

Cognition, Brain Structure, and Brain Function in Individuals with Obesity and Related Disorders.

PURPOSE OF REVIEW: Obesity is one of the most serious public health concerns. Excess adipose tissue, particularly with a centralized distribution, is associated with cognitive decline. Indeed, obesity has been associated with a number of adverse changes in brain function and structure that can be detected by neuroimaging techniques. These obesity-associated changes in the brain are associated with cognitive dysfunction. RECENT FINDINGS: While the pathways by which excess adipose tissue affects brain function are not fully understood, available evidence points towards insulin resistance, inflammation, and vascular dysfunction, as possible mechanisms responsible for the observed relations between obesity and cognitive impairment. It appears that weight loss is related to better brain and cognitive outcomes and that cognitive impairment due to obesity may be reversible.

Association of Dementia and Vascular Risk Scores With Cortical Thickness and Cognition in Low-risk Middle-aged Adults.

BACKGROUND: Increased risk for the future development of Alzheimer disease begins as early as midlife. Algorithm-based scores, such as the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score, and the Framingham general cardiovascular disease (CVD) risk score, have been used to determine future risk for the development of cognitive decline and dementia. We evaluated the association between neuroimaging and cognitive measures with the 2 risk scores in middle-aged, cognitively intact adults (49±6 y). METHODS: In a cohort of 132 participants collected in 2014, magnetic resonance imaging was used to determine measures of cortical thickness in a priori regions of interest and a neuropsychological battery to assess memory and executive function. RESULTS: The CAIDE dementia risk score was significantly and inversely associated with the cortical thickness of the parahippocampal (r=-0.266; P=0.002) and superior frontal gyrus (r=-0.261; P=0.002) despite a considerable percentage of individuals (99.3%) at low risk for CVD. There was a significant negative association between CAIDE and memory (r=-0.251; P=0.003). Framingham general CVD score was not associated with brain structure or cognitive function. CONCLUSIONS: These results indicate that the CAIDE dementia risk score is associated with cortical thickness and cognitive function at midlife in a low-risk population. These data provide insight into subclinical structural and functional changes occurring during midlife associated with future risk for the development of dementia.

Obesity and the Brain: Another Brain-Body Versus Body-Brain Conundrum.

Midlife obesity has been associated with poor cognitive functioning in older age, but the bidirectional pathways linking the brain and excessive adipose tissue require further research. In this issue of Psychosomatic Medicine, two investigations address the brain responses to food-related cues and psychological stressors relevant to obesity. Moazzami and colleagues document the relationship between abdominal obesity and brain responses to stress among patients with coronary artery disease and find that stress-related brain activity plays a potentially important role in the link between psychological distress, food cravings, and eating patterns relevant to obesity. Donofry and colleagues compare food cue-evoked functional connectivity in adults with obesity and report that brain areas involved in impaired self-regulation and reward processing may increase the risk of obesity by influencing decisions regarding diet and exercise. In this editorial, these findings are discussed in the context of brain-obesity interactions and the need for personalized multidisciplinary interventions for obesity. It is possible that functional magnetic resonance imaging and other indices of brain functioning will be useful in tailoring interventions that target weight reduction and/or cognitive functioning and monitoring treatment progress.

Exploring Relationships Among Peripheral Amyloid Beta, Tau, Cytokines, Cognitive Function, and Psychosomatic Symptoms in Breast Cancer Survivors.

OBJECTIVE: Accelerated brain aging has been proposed to explain cancer-related cognitive impairment, but empirical evidence for this relationship is lacking. The purpose of this study was to evaluate amyloid beta (Aß) and tau, biomarkers of neurodegeneration, in relation to cognition in breast cancer survivors (BCSs). We explored relationships among peripheral concentrations of Aß42, Aß-40, tau, and cytokines; cognitive function; and psychosomatic symptoms in a cohort of BCSs post-chemotherapy. METHODS: This secondary analysis of a cross-sectional study was conducted with 65 BCSs. Serum total Aß-42, Aß-40, and tau levels were measured with single molecule array technology. Cytokines (interleukin [IL]-6, tumor necrosis factor [TNF]-α, granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon [IFN]-g, IL-10, IL-12, IL-13, IL1-b, IL-2, IL-4, IL-5, IL-7, and IL-8) were simultaneously measured in serum using multiplex assays. Cognitive function was measured with five standardized neuropsychological tests and psychosomatic symptoms (stress, loneliness, anxiety, depressive symptoms, fatigue, sleep quality, and daytime sleepiness) with self-report questionnaires. Data analyses included correlations and random forest regression (RFR). RESULTS: Significant correlations were identified among hip-to-waste ratio, number of treatment modalities, Aß-42, Aß-40, and tau levels (rs = .27-.35, ps < .05). RFR modeling including Aß-42, Aß-40, tau, and cytokines as features explained significant variance in cognitive function (R2 = .71, F = 9.01, p < .0001) and psychosomatic symptoms (R2 = .74, F = 10.22, p < .0001). CONCLUSIONS: This study suggests that neurodegenerative biomarkers interact with cytokines to influence cognitive functioning and psychosomatic symptoms in BCSs following chemotherapy, but additional research is needed.

Apolipoprotein E genotype moderates the association between dietary polyunsaturated fat and brain function: an exploration of cerebral glutamate and cognitive performance.

Objective: To investigate the effect of Apolipoprotein E (APOE) genotype on the association between dietary polyunsaturated fat (PUFA), cognitive function, and cerebral glutamate. Methods: A participant sample of 122 middle-aged adults were grouped according to APOE genotype (ϵ4 carrier or ϵ4 non-carrier) and asked to record dietary intake for three consecutive days. All participants also underwent neuropsychological testing and a proton magnetic resonance spectroscopy (1H MRS) scan to assess glutamate in the posterior cingulate cortex. Results: Multiple regression analyses revealed a significant interaction between APOE genotype and PUFA intake on memory performance, F(1,113) = 6.749, p = .016. Greater PUFA intake was associated with better memory performance in healthy middle-aged adults who were APOE ϵ4 non-carriers, but not for ϵ4 carriers. Furthermore, there was a significant interaction between APOE genotype and PUFA intake on cerebral glutamate, in that dietary PUFA was associated with greater cerebral glutamate in APOE ϵ4 carriers, but not for ϵ4 non-carriers, F(1,114) = 5.173, p = .025. Conclusions: The findings suggest that PUFA action on the brain differs according to APOE polymorphism and points towards cerebral glutamate as a potential marker of genetic risk for Alzheimer's disease (AD). Early treatment consisting of PUFA supplementation that is tailored to APOE genotype may be an important intervention for the prevention of cognitive decline.

Phenotypic heterogeneity of obesity-related brain vulnerability: one-size interventions will not fit all.

Intact memory and problem solving are key to functional independence and quality of life in older age. Considering the unprecedented demographic shift toward a greater number of older adults than children in the United States in the next few decades, it is critically important for older adults to maintain work productivity and functional independence for as long as possible. Implementing early interventions focused on modifiable risk factors for cognitive decline at midlife is a strategy with the highest chance of success at present, bearing in mind the current lack of dementia cures. We present a selective, narrative review of evidence linking nutrition, body composition, vascular health, and brain function in midlife to highlight the phenotypic heterogeneity of obesity-related brain vulnerability and to endorse the development of individually tailored lifestyle modification plans for primary prevention of cognitive decline.

Associations of carotid arterial compliance and white matter diffusion metrics during midlife: modulation by sex.

Sex differences in cerebral white matter (WM) aging have been debated extensively over the past 2 decades without unequivocal resolution. We aimed to determine if the effects of age and arterial stiffness on WM microstructure differ between sexes. Artery elasticity via carotid artery compliance (CAC) and WM diffusion metrics via diffusion tensor image-derived fractional anisotropy (FA) and mean diffusivity (MD) were measured in 155 (87 females) middle-aged (40-62 years) adults. Males demonstrated poorer water diffusion metrics in WM than women in the corpus callosum body, cingulum, and cingulum (hippocampal). Age and CAC had greater effects on WM water diffusion in males than females in midlife independent of education and cardiovascular risk factors. Sex-moderated age (cingulum FA, cingulum [hippocampal] MD, and uncinate MD, all p < 0.05) and CAC (cingulum FA, p < 0.05) related reductions in regional WM diffusion metrics. CAC mediated age-related associations in regional WM diffusion metrics (cingulum FA, cingulum MD, superior corona radiata MD, and uncinate MD, all p < 0.05) in males but not in females. Age and CAC were associated with WM diffusion metrics independent of cardiovascular risk factors. These associations appear to be stronger in males than in females.

Physical activity mitigates adverse effect of metabolic syndrome on vessels and brain.

Metabolic syndrome (MetS) adversely affects the vasculature and cerebral white matter (CWM) integrity. Arterial stiffening has been associated with diminished CWM integrity. Physical activity (PA) can ameliorate components of MetS and subsequently affect arterial stiffening and CWM integrity. Our aim was to determine the role of PA on mitigating the adverse influence of MetS on arterial stiffness and CWM integrity. In a cross-sectional study design, sixty-six middle-aged adults (40-62 years) composed of 18 sedentary MetS (Sed MetS), 21 physically active MetS (Active MetS), and 27 healthy individuals absent of MetS risk factors were studied. Carotid artery stiffness was assessed via simultaneous ultrasound and tonometry. CWM integrity was measured using diffusion tensor imaging (DTI) through metrics of fractional anisotropy (FA) and mean diffusivity (MD). Carotid ß-stiffness index in Active MetS was lower than Sed MetS but was not different from Healthy controls (6.6 ± 1.5, 7.7 ± 2.1, and 5.6 ± 1.6 au, p = 0.001). CWM integrity was significantly greater in Active MetS subjects compared to Sed MetS subjects but statistically equal to Healthy controls in the anterior limb of the internal capsule, and splenium of the corpus callosum, uncinate fasciculus, and superior corona radiata (all p < 0.05). Middle-aged individuals with MetS who habitually perform PA demonstrated lower arterial stiffness and more favorable CWM integrity than their sedentary peers, indicating that PA may be effective in mitigating the adverse effects of MetS on the vasculature and brain at midlife.