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PubMed2025

Brain Health Loss Mediates the Effect of Infarct Volume on Functional Outcome in Ischemic Stroke.

IMPORTANCE: Brain health may facilitate resilience to detrimental consequences from neurological diseases. Infarct volume is associated with poor functional outcome after acute ischemic stroke (AIS), but potential mediating effects through stroke-related brain health loss have not been investigated. OBJECTIVE: To determine whether stroke-related brain health loss, quantified by change in MRI derived effective Reserve (eR), mediates the effect of acute infarct volume on functional outcome after AIS. DESIGN: Observational multicenter cohort study. SETTING: We analyzed data from the GASROS (n=488) and MRI-GENIE (n=560) cohorts, collected 2003-2011. PARTICIPANTS: Adult patients consecutively diagnosed with AIS, with available admission MRI. EXPOSURE: At admission, white matter hyperintensity (WMH) and normal-appearing brain volumes were assessed on T2-FLAIR, and acute infarct volume on diffusion weighted imaging. WMH was normalized by brain volume, creating WMH load. We quantified brain health using eR, a latent variable incorporating age, WMH load, and normal-appearing brain volume. ΔeR reflected the change in eR when acute infarct volume was included, representing stroke-related brain health decline. Mediation analysis was used to determine if ΔeR mediates the effect of infarct volume on functional outcome (modified Rankin Scale [mRS] at 90 days). MAIN OUTCOME MEASURE: Proportion of mediating effect. RESULTS: We included 1,048 patients (median age 67y, 38% females). At baseline, median NIHSS score was 3 (IQR 1-7), median infarct volume 3.1mL (IQR 0.9-15.5). At 90 days, median mRS score was 1 (IQR 1-3) and 51 (5%) patients had died. In mediation analysis, ΔeR significantly mediated 36% (95% CI 16-56%) of the total effect of infarct volume on functional outcome (direct effect (ß=0.15 [95% CI 0.09-0.22], p<0.001; indirect effect mediated through ΔeR: ß=0.09 [95% CI 0.04 to 0.14], p=0.001). In subgroup-analyses, the mediative effect was apparent among female but not male, and among patients aged >67y but not ≤67y. CONCLUSIONS AND RELEVANCE: Stroke-related structural brain health loss mediates about one third of the effect of acute infarct volume on functional outcome after ischemic stroke, with important sex and age differences. Brain health significantly influences outcome and recovery potential, and may be considered a key biomarker when modeling outcome after AIS.

acute ischemic stroke↗

PubMed2025

Associations Between Walking Pace, APOE-ε4 Genotype, and Brain Health in Middle-Aged to Older Adults.

PURPOSE: This study aimed to investigate whether self-reported walking pace (a marker of physical function) and the presence of APOE-ε4 allele interact to modify brain health outcomes. METHODS: We used data from a prospective cohort study of middle-aged to older adults from the UK Biobank who self-reported walking pace (slow or steady-to-brisk) and who were initially free of dementia ( n = 415,110). Incident all-cause dementia was obtained from hospital and death registry records, and structural brain volumes (right and left hippocampus volumes, total gray matter volume, and volume of white matter hyperintensities) were measured from a subset of participants ( n = 33,113). Cox proportional hazard models and generalized linear models were used to assess associations between exposures and outcomes. RESULTS: Slow walking pace and the presence of APOE-ε4 allele were associated with increased dementia risk (HR = 1.79 [95% CI = 1.66-1.93], P < 0.001; HR = 3.06 [2.90-3.23], P < 0.001, respectively), and there was an interaction between these associations, indicating that the association of walking pace with dementia risk is modified by APOE-ε4 status (reference group: HR Steady-Brisk/APOE-ε4- = 1; HR Slow/APOE-ε4- = 2.03 [1.84-2.25], P < 0.001; HR Steady-Brisk/APOE-ε4+ = 3.21 [3.02-3.41], P < 0.001; HR Slow/APOE-ε4+ = 4.99 [4.48-5.58], P < 0.001). Slow self-reported walking pace was associated with worse brain volume outcomes, and these associations were not modified by APOE-ε4 genotype. CONCLUSIONS: These results suggest walking pace and APOE-ε4 status independently influence brain volume outcomes, but both factors independently and jointly contribute to increased dementia risk. Individuals with both risk factors (slow walking pace and APOE-ε4 allele) show the strongest associations with dementia risk.

Self Report↗

PubMed2026

One brain, one mind: A joint EPA-EAN leadership perspective on brain health.

Neurology and psychiatry have operated as separate disciplines for over a century, yet this division reflects historical and institutional developments rather than the underlying biology of the brain. Contemporary neuroscience shows that brain and mental health disorders share genetic susceptibilities, inflammatory and metabolic pathways, environmental and social risk factors, and clinical features that cross diagnostic boundaries. Cognitive, emotional, sensory, and motor symptoms regularly appear across both neurological and psychiatric populations, and conditions such as seizures, psychosis, mood disorders, cognitive disorders, and sleep disorders are common to both. A brain health framework addresses this reality by treating the brain as a single biological organ whose function emerges from the interplay between genome and exposome - including stress, trauma, social context, existential meaning, pollution, and physical health - and which underlies perception, behaviour, cognition, emotion, resilience, and vulnerability. Translating this perspective into practice requires coordinated action across domains. Clinically, collaborative models such as joint neurology-psychiatry consultations and shared outpatient pathways can be implemented within existing resources to improve diagnostic clarity and continuity of care. In training, a more harmonised curriculum with shared foundations in neurobiology, joint seminars, and cross-rotations would equip clinicians with a common language while preserving specialist depth, and support the emerging fields of preventive neurology and preventive psychiatry. In research, organising studies around shared mechanisms and symptom dimensions, and launching joint funding calls, would enhance translational relevance and reduce duplication. To realise this vision, sustained leadership from European professional bodies is essential to establish collaboration as a shared professional standard.

Humans↗

PubMed2026

Loss of ovarian function and estrogen therapy remodel the brain's synaptic and metabolic proteome.

Menopause is linked to cognitive decline and reduced brain metabolism, whereas estrogen (E2) therapy has been shown to mitigate these effects. Understanding the molecular mechanisms by which ovarian hormones and E2 influence neuroprotection is essential for developing strategies to maintain brain health in women. In this study, we examined how the loss of ovarian hormones, with or without E2 treatment, affects the brain proteome and mitochondrial energy production in aged female C57BL/6J mice (36-40 wk). The mice underwent sham or ovariectomy (OVX) surgery and were fed a high-fat diet for 10 wk; 6 wk after surgery, OVX mice received either sesame oil or E2 treatment for 4 wk. Proteomic analysis of brain homogenates revealed 4,992 proteins regulated by E2, with pathway analysis showing increased signaling proteins related to synaptogenesis. OVX reduced proteins involved in synaptic function, branched-chain amino acid and ketone metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation (Complexes I, IV, and V), whereas E2 restored protein expression within these pathways. Despite alterations in OxPhos proteins, basal and state 3 mitochondrial respiration remained unchanged, although notable impairments in Complex IV enzymatic activity were apparent in OVX, which were partially reversed by E2 treatment. Overall, these results indicate that E2 supports brain health by maintaining proteins crucial for synaptic integrity and metabolism, while partially offsetting the functional decline in mitochondrial bioenergetics associated with menopause.NEW & NOTEWORTHY The menopausal transition, marked by declining estrogen levels, alters cognition, neuroplasticity, and brain metabolism. Although hormone therapy benefits cognition, its molecular effects on the brain remain unclear. Using whole-brain proteomics in aged ovariectomized (OVX) mice with or without estrogen treatment, we found that OVX reduced proteins linked to synaptogenesis and mitochondrial metabolism. Estrogen reversed these declines, restoring pathways supporting neuronal signaling and energy balance, identifying estrogen-regulated proteins critical for maintaining brain health during menopause.

Animals↗

PubMed2026

Causal relationships between somatic movement, brain structures, and mental well-being: A multi-stage Mendelian randomization study.

BACKGROUND: While the relationships between somatic movement, mental well-being, and brain health have been well established, the causal nature and underlying mechanisms of such associations remain incompletely understood. METHODS: By applying multi-stage Mendelian randomization to multi-source summary data derived from genome-wide association studies, we examined the causal effects of 4 somatic movement measures on 2 mental well-being indices and 13 types of brain structures, followed by testing the mediating roles of brain structures in accounting for the causal associations between somatic movement and mental well-being. RESULTS: Two-sample Mendelian randomization revealed that more physical activity was causally associated with greater mental well-being (life satisfaction and positive affect), while more sedentary behavior (longer leisure screen time and more sedentary behavior at work) with lower mental well-being. With respect to brain structures, sedentary behavior was causally linked to decreased volume, surface area, and local gyrification index in distributed cortical regions. Remarkably, decreased surface area of the piriform cortex was found to mediate the causal associations between sedentary behavior and lower mental well-being. CONCLUSIONS: Our findings not only complement and extend earlier reports on the associations of somatic movement with mental well-being and brain health by further resolving the causality but also help elucidate the neural mechanisms by which sedentary behavior adversely affects mental well-being.

Humans↗

PubMed2026

BRAIN-Diabetes: Acceptability of an adapted FINGER multidomain intervention among adults living with type 2 diabetes in rural border regions across the island of Ireland.

BackgroundIndividuals with type 2 diabetes mellitus (T2DM) face increased risk of cognitive decline and dementia. Multidomain lifestyle interventions offer a non-pharmacological strategy to support brain health in this high-risk group.ObjectiveThis study examined the acceptability of a culturally adapted FINGER-based intervention among adults living with T2DM in rural border regions of Ireland (BRAIN-Diabetes Trial).MethodsA 6-month pilot randomized controlled trial was conducted. The intervention group received a multidomain program targeting diet, physical activity, and computerized cognitive training (CCT). The control group received standard care. Acceptability was assessed using questionnaires (all participants) and semi-structured interviews (intervention participants). Quantitative data were analyzed descriptively and qualitative data using template analysis, guided by four a-priori themes: trial participation and engagement, dietary behavior change, exercise behavior change, and CCT behavior change.ResultsQuestionnaire data (intervention: n = 28; control: n = 36) indicated high overall acceptability. Dietary and exercise components were rated most positively, while CCT component was less well received. Interviews (n = 25) highlighted facilitators to trial engagement, including perceived health improvements, and social connection, with time constraints and limited personalization as barriers. Dietary change was supported by tailored guidance but hindered by cost and availability. Facilitators for exercise included accessible resources and perceived benefits, with barriers including competing priorities. CCT engagement was mixed, with challenges including digital access and repetitiveness.ConclusionsThe Brain-Diabetes intervention was acceptable and feasible among adults with T2DM. Personalized support and accessible resources were key to engagement. Future work should refine delivery to enhance scalability and long-term adherence among high-risk groups.

Humans↗

PubMed2026

Strategies for mosaic variant calling in brain disorders.

The human brain is a genomic mosaic, where postzygotic mutations arising from embryogenesis to senescence drive diverse neurodevelopmental and neurodegenerative diseases. Because of numerous sequencing artifacts at ultralow variant allele frequencies (VAFs), detecting these variants remains a significant analytical challenge. This review focuses on single-nucleotide variants and small indels, summarizing current strategies for aligning sampling methods, including bulk, laser capture microdissection, and single-cell genomics, with the expected clonal architecture of the brain. It emphasizes that mosaic detection sensitivity is fundamentally constrained by sequencing depth, since even the most advanced algorithms cannot identify variants not physically represented in the sequencing library. The review further recommends the selection of variant calling algorithms based on validated VAF detection performance, matching tools like MuTect2 and MosaicForecast to their optimal performance ranges. Furthermore, we discuss how multitissue sampling, as emphasized by the SMaHT project, addresses the matched-control dilemma and supports accurate variant classification via cross-tissue VAF gradients. Integrating these established pipelines with multiomics modalities, including transcriptomic and epigenetic data, could advance the field toward a functional understanding of how the somatic genome impacts human brain health and disease.

Humans↗

PubMed1977

The medical "brain drain" and health priorities in Latin America.

This analysis of the medical brain drain places the problem in the context of the health care infrastructure in the developing world. It emphasizes Latin American social realities as a corrective to the self-interest which characterizes much of the current debate in the United States. It is argued that the same factors constituting emigration "push" factors in Latin America simultaneously underscore the relative unimportance of medical manpower migration compared to other obstacles to health progress. That conclusion is supported by a comparison of the relative damage caused by the brain drain by itself and the damage caused by factors which the brain drain concomitantly symbolizes and flows from: elitist objectives, misdirected priorities, unrealistic policies, and inadequate planning on the part of most Latin American nations. In the absence of urgently needed change in traditional structures, merely closing the gates on foreign medical graduates will not serve to ameliorate health conditions in the region. Those who seek real health improvements for developing nations must address greater challenges than the brain drain.

Allied Health Personnel↗

PubMed2022

Improving risk indexes for Alzheimer's disease and related dementias for use in midlife.

Knowledge of a person's risk for Alzheimer's disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (N = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (β's from 0.16 to 0.22), white matter hyperintensities volume (β's from 0.16 to 0.19), hippocampal volume (β's from -0.08 to -0.11), tested cognitive deficits (β's from -0.36 to -0.49), everyday cognitive problems (β's from 0.14 to 0.38), and longitudinal cognitive decline (β's from -0.18 to -0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.

Alzheimer’s disease↗

PubMed2026

Regulators of interferon-responsive microglia uncovered by Genome-wide CRISPRi screening.

Microglia dynamically support brain health through the induction of specialized activation states in response to injury or disease. Activation of the interferon-responsive microglia (IRM) state has been identified across neurodevelopmental windows, age-related cognitive decline, and neurodegenerative diseases. Functionally, IRM have been linked to synaptic pruning, dead cell removal, and neuroinflammation, making this state critical to brain homeostasis. While the functional importance of this state is becoming increasingly clear, our understanding of the regulatory networks that govern IRM induction remain incomplete. To systematically identify genetic regulators of the IRM state, we conducted a genome-wide CRISPR interference screen in human iPSC-derived microglia using IFIT1 as a representative IRM marker. We identified 772 genes that modulate IRM, including canonical type I interferon signaling genes (IFNAR2, TYK2, STAT1/2, USP18) and newly described regulators. We uncovered a non-canonical role for the CCR4-NOT transcription complex subunit 10, CNOT10, in IRM activation. This work provides a comprehensive resource that can be applied to dissect the functions of interferon-responsive microglia and highlights both established and novel targets for modulating microglial interferon signaling in health and disease.

Computational biology and bioinformatics↗

PubMed2026

Genetic evidence that advanced COVID-19 accelerates longitudinal brain atrophy: A Mendelian randomization study.

Coronavirus disease 2019 (COVID-19) was reported to persist long-term in the brain and leave several long-term neurologic sequelae. However, the causal relationship between COVID-19 and brain aging is still unknown. The genome-wide association study (GWAS) data on COVID-19 phenotypes (susceptibility, hospitalization, and severity), involving a total of 5,779,391 participants, were collected from the COVID-19 Host Genetics Initiative. In addition, GWAS data on longitudinal changes in 15 brain structures, assessed via magnetic resonance imaging across the lifespan, were sourced from the ENIGMA Consortium and involved 15,640 participants. Two-sample Mendelian randomization was conducted to infer the causal relationship between COVID-19 and longitudinal brain changes. Multi-trait GWAS meta-analysis, colocalization, and fine-mapping analyses were performed to identify shared genetic etiologies. H3K27me3 ChIP-seq was used to evaluate the regulatory effect of colocalized loci. Two-step Mendelian randomization was applied to explore potential mediating mechanisms across multi-omics layers, including proteomics, metabolomics, and immunomics. Our results showed that COVID-19 hospitalization (β = -262.405, P = .041) and severity (β = -177.676, P = .049) were genetically associated with atrophied volume of total brain during longitudinal change. This suggests that individuals with advanced COVID-19 may be more susceptible to accelerated global brain aging. Caudate was genetically affected by all COVID-19 phenotypes. Seven variants were shared between advanced COVID-19 and global brain aging. rs117169628 was colocalized between advanced COVID-19 and global brain aging, and exerted an inhibitory effect on CDH15 expression, further strengthening the causality. Six metabolites, 1 protein, and 1 immune trait were identified as potential mediators. Our study indicates that advanced COVID-19 might be genetically associated with accelerated brain aging. Brain health should be paid more attention in long COVID-19.

Humans↗

PubMed2026

Proteomic profiling identifies systemic drivers of blood-brain barrier injury in sickle cell disease.

Sickle cell disease (SCD) causes brain injury and cognitive disability. Systemic inflammation and endothelial injury are central to SCD pathophysiology, yet the relationship between systemic drivers of blood-brain barrier (BBB) disruption and brain injury remains understudied. This cross-sectional study assessed whole-brain and regional BBB permeability (Ktrans) using dynamic contrast-enhanced magnetic resonance imaging for 37 adults with SCD in steady state and 37 adults without SCD. Cerebral oxygen extraction fraction (OEF) and white matter mean diffusivity (MD) measured tissue hypoxia and microstructural injury, respectively. The SCD cohort showed elevated Ktrans compared with controls (3.6 × 10-4·min-1 vs 2.58 × 10-4·min-1; 95% confidence interval [CI] median difference, 0.36 × 10-4·min-1 to 1.30 × 10-4·min-1; P< .001), indicating BBB disruption. In SCD, white matter Ktrans was associated with MD (β, 6.25 [95% CI, 1.72-10.77]; P = .008), independent of OEF (β, 0.22 [95% CI, 0.09-0.35]), and silent cerebral infarcts (β, 0.01 [95% CI, 0.00-0.02]). The interaction (P = .037) between Ktrans and OEF on MD suggested a combined, deleterious effect of BBB disruption and hypoxia on microstructural injury. High-throughput plasma proteomics followed by differential expression analysis, and weighted gene correlation network analysis in a subset of 61 participants revealed that 79 proteins associated with BBB permeability belonged to iron homeostasis, response to hypoxia, immune dysregulation, extracellular matrix degradation, lipoprotein homeostasis, and arginine-proline metabolism pathways. All pathways were independently associated with microstructural injury. BBB permeability was a mediator of brain injury for all pathways except extracellular matrix degradation. Targeting specific systemic pathways to protect the BBB may represent a therapeutic approach to preserve brain health in SCD.

Humans↗

PubMed2026

The interplay between circadian misalignment or sleep disturbances and cognition and brain function in individuals with different degrees of insulin resistance - a systematic review.

Disruption of sleep increases the risk of type 2 diabetes and worsens cognitive outcomes, yet few studies have evaluated the interaction between insulin resistance and sleep parameters in relation to cognitive outcomes or the risk of dementia. This systematic review examines how circadian misalignment and sleep disturbances affect cognition and neuroimaging findings in individuals with varying degrees of insulin resistance. Across 27 studies, disrupted circadian rhythmicity and sleep disturbances were negatively associated with brain health, possibly through its effects on insulin sensitivity, whereas the impact of sleep duration and quality were inconclusive. Methodological heterogeneity, reliance on cross-sectional designs, and limited control for confounders restricted definitive conclusions and highlighted the need for longitudinal and interventional studies with objective measurements. Nonetheless, the findings support circadian rhythmicity as a potentially modifiable risk factor for preserving cognition in insulin-resistant populations. Future research should prioritise prospective and interventional studies and focus on biological markers rather than self-reported outcomes.

Humans↗

PubMed2026

Association of high-sensitivity cardiac troponin I levels below the sex-specific 99th percentile with late-life dementia: the Perth Longitudinal Study of Ageing Women.

BACKGROUND: Elevated high-sensitivity cardiac troponin (hs-cTn) levels are linked with cardiovascular disease and cognitive impairment, both of which are strong risk factors for late-life dementia (LLD). This study examined the association between hs-cTnI levels below the sex-specific 99th percentile for myocardial injury and the incidence of LLD in older women. METHODS: 986 community-dwelling women aged ≥70 years without prior LLD and with hs-cTnI <15.6 ng/L (stratified into quartiles) were included from the Perth Longitudinal Study of Ageing Women. The primary outcome was incident LLD events, including LLD hospitalisation or death, over 14.5 years obtained from linked health records. Associations between hs-cTnI and LLD outcomes were explored using multivariable-adjusted Cox models, as part of restricted cubic splines. RESULTS: At baseline, participants' mean (±SD) age was 75.2±2.7 years. Over 14.5 years of follow-up, LLD events (n=174, 17.7%), hospitalisations (n=155, 15.7%) and deaths (n=68, 6.9%) were recorded. Compared with those in the lowest quartile (Q1, median 3.1 ng/L), women in the highest quartile of hs-cTnI (Q4, median 7.3 ng/L) had a greater risk of developing LLD-related events (adjusted HR: 1.88, 95% CI: 1.22 to 2.91), hospitalisation (adjusted HR: 1.65, 95% CI: 1.04 to 2.64) and death (adjusted HR: 2.27, 95% CI: 1.13 to 4.59), after adjusting for established cardiovascular and dementia risk factors, including apolipoprotein E (APOE) genotype. CONCLUSION: Among older women, hs-cTnI levels below the sex-specific 99th percentile for myocardial injury were associated with an increased risk of LLD events over 14.5 years. These findings suggest that hs-cTnI may identify older women at higher risk of LLD, capturing both cardiovascular and brain health vulnerability in older age. TRIAL REGISTRATION NUMBER: ACTRN12617000640303.

Humans↗

PubMed2026

A combined stimulus of acute fasting and exercise modulates hippocampal mitochondrial quality control in healthy mice.

BACKGROUND AND AIMS: Exercise and fasting are recognized for their ability to improve brain health and mitigate neurodegeneration. However, little is known about how these interventions acutely impact mitochondrial quality control mechanisms including mitophagy. METHODS: We examined the effects of a single bout of fasting and exercise (FEx) on hippocampal mitochondrial function and proteomic remodeling in male and female mice. To assess in vivo autophagy dynamics, we combined proteomics with chloroquine (CQ) inhibition of autophagic flux. Mice were assigned to sedentary (Sed), fasting (F), exercise (Ex), or combined FEx groups and received unilateral intrahippocampal injections of CQ or PBS following treatments. Four hours later, hippocampi were collected for analysis. RESULTS: LC3-II levels significantly increased in the FEx group only following CQ treatment, indicating enhanced autophagic flux. Proteomic profiling showed sedentary males failed to mount a robust response to FEx however females exhibited upregulation of proteins involved in the TCA cycle, glutathione metabolism, and oxidative phosphorylation, suggesting greater mitochondrial adaptability. Functional assays supported these findings, females showed increased complex IV activity post-FEx. The mitochondrial DNA / nuclear DNA ratio increased after FEx regardless of sex, and upstream regulator analysis predicted activation of mitochondrial biogenesis. CONCLUSIONS: Together, these data reveal sex-specific mitochondrial remodeling in response to acute fasting and exercise. Defining these normative responses is critical for understanding how mitochondrial adaptability shapes resilience or vulnerability to neurological challenges.

Animals↗

PubMed2024

Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures.

Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs.

Animals↗

PubMed2025

The Role of Genomic-Informed Risk Assessments in Predicting Dementia Outcomes.

INTRODUCTION: By integrating genetic and clinical risk factors into genomic-informed dementia risk reports, healthcare providers can offer patients detailed risk profiles to facilitate understanding of individual risk and support the implementation of personalized strategies for promoting brain health. METHODS: We constructed an additive score comprising the modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score (mCAIDE), family history of dementia, APOE genotype, and an AD polygenic risk score in NACC and ADNI, and assessed its association with progression to all-cause dementia. RESULTS: 81% of participants had at least one high-risk indicator for dementia, with each additional risk indicator linked to a 34% increase in the hazard of dementia onset. DISCUSSION: We found that most participants in memory and aging clinics had at least one high-risk indicator for dementia. Furthermore, we observed a dose-response relationship where a greater number of risk indicators was associated with an increased risk of incident dementia.

dementia risk scores↗

PubMed2023

Common Genetic Factors and Pathways in Alzheimer's Disease and Ischemic Stroke: Evidences from GWAS.

Alzheimer's disease (AD) and ischemic stroke (IS) are common neurological disorders, and the comorbidity of these two brain diseases is often seen. Although AD and IS were regarded as two distinct disease entities, in terms of different etiologies and clinical presentation, recent genome-wide association studies (GWASs) revealed that there were common risk genes between AD and IS, indicating common molecular pathways and their common pathophysiology. In this review, we summarize AD and IS risk single nucleotide polymorphisms (SNPs) and their representative genes from the GWAS Catalog database, and find thirteen common risk genes, but no common risk SNPs. Furthermore, the common molecular pathways associated with these risk gene products are summarized from the GeneCards database and clustered into inflammation and immunity, G protein-coupled receptor, and signal transduction. At least seven of these thirteen genes can be regulated by 23 microRNAs identified from the TargetScan database. Taken together, the imbalance of these molecular pathways may give rise to these two common brain disorders. This review sheds light on the pathogenesis of comorbidity of AD and IS, and provides molecular targets for disease prevention, manipulation, and brain health maintenance.

Humans↗