Molecular Psychiatry最新文献

{"title":"Metabolic plasticity: an evolutionary perspective on metabolic and circadian dysregulation in bipolar disorder","authors":"Iain H. Campbell, Mark A. Frye, Harry Campbell","doi":"10.1038/s41380-025-03123-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03123-9","url":null,"abstract":"<p>The emerging field of metabolic psychiatry has brought mechanisms of metabolic dysfunction into focus in bipolar disorder research. In this manuscript, we propose that the metabolic features of bipolar disorder provide a new vector from which to understand the role of circadian dysfunction in this condition. A notable feature of bipolar disorder is the photoperiod driven, seasonal occurrence of symptoms and episodes mediated by circadian systems, with mania occurring more frequently in the spring and autumn at times of rapid rate of change in photoperiod, and depression being more prevalent in the winter when photoperiod is attenuated. In this manuscript we note that seasonal adaptations in metabolism are highly conserved evolutionary traits across diverse taxa. Several of the underlying mechanisms mediating seasonal changes in metabolism are conserved in human biology and are implicated in bipolar disorder pathophysiology. Such mechanisms encompass targets of lithium involved in insulin signaling (the phosphatidylinositol cycle, GSK3β and Akt), clock genes (CLOCK and BMAL1), targets of psychiatric and metabolic medications (mTOR and AMPK) and hormonal signaling (melatonin and cortisol). We propose that bipolar disorder may represent a dysregulation of conserved mechanisms of chronometabolic regulation and provide a discussion of the evolutionary context of such mechanisms. Genetic predisposition coupled to novel environmental inputs to human biology including artificial light at night and sustained refined sugar and carbohydrate intake may contribute to states of metabolic and circadian dysregulation in bipolar disorder underlying episodes of mania and depression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"109 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripartum sertraline impacts maternal neurobehavioral and neurodegenerative mechanisms in pregnant and postpartum mice","authors":"Brianna Blaine, Mushroor Kamal, Mizani Roberts, Brandon Schickling, Marisol Lauffer, Yuping Zhang, Aimee Bertolli, Matthew A. Weber, Robert Taylor, Sana Nadeem, Krushi Patel, Lynn Teesch, Georgina Aldridge, Donna Santillan, Mark Santillan, Serena Gumusoglu","doi":"10.1038/s41380-025-03094-x","DOIUrl":"https://doi.org/10.1038/s41380-025-03094-x","url":null,"abstract":"<p>Selective Serotonin Reuptake Inhibitors (SSRIs) are among the most common medications used for depression in postpartum and lactating people, who experience increased depression risk. However, there is a limited understanding of peripartum SSRI impacts on maternal neurobehavioral responses, and particularly those of sertraline, the most prescribed SSRI in United States (US) pregnancies. We administered C57Bl/6 females sertraline via a non-invasive, naturalistic approach (167 mg/L drinking water) from 2 weeks pre-conception through lactation (PND21) or for an equivalent duration in nonpregnant controls. We assessed behavior and molecular brain changes intrapartum and postpartum at ~1 year of age. Chronic sertraline reduced depressive- and anxiety-like behaviors. Pregnancy itself decreased anxiety-like and hedonic behaviors. RNA sequencing of maternal brain revealed only 52 differentially expressed genes (DEGs) in frontal cortex with sertraline. These DEGs over-represented functions related to immunity. In contrast, sertraline altered 962 targets in maternal hypothalamic paraventricular nucleus, with DEGs overrepresenting neurotransmission and neurodegeneration. We then discontinued sertraline and aged animals to approximately 1 year to test neurodegenerative phenotypes. Having one prior litter, regardless of peripartum sertraline, improved aged females' spatial learning and memory. Sertraline, regardless of postpartum status, improved working memory. Further, we found buffering of neurodegeneration-related gene network changes and increased excitatory synapse density in the hippocampus after peripartum sertraline. Peripartum sertraline alters maternal neurobiology and behavior in pregnancy and beyond, with long-term benefits to neurodegenerative processes. Pregnancy also exerts its own, lasting effects on learning and memory. These findings might be exploited in the future to abrogate neurodegenerative disease.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"10 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adult hippocampal neurogenesis-mediated cognitive behavior participates in stress resilience to anxiety and depression-like behaviors in postpartum dams","authors":"Lin Zhou, Zuotian Wu, Yixin Li, Yumeng Xie, Limin Sun, Shanshan Lin, Ling Xiao, Huiling Wang, Gaohua Wang","doi":"10.1038/s41380-025-03082-1","DOIUrl":"https://doi.org/10.1038/s41380-025-03082-1","url":null,"abstract":"<p>Postpartum period being a critical phase affecting women’s health recovery, and stressful events during this period are major risk factors for postpartum depression. Pup separation (PS) serves as a natural model of postpartum maternal care. However, the effects of different PS (no separation, NPS; 15 min/day, PS15, brief PS; 180 min/day, PS180, long PS) during lactation on stress-induced behavioral deficits in dams, along with the underlying mechanisms of resilience remain unclear. In this study, we assessed cognitive and emotional behaviors in lactating C57BL/6 J dams subjected to different PS from postnatal day 1 to day 21, along with chronic restraint stress (CRS). Subsequently, hippocampal samples were collected to analyze the expression of NLRP3, IL-18, and IL-1β, along with microglial activation and adult hippocampal neurogenesis (AHN) in the hippocampal dentate gyrus. We further modulated AHN using viral and examined the effects of AHN overexpression or inhibition on behavior and hippocampal neuroinflammation. Dams subjected to brief PS exhibited reduced anxiety and depressive-like behaviors and improved cognitive function. Additionally, PS15 dams showed decreased hippocampal expression of NLRP3, IL-18, and IL-1β, reduced microglia activation, and increased AHN. Overexpression of AHN can significantly improved cognitive function, but no significant changes in emotional behaviors were observed. Besides, AHN-mediated cognitive behavior participates in resilience to anxiety and depression-like behaviors of dams after CRS. Similarly, inhibition of hippocampal NLRP3 expression enhanced AHN-related cognitive behavior and promoted stress resilience in adult female mice. Brief PS resulted in resilience to anxiety and depressive-like behaviors in dams and mitigated memory impairments induced by CRS. This study confirmed AHN-mediated cognitive behavior participates in stress resilience to anxiety and depression-like behaviors in postpartum dams after CRS.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"13 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease clusters and their genetic determinants following a diagnosis of depression: analyses based on a novel three-dimensional disease network approach","authors":"Can Hou, Haowen Liu, Yu Zeng, Yike Gong, Huazhen Yang, Weimin Ye, Fang Fang, Unnur A. Valdimarsdóttir, Huan Song","doi":"10.1038/s41380-025-03120-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03120-y","url":null,"abstract":"<p>Depression is strongly associated with a range of subsequent diseases. To elucidate key mechanistic pathways for targeted interventions, this study aimed to determine the main disease networks associated with depression as well as their underlying genetic determinants. We developed a novel three-dimensional network approach which refines disease association verification by incorporating regularized partial correlations, and facilitates robust identification and visualization of disease clusters (i.e., groups of depression-associated diseases with high within-group connectivity) through both non-temporal (illustrating by x-axis and y-axis) and temporal (by z-axis) dimensions. We applied this approach to a matched cohort of 54,284 middle aged patients diagnosed with depression and their 496,005 age- and sex-matched unexposed individuals from the Swedish national registers and validated our findings in a cohort from the UK Biobank. Additionally, we conducted genetic analyses, including polygenic risk score (PRS) and genome-wide association studies (GWAS), using genetic data from 10,754 depression patients in the UK Biobank. Our analysis of the Swedish cohort identified nine reliable disease clusters consisting of 85 component diseases associated with depression, of which six clusters with 30 diseases were successfully validated using the UK Biobank cohort. These were clusters characterized by central nervous system (CNS) diseases, respiratory system diseases, cardiovascular and metabolic diseases, gastrointestinal diseases, musculoskeletal diseases, and mental disorders. PRS analysis revealed a dose-response relationship between genetic liability to depression and the susceptibility for subsequent disease clusters, while GWAS identified eight genome-wide significant loci in four of the clusters. Overall, our novel three-dimensional disease network approach identified six robust disease clusters after depression across two large cohorts, each with shared and cluster-specific genetic underpinnings. These findings warrant further research on genetic-based risk prediction and the development of therapeutic interventions aimed at health improvement for patients with depression.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"46 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene expression signatures of response to fluoxetine treatment: systematic review and meta-analyses","authors":"David G. Cooper, J. Paige Cowden, Patrick M. Vo, Parker A. Stanley, Jack T. Karbowski, Victoria S. Gaertig, Caiden J. Lukan, Ariel D. Worthington, Caleb A. Class","doi":"10.1038/s41380-025-03118-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03118-6","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Genomic (and other ‘omic) data have provided valuable insights on the pharmacological signatures of antidepressant response, but results from individual studies are largely heterogeneous. In this work, we synthesized gene expression data for fluoxetine treatment in both human patients and rodent models, to better understand biological pathways affected by treatment, as well as those that may distinguish clinical or behavioral response.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>Following the PRISMA guidelines, we searched the Gene Expression Omnibus (GEO) for studies profiling humans or rodent models with treatment of the antidepressant fluoxetine, excluding those not done in the context of depression or anxiety, in an irrelevant tissue type, or with fewer than three samples per group. Included studies were systematically reanalyzed by differential expression analysis and Gene Set Enrichment Analysis (GSEA). Individual pathway and gene statistics were synthesized across studies by three p-value combination methods, and then corrected for false discovery.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Of the 74 data sets that were screened, 20 were included: 18 in rodents, and two in tissue from human patients. Studies were highly heterogeneous in the comparisons of both treated vs. control samples and responders vs. non-responders, with 691 and 357 pathways, respectively, identified as significantly different between groups in at least one study. However, 18 pathways were identified as consistently different in responders vs. non-responders, including toll-like receptor (TLR) and other immune pathways. Signal transduction pathways were identified as consistently affected by fluoxetine treatment in depressed patients and rodent models.</p><h3 data-test=\"abstract-sub-heading\">Discussion</h3><p>These meta-analyses confirm known pathways and provide new hints toward antidepressant resistance, but more work is needed. Most included studies involved rodent models, and both patient studies had small cohorts. Additional large-cohort studies applying additional ‘omics technologies are necessary to understand the intricacies and heterogeneity of antidepressant response.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"12 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multivariate patterns linking brain microstructure to temperament and behavior in adolescent eating disorders","authors":"Carolina Makowski, Golia Shafiei, Megan Martinho, Donald J. Hagler, Diliana Pecheva, Anders M. Dale, Christine Fennema-Notestine, Amanda Bischoff-Grethe, Christina E. Wierenga","doi":"10.1038/s41380-025-03117-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03117-7","url":null,"abstract":"<p>Eating disorders (EDs) are multifaceted psychiatric disorders characterized by varying behaviors, traits, and cognitive profiles driving symptom heterogeneity and severity. Non-invasive neuroimaging studies have been critical to elucidate the neurobiological circuitry involved in ED-related behaviors, but often focused on a limited set of regions of interest and/or symptoms. The current study harnesses multivariate methods to map microstructural and morphometric patterns across the entire brain to multiple domains of behavior and symptomatology in adolescents with EDs. Diffusion-weighted images, modeled with restriction spectrum imaging, were analyzed for 91 adolescents with an ED and 48 healthy controls. Partial least squares analysis was applied to map 38 behavioral measures (encompassing cognition, temperament, and ED symptoms) to restricted diffusion in white matter tracts and subcortical structures across 65 regions of interest. The first significant latent variable explained 46.9% of the covariance between microstructure and behavior. This latent variable retained a significant brain-behavior correlation in held-out data, where an ‘undercontrolled’ behavioral profile (e.g., higher emotional dysregulation, novelty seeking; lower effortful control and interoceptive awareness) was linked to increased restricted diffusion across white matter tracts, particularly those joining frontal, limbic, and thalamic regions. Individually-derived brain and behavior scores for this latent variable were higher in individuals with binge-purge symptoms, compared to those with only restrictive eating symptoms. Findings demonstrate the value of applying multivariate modeling to the array of brain-behavior relationships inherent to the clinical presentation of EDs, and their relevance for providing a neurobiologically-informed model for future clinical subtyping and prediction efforts.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"24 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dietary ligands, omega-3 fatty acid endocannabinoids and short-chain fatty acids prevent cytokine-induced reduction of human hippocampal neurogenesis and alter the expression of genes involved in neuroinflammation and neuroplasticity","authors":"Gargi Mandal, Silvia Alboni, Nadia Cattane, Moira Marizzoni, Samantha Saleri, Nikita Arslanovski, Nicole Mariani, Madeline Kirkpatrick, Annamaria Cattaneo, Carmine M. Pariante, Alessandra Borsini","doi":"10.1038/s41380-025-03119-5","DOIUrl":"https://doi.org/10.1038/s41380-025-03119-5","url":null,"abstract":"<p>The dietary ligands, omega-3 fatty acid endocannabinoids (eCBs) eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA), and short-chain fatty acids (SCFAs) acetate, propionate and butyrate, have anti-inflammatory and antidepressant properties. However, the molecular mechanisms underlying their action in the human brain remain elusive. Here, we treated human hippocampal neurons (HPC0A07/03 C) with eCBs (EPEA (300 pM) or DHEA (700 pM)), or SCFAs (acetate (200 uM), propionate (30 uM), butyrate (20 uM)), followed by interleukin (IL)1β (10,000 pg/ml) or IL6 (50 pg/ml). We found that treatment with either eCBs or SCFAs prevented IL1β- and IL6-induced reduction in neurogenesis and increase in apoptosis. These effects were mediated by IL1β-induced production of IL6, interferon-gamma (IFNγ) and tumour necrosis factor-alpha (TNFα), and by IL6-induced IL1β, IL8 and IL13, all of which were prevented by treatment with eCBs. In contrast, IL1β-induced production of IL6, IL12 and fractalkine (CX3CL1), and IL6-induced production of CX3CL1, were prevented by SCFAs. Treatment with IL1β and IL6 also increased the production of candidate kynurenine pathway metabolites, such as kynurenine (KYN) and nicotinic acid (NICA), which again were prevented by eCBs and SCFAs. We then conducted mRNA sequencing analysis to investigate cellular genes and signalling pathways relevant for the neuro-inflammatory changes previously observed, and putatively prevented by eCB and SCFA treatment. We found that IL1β decreased the expression of the neuroplasticity gene, FRY microtubule binding gene (<i>FRY)</i>, and increased the expression of the neuroinflammation gene, U3 small nucleolar ribonucleoprotein homolog C subunit processome component (<i>UTP14C)</i>, and both these effects were prevented by either acetate or propionate. Similarly, the expression of the proinflammatory gene, ADAM metallopeptidase with thrombospondin type 1 motif 1 (<i>ADAMTS1</i>), was increased by IL6, an effect that was prevented by either EPEA or acetate. Altogether, we identify novel anti-inflammatory and neurogenic mechanisms mediating the effect of eCBs and SCFAs on human hippocampal neurogenesis, which can be significant as potential future treatment candidates in the context of neuropsychiatric disorders.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"109 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRAF6 regulates ubiquitination-independent TDP-43 condensation and related neurodegeneration","authors":"Shupan Guo, Xueyin Zu, Fei Tang, Aolan Zhou, Xinru Yan, Zhihui Zhou, Xin Liu, Pan Li, Shiqian Qi, Wei Cheng, Peng Lei, Haiyan Ren","doi":"10.1038/s41380-025-03122-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03122-w","url":null,"abstract":"<p>Cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases. However, the underlying mechanisms driving TDP-43 pathological aggregation remain elusive. In this study, we revealed that TNF receptor-associated factor 6 (TRAF6) promotes TDP-43 condensation, and disrupting TRAF6-TDP-43 interactions effectively suppresses its aggregation. Our findings reveal that TRAF6 expression increases during senescence and preferentially interacts with RNA-binding-deficient TDP-43, a variant associated with neurotoxicity. Importantly, TRAF6 facilitates TDP-43 aggregation through a mechanism independent of its E3 ligase activity. Furthermore, we identified the motif of TDP-43 responsible for its interaction with TRAF6, enabling the design of a peptide inhibitor. This peptide effectively reduces pathological TDP-43 aggregation in cells and alleviates movement disorders and cognitive decline in mouse models. Together, these results establish a direct link between TRAF6 and TDP-43 neurotoxicity, emphasizing TRAF6’s role in driving TDP-43 pathology, and position TRAF6 as a promising target for combating TDP-43-related neurodegenerative diseases.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"12 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural mechanisms and neuromodulation therapies for non-suicidal self-injury","authors":"Dongpeng Wu, Shaoyang Wang, Hongping Wang, Jiahua Zhang, Yanghua Tian","doi":"10.1038/s41380-025-03125-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03125-7","url":null,"abstract":"<p>Non-suicidal self-injury (NSSI) refers to intentional self-inflicted bodily harm without suicidal intent. NSSI has been linked to various neurobiological dysfunctions, but its precise neural mechanisms have not been fully elucidated. Clinically, conventional pharmacological and psychotherapeutic interventions often exhibit prolonged treatment durations, delayed onset of efficacy, and considerable side effects, limiting their ability to effectively target the core pathological mechanisms of NSSI. These limitations highlight the urgent need for novel therapeutic approaches. Neuromodulation techniques, which have the potential to directly modulate neural activity, have recently been explored as promising interventions for NSSI. However, research in this field remains in its early stages. Existing evidence is limited and heterogeneous, with substantial interindividual variability in treatment response and a lack of high-quality, systematic clinical data. This review synthesizes findings from recent neuroimaging studies to examine the neural circuits potentially involved in NSSI from four key domains: emotion regulation, reward feedback, pain processing, and impulse control. By elucidating the underlying neurobiological mechanisms, summarizing current evidence on neuromodulation, and exploring future directions for therapeutic innovation and optimization, this review aims to provide a foundation for advancing neuromodulation-based treatments for NSSI.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"13 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential associations of APOE and TREM2 variants with glial fibrillary acidic protein and neurofilament light in plasma of UK Biobank participants support distinct disease mechanisms","authors":"Yun Freudenberg-Hua, Luca Giliberto, Cristina d’Abramo, Wentian Li, Yilong Ma, Alison Goate, Jeremy Koppel","doi":"10.1038/s41380-025-03098-7","DOIUrl":"https://doi.org/10.1038/s41380-025-03098-7","url":null,"abstract":"<p>Plasma levels of glial fibrillary acidic protein (GFAP) and neurofilament light (NEFL) are key dementia biomarkers. GFAP and NEFL represent different underlying disease processes, i.e. astrocytic activation vs. neuronal damage. The associations of established genetic risk variants with these biomarkers may reflect time course and mechanisms by which the respective genes influence disease risk. Therefore, we investigated the association of the established high-effect dementia variants in <i>APOE</i> and <i>TREM2</i> with these biomarkers, in a large population cohort of over 50,000 participants from the UK Biobank (UKB). The results show that <i>APOE4</i> is associated with elevated levels of plasma GFAP, and to a lesser extent, NEFL. The <i>APOE4</i> effect on GFAP increases with age and the number of <i>APOE4</i> alleles. The risk variants R47H and R62H in <i>TREM2</i> are associated with higher NEFL levels, but not with GFAP, and the effect sizes do not increase with age. In contrast, the protective <i>APOE2</i> allele showed no effect on GFAP or NEFL. In conclusion, we find that major genetic risk factors for Alzheimer’s disease exhibit distinct patterns of effect on these biomarkers, with <i>APOE4</i> primarily affecting astrocyte activation starting in midlife, while <i>TREM2</i> variants affect NEFL but not GFAP, and the protective effects of <i>APOE2</i> are not captured by either of these biomarkers.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"671 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}