Infections remain a major cause of mortality and may threaten healthy aging. Previous studies have focused on isolated severe infections rather than longitudinal infection burden. We aimed to examine associations of infection trajectories with biological age acceleration (BAA) and assessed infection severity and genetic susceptibility. We included adults aged 20–74 years from the Shanghai Suburban Adult Cohort and Biobank, China, enrolled between 2016 and 2019 with valid biological age (BA) measurements at baseline and follow-up. Infection-related episodes were identified from linked local health information systems and summarized quarterly between baseline and first follow-up. Group-based trajectory modeling identified infection trajectories. BA was estimated using the Klemera-Doubal method and BAA was defined as the residual from regressing BA on chronological age. Linear mixed-effects models assessed associations with annual BAA change. Polygenic risk scores and Cox models evaluated genetic susceptibility and all-cause mortality. Among 7614 participants, four infection trajectories were identified: infrequent (71.15
Workplace stress is an increasingly recognized determinant of both workforce well-being and healthy aging. However, few longitudinal studies have systematically integrated stress assessment into large occupational cohorts with an explicit focus on aging processes. The Semmelweis Study, launched in 2024, addresses this gap by embedding validated stress assessment tools into a comprehensive, multidisciplinary framework designed to explore the biological, psychological, and social determinants of healthy and unhealthy aging in a university workforce. This paper presents the conceptual foundation, methodology, and early applications of workplace stress assessment within the Semmelweis Study. We outline research hypotheses linking stress to aging outcomes and describe a pilot investigation among a high-risk subgroup-conductors trained at the András Pető Faculty of Semmelweis University. Stress is assessed using validated psychometric tools, including the Perceived Stress Scale, Effort-Reward Imbalance Questionnaire, Maslach Burnout Inventory, resilience measures, and social support scales. These are integrated with biological aging markers, cognitive assessments, mental health indicators, lifestyle factors, and detailed occupational data. A pilot study applying this framework was conducted among conductors, a professional group known for high emotional demands and role strain. Preliminary findings indicate elevated stress levels and burnout symptoms among conductors, with workload, perfectionism, and emotional burden identified as key stressors. Participants expressed strong interest in workplace-based stress management resources, informing plans for targeted interventions within this group. The integration of workplace stress assessment into the Semmelweis Study offers a novel platform for advancing healthy aging research and informing real-world prevention strategies. By systematically linking stress measurement to aging outcomes, and by addressing occupational stress through targeted interventions, Semmelweis University exemplifies how academic institutions can act as both research leaders and models of healthy workplace practices. These efforts align with the Semmelweis-EUniWell Workplace Health Promotion Model Program and contribute to broader European efforts to promote resilience, well-being, and healthy longevity across the working life course.
Language impairment is increasingly recognized as an early marker of neurodegeneration in mild cognitive impairment (MCI). L5, an electronegative subfraction of low-density lipoprotein cholesterol, has been implicated in both vasculopathy and neurodegenerative processes, positioning it as a potential contributing factor to MCI pathology. This study investigates alterations in the connectivity and dynamics of core language networks and aims to elucidate the diverse pathophysiological processes underlying language decline. We enrolled 22 patients with clinically defined MCI and 30 cognitively normal individuals. Cognitive function was assessed using the Cognitive Abilities Screening Instrument. Serum L5 levels were quantified by anion-exchange chromatography. Resting-state functional magnetic resonance imaging (MRI) was used to evaluate functional connectivity and Granger causal interactions within predefined language-related regions. Correlation analyses and prespecified multivariable linear regression models were performed to examine the independent associations among serum L5 percentage (L5
Alzheimer's disease (AD) is increasingly recognized as a neurodegenerative disorder associated with chronic low-grade inflammation and age-related immune dysregulation. Microglial-derived extracellular vesicles (MDEVs) are emerging as important mediators of neuroimmune communication and potential biomarkers reflecting pathological processes occurring within the central nervous system (CNS). However, how EV-associated inflammatory signalling changes across different stages of AD remains poorly understood. In this study, we characterized the inflammatory molecular profile of serum-derived MDEVs in 22 AD patients, 19 prodromal AD subjects, and 23 healthy controls (HC). Cytokine concentrations were also evaluated in paired serum and cerebrospinal fluid (CSF) samples to compare vesicle-associated and soluble inflammatory signals across biological compartments. MDEVs were isolated by size exclusion chromatography followed by TMEM119-based immunoenrichment. Cytokine quantification was performed using the Ella Simple Plex automated immunoassay platform. MDEVs from AD patients showed a generalized reduction in both pro- and anti-inflammatory cytokines compared to HC, including IL-1β, TNF-α, IL-2, IFN-γ, IL-6, IL-12p70, IL-10, and IL-4. Notably, several alterations were already detectable at the prodromal stage. In contrast, soluble cytokines in serum and CSF displayed a predominantly pro-inflammatory profile in AD patients, with increased levels of IL-1β, TNF-α, and IL-12p70. No significant correlations were observed between cytokine levels measured in MDEVs and those detected in serum or CSF. Overall, these findings support the presence of a compartment-specific reorganization of inflammatory signalling during AD progression. Early alterations in MDEV inflammatory cargo may reflect disrupted EV-mediated neuroimmune communication and highlight the potential of MDEVs as accessible peripheral biomarkers of neuroinflammatory processes in AD.
Excessive alcohol consumption accelerates cardiovascular aging by promoting oxidative stress, inflammation, lipid dysregulation, fibrotic remodeling, and loss of ventricular-vascular reserve. PCSK9, a key regulator of cholesterol metabolism, has emerged as a mediator of age-related cardiovascular dysfunction and alcohol-associated liver and neurovascular injury. We investigated whether PCSK9 inhibition protects against alcohol-induced cardiovascular dysfunction and associated cardiac-hepatic injury in rats. Male Sprague–Dawley rats were assigned to pair-fed control or 35
Chemotherapy-induced bone loss represents a major clinical challenge, particularly in aging populations, yet the contribution of cellular senescence to this process and its therapeutic potential remain incompletely understood. Here, we investigated the role of chemotherapy-induced cellular senescence in mediating skeletal deterioration following chemotherapy and evaluated the therapeutic potential of senolytic treatment. Young (3-month-old) and aged (20-month-old) male and female mice were treated with doxorubicin (DX), a chemotherapeutic agent, dasatinib/quercetin (DQ), senolytic agents, or their combination (DX/DQ). Chemotherapy-induced hallmark features of accelerated skeletal aging, including trabecular bone loss, increased marrow adiposity, and upregulation of senescence-associated and inflammatory gene expression. These effects were sex- and age-dependent and were more pronounced in females. Senolytic treatment with DQ partially restored osteogenic gene expression, including Alpl, Runx2, and Dmp1, and reduced marrow adiposity, particularly in aged females, indicating preservation of bone marrow niche function. Proteomic analysis of cortical bone revealed that DX-induced cellular senescence was associated with extracellular matrix remodeling and a metabolic shift toward glycolysis, characterized by increased inflammatory collagen isoforms and glycolytic enzymes. DQ treatment partially reversed these molecular signatures, including restoration of several extracellular matrix proteins associated with bone architecture and mineralization. Despite these molecular improvements, recovery of trabecular bone architecture remained modest, suggesting that senolytic-mediated molecular remodeling precedes detectable skeletal recovery. Collectively, these findings support a model in which chemotherapy-induced bone loss is driven by both early osteoblast suppression and senescence-driven microenvironmental dysfunction, identifying cellular senescence as a potential therapeutic target for preserving skeletal health following chemotherapy.
Aging is a multifaceted process where physiological metrics, such as brain age and muscle age (MA), provide deeper insights than chronological age alone. These nonlinear trajectories are heavily influenced by exogenous factors like lifestyle and nutrition. In older populations, muscle age acceleration (MAA) critically impacts functional autonomy and cognitive health, necessitating research into its link with brain network organization to refine assessments and, based on these, integrated motor and cognitive rehabilitation strategies. In this study, eyes-closed resting-state electroencephalography (EEG) was recorded from 101 healthy, neurologically intact older adults. MA and MAA were quantified using a regression model incorporating the functional assessments recommended by the European Working Group on Sarcopenia in Older People (EWGSOP-2) consensus (anthropometrics, muscle strength, and motor functional tests). Participants were stratified into three groups based on their MAA: decelerated MA, normal MA, and accelerated MA. Brain connectivity was assessed through magnitude-squared coherence (MSCoh) and node strength analyses. The results demonstrated that decelerated MA subjects exhibit significantly lower MSCoh compared to the normal and accelerated groups in the Alpha 1, Alpha 2, and Beta 1 bands. Furthermore, node strength analysis revealed that the decelerated MA group possessed lower values in the right frontal area across Alpha 1, Beta 1, and Beta 2 bands. Conversely, the normal MA group exhibited lower values in the right temporal region compared to the accelerated MA group. These findings may suggest that divergent muscle aging trajectories significantly modulate brain network topography. This brain–body interconnection highlights the potential for personalized interventions designed to redirect muscle aging trajectories, ultimately enhancing global functioning and quality of life of older people.
Dietary isoleucine restriction improves metabolic health and lifespan in animal models. It is hypothesized that shifts in branched-chain amino acid catabolism drive longevity. We investigated dietary isoleucine restriction on organismal branched-chain amino acid catabolism and its association with longevity and reproduction. In two main experiments, adult female Lubber grasshoppers were assigned to a high-quality diet (Bal ile) or diets with two levels of isoleucine content (moderate isoleucine restriction [Mod ile-R] or severe isoleucine restriction [Sev ile-R]). In Experiment 2, we used a low-energy (Low Lett) group as a positive control for catabolism. In Experiment 3, we used an ad libitum lettuce (Ad Lib Lett) control to show the reproduction-longevity trade-off. Nutrient-specific, organismal catabolism was measured by tracking 13C in an ingested amino acid through catabolism to breath CO2. The Bal ile, Mod ile-R, and Sev ile-R diets extended lifespan and increased leucine catabolism relative to the Ad Lib Lett group. The Sev ile-R and Low Lett groups showed the highest leucine catabolism but greatly reduced reproduction. The Bal ile group showed intermediate leucine catabolism while sustaining reproduction. The Mod ile-R group had intermediate leucine catabolism but delayed reproduction. There was no compensatory feeding on low isoleucine diets. Valine catabolism did not show statistical significance but tended to show similar trends to leucine catabolism. Weak leucine catabolism is linked to a short lifespan, while excessive leucine catabolism is linked to impaired reproduction. Intermediate levels of leucine catabolism were associated with longevity and sustained reproduction.
Naturally aged mice provide an important platform for studying frailty because functional decline emerges during biological aging rather than through acute injury or artificial manipulation. This review critically examines major frailty assessment tools used in aged mice, including the mouse frailty index, mouse frailty phenotype, physical function score/vitality score, mouse social frailty index, and mouse cognitive frailty index. We compare their conceptual foundations, scoring procedures, dimensional coverage, reproducibility, mortality associations, intervention responsiveness, and translational correspondence with clinical models such as the Fried phenotype and deficit accumulation frailty index. We also discuss how biological mechanisms linked to the hallmarks of aging, including inflammaging, immunosenescence, mitochondrial dysfunction, cellular senescence, altered nutrient sensing, and impaired stress resilience, may contribute to frailty development. Current instruments capture complementary aspects of frailty but differ in their dependence on subjective observation, cohort-specific thresholds, testing conditions, and validation across sex, strain, laboratory, and outcome. Digital phenotyping, longitudinal trajectories, secondary prognostic models, and measures of latent vulnerability may extend current approaches, but these strategies remain exploratory. Alternative weighting systems and the proposed distinction between pre-frailty and subclinical frailty require prospective validation before they can be considered standardized methods. Clear separation of established instruments from conceptual future directions will improve methodological rigor and translational relevance.
Although motor and cognitive functions are closely interconnected in daily life, they are typically assessed separately in fall assessments. This dual-center cross-sectional, observational study examined the discriminative performance of agility and motor-cognitive assessments to distinguish between community-dwelling older adults with and without a history of falls, compared with established motor and cognitive tests. A total of 231 participants (103 with a history of falls; age 71.9 ± 7.5 years) completed a SKILLCOURT test battery, including the Random Star Run (unplanned, reactive changes of direction; agility) and motor-cognitive stepping tasks involving reactive responses while standing to simple and choice reaction, task-switching, 2-back, and Stroop word-color stimuli. Motor tests included the Timed-Up-and-Go (TUG), Sit-to-Stand, and walking speed, each performed under both single- and dual-task conditions. Seated PC-based cognitive tests assessed reaction speed and executive functions corresponding to the SKILLCOURT tasks. Age- and study location-adjusted general linear models identified significant group effects after Holm adjustment for the Random Star Run (η2p = 0.04, p = .050) and the simple stepping reaction task (η2p = 0.03, p = .048), with faster completion and response times for participants without a history of falls, whereas established assessments showed no relevant group differences (η2p = 0.001–0.013, p > .05). Z-standardised adjusted logistic regression analyses revealed significant associations between Random Star Run performance and fall history (Odds Ratio; OR = 1.82 per 1 SD increase, p = .009), with longer completion times associated with higher odds of having a history of falls. The adjusted model yielded an AUC value of 0.73, with 70
Pulmonary hypertension (PH) frequently complicates heart failure with reduced ejection fraction (HFrEF), worsening prognosis despite limited therapeutic options. Whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve PH beyond their established hemodynamic effects remains unclear. Seventy-four patients with ischemic HFrEF after acute myocardial infarction and a high echocardiographic probability of PH were prospectively enrolled in a single-center, non-randomized study. Patients received either an SGLT2i (dapagliflozin or empagliflozin, 10 mg/day; n = 42) plus guideline-directed medical therapy or guideline-directed medical therapy alone (n = 32). Untargeted plasma proteomics (pooled samples), microRNA profiling, and selected biomarkers of senescence and oxidative stress were performed. Candidate findings were validated by ELISA and qRT-PCR. Complementary in vivo and in vitro experiments evaluated empagliflozin in ischemia/reperfusion injury and hypoxic human pulmonary artery endothelial cells and cardiomyocytes. SGLT2i therapy was associated with lower circulating activin A and miR-1306-5p levels, improved World Health Organization functional class, fewer signs of right-heart failure, reduced echocardiographic probability of PH, and enhanced right ventricle–pulmonary artery coupling. In experimental models, empagliflozin reduced activin A, increased BMPR2 expression, and improved post-ischemic ventricular function. Similar molecular changes were observed in hypoxic endothelial cells and cardiomyocytes. Chloroquine partially attenuated these effects, suggesting a possible involvement of autophagy. Across complementary clinical and experimental models, SGLT2i treatment was consistently associated with reduced activin A signaling. Modulation of the BMP/activin/TGFβ pathway represents a biologically plausible mechanism associated with SGLT2 inhibitor therapy that may contribute to the observed phenotype in ischemic HFrEF with a high echocardiographic probability of PH.
To investigate associations between body roundness index (BRI) and progression of cardio-renal-metabolic diseases (CRMDs). This study included 442,489 UK Biobank participants aged ≥ 40 years without CRMDs at baseline. BRI was analyzed continuously and by tertiles. Primary outcomes were first CRMD (FCRMD), cardio-renal-metabolic multimorbidity (CRMM), and all-cause mortality. Hazard ratios (HRs) and population attributable fractions (PAFs) were estimated using Cox and multistate models. Higher BRI was consistently associated with increased risks of CRMD onset and all-cause mortality, with strongest associations in the highest tertile for T2D (HR 6.94, 95
Early-onset Alzheimer’s disease (EOAD) and late-onset Alzheimer’s disease (LOAD) have different clinical and neuroimaging characteristics, and non-cognitive deficits usually observed are suggestive of hypothalamic dysfunctions. Here, we assessed in vivo the hypothalamic volumetry in EOAD and LOAD and explored its association with cognitive and non-cognitive features. The hypothalamus and its subunits were segmented on T1-weighted MRIs from 14 younger and 23 elderly controls (EC), 14 EOAD, and 28 LOAD. Amyloid or fluid biomarker confirmation was not available for all participants, and diagnostic classification was primarily based on clinical criteria. Volumes were correlated with cognitive (global cognition, memory) and non-cognitive (mood, body mass index) features. Lower bilateral volumes of the whole and posterior hypothalamus were observed in LOAD compared with EC (p < 0.010), while lower right anterior-inferior subunit was a common feature in patients than in controls (p = 0.007). These alterations were associated with abnormal cognition (rho ranging from −0.35 to −0.30, p < 0.041), as well as with memory (rho = 0.30, p = 0.041) and depressive mood (rho ranging from −0.82 to −0.68, p < 0.031) in the LOAD-EC pooled group. Our study provided a valuable insight into the heterogeneity of EOAD and LOAD, extending current understanding of the differential involvement of brain regions and highlighting the importance of hypothalamic involvement as a potential target for further investigation in conjunction with clinical assessment.
The planet is experiencing an unprecedented growth in its human population aged 65 years and older, underscoring the urgent need for comprehensive aging-centered biobehavioral data to guide public health interventions. The Arlington Study of Healthy Aging (ASHA) is a multidisciplinary community cohort study designed to investigate the biological, psychological, and social mechanisms underlying age-related functional decline. Here, we present the study’s rationale, design, and methodological framework. Utilizing a comprehensive, multi-modal assessment strategy—including whole-body MRI, vascular function testing, venous blood biomarkers, cognitive and physical function evaluations, DEXA scans, and continuous remote monitoring of activity, sleep, blood pressure, and glucose—the study captures both quantitative and qualitative dimensions of aging across multiple organ systems (brain, heart, muscle, liver, adipose tissue). A central aim is to identify modifiable risk factors and protective mechanisms that influence aging trajectories. Through interdisciplinary collaboration, ASHA seeks to generate actionable insights to enhance longevity, independence, and quality of life among older adults. NCT 06857877, 2024-09-24.
The locus coeruleus (LC), the earliest site of tau accumulation in Alzheimer’s disease, directly influences pupillary and vergence oculomotor systems. Whether task-evoked oculomotor dynamics can non-invasively differentiate AT(N) profiles, A+T+ (biological Alzheimer’s disease) and A−T+ (suspected non-Alzheimer’s tauopathy), remains unexamined despite their differential impact on LC-mediated modulation and cortical network integrity. Thirty-eight MCI individuals (12 A−T+, 26 A+T+), classified using validated CSF biomarker thresholds, completed a visual oddball paradigm under binocular eye-tracking. Linear mixed-effects models examined profile × condition interactions across full time series and six trial-level features; participant-level associations were tested using Firth-penalized logistic regression to account for the small and imbalanced sample. Profiles did not differ in oculomotor magnitude but diverged in temporal organization. Profile × condition interactions were significant for vergence global slope, vergence time to peak, and pupillary time to peak (all p-Holm ≤ 0.048). Timing differences were condition-dependent: A−T+ showed later responses during distractor trials, while A+T+ showed the most delayed timing during target trials. Subject-level associations were significant for vergence and pupillary time to peak, with greater condition-dependent modulation predicting higher A+T+ probability (ORs = 0.43 and 0.35; both p < 0.05); vergence global slope delta did not reach significance at the subject level. A−T+ showed superior target detection accuracy (89.7
Premature ovarian insufficiency (POI) is a leading cause of female infertility. Its mechanisms are poorly understood, and effective therapies are lacking. In this study, we aimed to identify novel druggable targets and repurposable drugs for POI through an integrated multiomics and computational pharmacology approach. We integrated large-scale proteomic data from two independent cohorts (deCODE, N = 35,559; UK Biobank, N = 54,219) using Mendelian randomization, Bayesian colocalization, and single-cell RNA sequencing. Seven high-confidence targets were identified: EPHA4, FSTL3, NUCB2, OXT, SERPINA12, TNFRSF6B, and FABP1. Among these genes, EPHA4, FSTL3, and NUCB2 were significantly dysregulated in cisplatin-induced mouse and human granulosa cell models (P < 0.05 to P < 0.001) and exhibited high diagnostic accuracy (AUC = 0.92–0.96), supporting their potential as both biomarkers and therapeutic targets. Molecular docking revealed strong binding affinities, notably for cycloheximide binding to EPHA4 (−7.8 kcal/mol), with molecular dynamics confirming stable interactions (root mean square deviation, RMSD < 2.0 Å), providing a structural basis for drug repurposing or lead optimization. The functional enrichment results suggested that fibrosis, inflammation, and metabolic dysregulation are involved in POI pathogenesis. Collectively, our findings establish a multiomics-to-therapy pipeline that not only prioritizes causal targets for POI but also provides translational opportunities, from biomarker-guided diagnosis to computationally driven drug repositioning, paving the way for mechanism-based interventions in ovarian aging.
Epigenetic changes, such as DNA methylation (DNAm), offer a measure of biological age distinct from chronological age. DNAm PhenoAge is one such biomarker that is more strongly related to morbidity, mortality, and physical function than chronological age. More accurate risk stratification methods are needed for ASD surgeries, where complications remain difficult to predict with an increasingly aged population. A multicenter ASD registry was queried. DNAm PhenoAge was calculated as per Levine et al. (6). Multivariable logistic regression examined the associations of DNAm PhenoAge and chronological age with perioperative adverse events (AE). The relative improvements in model discrimination, fit, and classification performance were compared. Adjusted odds ratios compared the risk of 55 versus 75 years for each age metric. Laboratory data were available for 200 patients. Mean DNAm PhenoAge was lower than chronological (DNAm PhenoAge, 53.7 ± 18.1; chronological, 61.1 ± 15.4; p < 0.001; 95
Aging is accompanied by arterial dysfunction, defined by impaired endothelial function and increased large artery stiffness, yet the contribution of the endothelial glycocalyx (eGC) and its constituent, hyaluronan (HA), to this process remains incompletely understood. We tested the hypothesis that decreasing endothelial HA synthesis via a reduction in endothelial-specific HA synthase 2 (HAS2) compromises eGC integrity and contributes to arterial dysfunction with advancing age. Both endothelial-specific HAS2 reduction and aging impair eGC integrity, evidenced by impaired barrier function and reduced eGC thickness in vivo, and aging led to a reduction in circulating HA and an increase in syndecan-1. Similar to aging, reduced endothelial HA selectively attenuated flow-induced endothelium-dependent dilation (EDD) and eNOS activation, whereas agonist-induced EDD was preserved in young arteries despite the concomitant eGC dysfunction. In parallel, reduced HAS2 expression and advancing age were each associated with increased aortic stiffness and adverse arterial remodeling, including excessive collagen deposition and reduced elastin. Collectively, these findings identify endothelial HA as a key determinant of eGC integrity and endothelial function, linking impaired HA availability to the development of arterial dysfunction with advancing age.
Aging is associated with blood–brain barrier (BBB) breakdown and microvascular rarefaction, key contributors to cerebral neuroinflammation, hypoperfusion, and vascular cognitive impairment and dementia (VCID). Exposure to a young systemic milieu through heterochronic parabiosis has been shown to restore BBB integrity and enhance cerebrovascular function in aged mice, suggesting that circulating factors can rejuvenate the aging brain. However, the molecular mediators responsible for these effects remain poorly defined. Circulating insulin-like growth factor-1 (IGF-1) declines markedly with age and has been implicated in endothelial dysfunction and BBB disruption, raising the possibility that IGF-1/IGF-1 receptor (IGF-1R) signaling contributes to the vascular rejuvenation induced by young blood. To test this hypothesis, we combined heterochronic parabiosis with complementary transgenic approaches targeting either endothelial IGF-1R deletion (VE-Cadherin-CreERT2/Igf1rfl/fl) or systemic IGF-1 knockdown (TBG-Cre-AAV8/Igf1fl/fl). BBB permeability to fluorescent tracers and cortical microvascular density were quantified by intravital two-photon microscopy through chronic cranial windows. We found that exposure of aged mice to young circulation markedly reduced BBB leakage and increased cortical capillary density. These beneficial effects were significantly attenuated in aged parabionts lacking endothelial IGF-1R or paired with young partners deficient in systemic IGF-1, demonstrating that both endothelial receptor activation and circulating IGF-1 availability are required for full cerebrovascular rejuvenation. Despite this attenuation, partial improvement persisted, indicating that IGF-1/IGF-1R signaling contributes to, but does not fully account for, the vascular benefits of young blood. These findings identify the IGF-1/IGF-1R axis as an important mediator of young blood–induced restoration of BBB integrity and microvascular density. Targeting downstream effectors of IGF-1R signaling, together with lifestyle interventions that enhance somatotropic axis responsiveness, may offer geroscience-guided strategies to preserve BBB function and cognitive resilience in aging.
Brain modulation interventions (BMIs) targeting cognitive and neuropsychiatric symptoms have shown substantial heterogeneity in response, limiting their clinical utility. Resting-state functional connectivity (rsFC) may capture BMI-induced neuroplasticity and support patient stratification. However, examining these biomarkers within small, heterogeneous intervention samples remains challenging. The objective of this study is to present BRAIN-DISC, an analytic framework that links large-scale cohort-derived rsFC patterns with evaluation in targeted BMI trials. Three demonstrations were conducted. In the CogTE trial (n = 74), the Alzheimer’s-resilient connectome (ARC), derived from cohort contrasts of Superagers and Alzheimer’s disease, was evaluated as a response biomarker for cognitive training in mild cognitive impairment (MCI). In the BEEM trial (n = 26), a brain-derived neuropsychiatric phenotyping (BNP) subtype was used to stratify response to transcranial direct current stimulation combined with training. In a third demonstration, we conducted an end-to-end implementation by discovering rsFC biotypes jointly informed by autonomic nervous system (ANS) and cognitive function (rsFC-AC) in the MIDUS cohort (n = 208), and evaluating it as a predictive biomarker in BREATHE trial (n = 56). In CogTE, greater shifts toward the ARC pattern were associated with improvements in executive function and episodic memory. In BEEM, individuals with the affective dysregulation subtype showed greater improvement in corresponding neuropsychiatric domains. In the third demo, three rsFC-AC biotypes were discovered in MIDUS cohort; the high-ANS subtype showed greater improvement in episodic memory in BREATHE trial. BRAIN-DISC provides a scalable framework for translating cohort-derived rsFC signatures into intervention settings to support both response monitoring and patient stratification.
