Molecular Psychiatry最新文献

{"title":"Low-intensity transcranial focused ultrasound amygdala neuromodulation: a double-blind sham-controlled target engagement study and unblinded single-arm clinical trial","authors":"Bryan R. Barksdale, Lauren Enten, Annamarie DeMarco, Rachel Kline, Manoj K. Doss, Charles B. Nemeroff, Gregory A. Fonzo","doi":"10.1038/s41380-025-03033-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03033-w","url":null,"abstract":"<p>Mood, anxiety, and trauma-related disorders (MATRDs) are highly prevalent and comorbid. A sizable number of patients do not respond to first-line treatments. Non-invasive neuromodulation is a second-line treatment approach, but current methods rely on cortical targets to indirectly modulate subcortical structures, e.g., the amygdala, implicated in MATRDs. Low-intensity transcranial focused ultrasound (tFUS) is a non-invasive technique for direct subcortical neuromodulation, but its safety, feasibility, and promise as a potential treatment is largely unknown. In a target engagement study, magnetic resonance imaging (MRI)-guided tFUS to the left amygdala was administered during functional MRI (tFUS/fMRI) to test for acute modulation of blood oxygenation level dependent (BOLD) signal in a double-blind, within-subject, sham-controlled design in patients with MATRDs (N = 29) and healthy comparison subjects (N = 23). In an unblinded treatment trial, the same patients then underwent 3-week daily (15 sessions) MRI-guided repetitive tFUS (rtFUS) to the left amygdala to examine safety, feasibility, symptom change, and change in amygdala reactivity to emotional faces. Active vs. sham tFUS/fMRI reduced, on average, left amygdala BOLD signal and produced patient-related differences in hippocampal and insular responses. rtFUS was well-tolerated with no serious adverse events. There were significant reductions on the primary outcome (Mood and Anxiety Symptom Questionnaire General Distress subscale; <i>p</i> = 0.001, Cohen’s <i>d</i> = 0.77), secondary outcomes (Cohen’s <i>d of</i> 0.43–1.50), and amygdala activation to emotional stimuli. Findings provide initial evidence of tFUS capability to modulate amygdala function, rtFUS safety and feasibility in MATRDs, and motivate double-blind randomized controlled trials to examine efficacy.</p><p>ClinicalTrials.gov registration: NCT05228964</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"2 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872686","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":"Estradiol, via estrogen receptor β signaling, mediates stress-susceptibility in the male brain","authors":"Polymnia Georgiou, Abagail F. Postle, Ta-Chung M. Mou, Liam E. Potter, Xiaoxian An, Panos Zanos, Michael S. Patton, Katherine J. Pultorak, Sarah M. Clark, Vien Ngyuyen, Chris F. Powels, Katalin Prokai-Tatrai, Antonis Kirmizis, Istvan Merchenthaler, Laszlo Prokai, Margaret M. McCarthy, Brian N. Mathur, Todd D. Gould","doi":"10.1038/s41380-025-03027-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03027-8","url":null,"abstract":"<p>Dysregulation of normal reward processing via psychological stress contributes to the development of psychiatric disorders. Estrogen is involved in reward processing in females, but this effect has not been well studied in males despite the abundant conversion of androgens to estrogens in the male brain. Here, we used a combination of genetic deletions, behavioral assays, pharmacology, circuit dissection, electrophysiology, in vivo fiber photometry, and optogenetics/chemogenetics to determine the role of the most prevalent and potent estrogen, 17β-estradiol, in male stress-induced reward processing dysfunction. We found that absence of estrogen receptor (ER) β renders male but not female mice susceptible to stress-induced maladaptive reward-processing behaviors. We demonstrated that activation of ERβ-projecting neurons from the basolateral amygdala to nucleus accumbens induced rewarding effects in male, but not female mice. Moreover, we show that the activity of ERβ-expressing neurons projecting from the basolateral amygdala to nucleus accumbens is reduced in hypogonadal male mice subjected to stress, while activation of this circuit reverses stress-induced maladaptive reward processing behaviors and inhibition induces stress susceptibility. We identified that absence of estradiol, but not testosterone per se, underlies susceptibility to stress-mediated dysfunction of rewarding behaviors and that brain-selective delivery of estradiol and intra-basolateral amygdala administration of an ERβ-specific agonist prevent maladaptive reward-processing behaviors in hypogonadal male mice. These findings delineate an estrogen-based mechanism underlying stress susceptibility and provide a novel therapeutic strategy for the treatment of reward-related disorders associated with hypogonadal conditions.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"70 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866708","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":"Reflections on “mitochondrial DNA abundance in blood is associated with Alzheimer’s disease- and dementia-risk”","authors":"Huan Wang, Tianyi Ning, Ziyin Cui, Zedong Cheng","doi":"10.1038/s41380-025-02958-6","DOIUrl":"https://doi.org/10.1038/s41380-025-02958-6","url":null,"abstract":"<p><b>TO THE EDITOR:</b></p><p>We read with great interest the research article titled “Mitochondrial DNA abundance in blood is associated with Alzheimer’s disease- and dementia-risk” [1]. The article by Hannah Stocker et al. offers a significant contribution to the field of dementia research by investigating the association between mitochondrial DNA copy number (mtDNAcn) and the risk of developing Alzheimer’s disease (AD) and other forms of dementia. The study leverages the extensive data from the ESTHER cohort, a large-scale, population-based study in Germany, which followed nearly 10,000 participants over 17 years. This long-term perspective and the comprehensive data collection are major strengths, providing a robust foundation for analyzing the complex relationship between mtDNAcn and dementia risk.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"7 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872685","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":"Subcellular functions of tau mediate repair response and synaptic homeostasis in injury","authors":"Riya Thomas, Die Zhang, Christopher A. Cronkite, Rintu Thomas, Sanjay K. Singh, Lawrence F. Bronk, Rodrigo F. Morales, Joseph G. Duman, David R. Grosshans","doi":"10.1038/s41380-025-03029-6","DOIUrl":"https://doi.org/10.1038/s41380-025-03029-6","url":null,"abstract":"<p>Injury responses in terminally differentiated cells such as neurons are tightly regulated by pathways aiding homeostatic maintenance. Cancer patients subjected to neuronal injury in brain radiation experience cognitive declines similar to those seen in primary neurodegenerative diseases. Numerous studies have investigated the effect of radiation in proliferating cells of the brain, yet the impact in differentiated, post-mitotic neurons, especially the structural and functional alterations remain largely elusive. We identified that microtubule-associated tau is a critical player in neuronal injury response via compartmentalized functions in both repair-centric and synaptic regulatory pathways. Ionizing radiation-induced injury acutely induces an increase in phosphorylated tau in the nucleus where it directly interacts with histone 2AX (H2AX), a DNA damage repair (DDR) marker. Loss of tau significantly reduced H2AX phosphorylation after irradiation, indicating that tau may play an important role in the neuronal DDR response. We also observed that loss of tau increases eukaryotic elongation factor levels, a positive regulator of protein translation after irradiation. This initial response cascades into a significant increase in synaptic proteins, resulting in disrupted homeostasis. Downstream, the novel object recognition test showed a decrease in learning and memory in tau-knockout mice after irradiation, and electroencephalographic activity contained increased delta and theta band oscillations, often seen in dementia patients. Our findings demonstrate tau’s previously undefined, multifunctional role in acute responses to injury, ranging from DDR response in the nucleus to synaptic function within neurons. Such knowledge is vital to develop therapeutic strategies targeting neuronal injury in cognitive decline for at risk and vulnerable populations.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"21 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143862943","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":"Integrative analysis of miRNA expression profiles reveals distinct and common molecular mechanisms underlying broad diagnostic groups of severe mental disorders","authors":"Pierre Solomon, Lalit Kaurani, Monika Budde, Jean-Baptiste Guiné, Dennis Manfred Krüger, Kevin Riquin, Tonatiuh Pena, Susanne Burkhardt, Cynthia Fourgeux, Kristina Adorjan, Maria Heilbronner, Janos L. Kalman, Mojtaba Oraki Kohshour, Sergi Papiol, Daniela Reich-Erkelenz, Sabrina K. Schaupp, Eva C. Schulte, Fanny Senner, Thomas Vogl, Ion-George Anghelescu, Volker Arolt, Bernhardt T. Baune, Udo Dannlowski, Detlef E. Dietrich, Andreas J. Fallgatter, Christian Figge, Georg Juckel, Carsten Konrad, Jens Reimer, Eva Z. Reininghaus, Max Schmauß, Carsten Spitzer, Jens Wiltfang, Jörg Zimmermann, Anna-Lena Schütz, Farahnaz Sananbenesi, Anne Sauvaget, Peter Falkai, Thomas G. Schulze, André Fischer, Urs Heilbronner, Jeremie Poschmann","doi":"10.1038/s41380-025-03018-9","DOIUrl":"https://doi.org/10.1038/s41380-025-03018-9","url":null,"abstract":"<p>Micro RNAs (miRNAs) play a crucial role as regulators of various biological processes and have been implicated in the pathogenesis of mental disorders such as schizophrenia and bipolar disorders. In this study, we investigate the expression patterns of miRNAs in the PsyCourse Study (<i>n</i> = 1786), contrasting three broad diagnostic groups: Psychotic (Schizophrenia-spectrum disorders), Affective (Bipolar Disorder I, II and recurrent Depression), and neurotypic healthy individuals. Through comprehensive analyses, including differential miRNA expression, miRNA transcriptome-wide association study (TWAS), and predictive modelling, we identified multiple miRNAs unique to Psychotic and Affective groups as well as shared by both. Furthermore, we performed integrative analysis to identify the target genes of the dysregulated miRNAs and elucidate their potential roles in psychosis. Our findings reveal significant alterations of multiple miRNAs such as miR-584-3p and miR-99b-5p across the studied diagnostic groups, highlighting their role as molecular correlates. Additionally, the miRNA TWAS analysis discovered previously known and novel genetically dysregulated miRNAs confirming the relevance in the etiology of the diagnostic groups. Importantly, novel factors and putative molecular mechanisms underlying these groups were uncovered through the integration of miRNA-target gene interactions. This comprehensive investigation provides valuable insights into the molecular underpinnings of severe mental disorders, shedding light on the complex regulatory networks involving miRNAs.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"26 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863001","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":"LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons","authors":"Chuyu Chen, Meghan Masotti, Nathaniel Shepard, Vanessa Promes, Giulia Tombesi, Daniel Arango, Claudia Manzoni, Elisa Greggio, Sabine Hilfiker, Yevgenia Kozorovitskiy, Loukia Parisiadou","doi":"10.1038/s41380-025-03030-z","DOIUrl":"https://doi.org/10.1038/s41380-025-03030-z","url":null,"abstract":"<p>Haloperidol is used to manage psychotic symptoms in several neurological disorders through mechanisms that involve antagonism of dopamine D2 receptors that are highly expressed in the striatum. Significant side effects of haloperidol, known as extrapyramidal symptoms, lead to motor deficits similar to those seen in Parkinson’s disease and present a major challenge in clinical settings. The underlying molecular mechanisms responsible for these side effects remain poorly understood. Parkinson’s disease-associated leucine-rich repeat kinase 2 (LRRK2) has an essential role in striatal physiology and a known link to dopamine D2 receptor signaling. Here, we systematically explore convergent signaling of haloperidol and LRRK2 through pharmacological or genetic inhibition of LRRK2 kinase, as well as knock-in mouse models expressing pathogenic mutant LRRK2 with increased kinase activity. Behavioral assays show that LRRK2 kinase inhibition ameliorates haloperidol-induced motor changes in mice. A combination of electrophysiological and anatomical approaches reveals that LRRK2 kinase inhibition interferes with haloperidol-induced changes, specifically in striatal neurons of the indirect pathway. Proteomic studies and targeted intracellular pathway analyses demonstrate that haloperidol induces a similar pattern of intracellular signaling as increased LRRK2 kinase activity. Our study suggests that LRRK2 kinase plays a key role in striatal dopamine D2 receptor signaling underlying the undesirable motor side effects of haloperidol. This work opens up new therapeutic avenues for dopamine-related disorders, such as psychosis, also furthering our understanding of Parkinson’s disease pathophysiology.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"32 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866709","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":"Associations among white matter microstructural changes and the development of emotional reactivity and regulation in infancy","authors":"Yicheng Zhang, Layla Banihashemi, Amelia Versace, Alyssa Samolyk, Mahmood Abdelkader, Megan Taylor, Gabrielle English, Vanessa J. Schmithorst, Vincent K. Lee, Richelle Stiffler, Haris Aslam, Ashok Panigrahy, Alison E. Hipwell, Mary L. Phillips","doi":"10.1038/s41380-025-03025-w","DOIUrl":"https://doi.org/10.1038/s41380-025-03025-w","url":null,"abstract":"<p>Deficits in emotional reactivity and regulation assessed in infancy, including high levels of negative emotionality (NE), low positive emotionality (PE) and low soothability, can predict future affective and behavioral disorders. White matter (WM) tracts develop rapidly in the first postnatal year, paralleling the development of emotional regulation. During this period, examining the development of white matter microstructure in tracts connecting cortical and/or subcortical regions supporting emotional regulation, including the cingulum bundle (CB), uncinate fasciculus (UF), and forceps minor (FM), can provide neural markers reflecting pathophysiological processes underlying early emotional regulation development. The Neurite Orientation Dispersion and Density Imaging (NODDI) model can be used to estimate with high intercellular specificity microstructural integrity and myelination using the neurite density index (NDI), and dispersion, using the orientation dispersion index (ODI). Examining relationships among changes in WM tract NODDI measures and changes in emotional reactivity and regulation during the first 3-to-9-months of age (<i>n</i> = 39), we showed that larger 3-to-9-month increases in right UF, FM, and left CB ODI were associated with larger decreases or smaller increases in soothability during this period, while a larger increase in right UF NDI was associated with a smaller increase in PE. These findings suggest that in infancy, larger microstructural changes in major WM tracts interconnecting neural networks supporting emotional regulation are associated with disrupted development of PE and soothability. These findings could provide early neural markers of child emotional dysregulation and may have implications for future affective or behavioral trajectories.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"50 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863000","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":"Advances in discerning the mechanisms underlying depression and resiliency: relation to the neurobiology of stress and the effects of antidepressants","authors":"Philip W. Gold, Ma-Li Wong","doi":"10.1038/s41380-025-03019-8","DOIUrl":"https://doi.org/10.1038/s41380-025-03019-8","url":null,"abstract":"<p>Depression denotes a dysregulated stress response with significant mental and health implications. This review examines the neurobiological mechanisms underlying depression and resilience, focusing on how stress mediators influence vulnerability to severe stressors contrasted with resilience. We analyze structural and functional alterations in key brain regions, genetic factors, and potential therapeutic interventions. Understanding these mechanisms offers insights into preventing depression onset instead of solely treating its manifestations.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"20 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863002","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":"Exploring the implications of case selection methods for psychiatric molecular genetic studies","authors":"Kenneth S. Kendler, Henrik Ohlsson, Jan Sundquist, Kristina Sundquist","doi":"10.1038/s41380-025-03015-y","DOIUrl":"https://doi.org/10.1038/s41380-025-03015-y","url":null,"abstract":"<p>Researchers selecting probands for molecular genetic studies confront a range of sampling issues with modest empirical guidance. In this paper, using cases of major depression (MD), anxiety disorders (AD) alcohol use disorder (AUD), drug use disorder (DUD), bipolar disorder (BD) and schizophrenia (SZ) from a large population cohort of all native Swedes born 1940–2003, we examine the implications of three proband selection decisions by exploring profiles of genetic risks assessed using the validated family genetic risk scores. The impact of censoring cases with comorbid diagnoses is quite variable, depending on the frequency of that disorder in the case sample and the genetic relationship of the censored to the primary disorder. In an MD cohort, censoring SZ cases produces only a focal small decrease in schizophrenia genetic risk while censoring AD cases produces a wide-spread reduction in genetic risk for MD and most other disorders. We examine the value of censoring cases of SZ, BD and MD whose onset was preceded by one to two years by first episodes of DUD or AUD. We do not see any increase in genetic risk for these “screened” cohorts. Secondary ascertainment, where disorder A is ascertained as a comorbid diagnosis in a sample collected for disorder B, can, in certain situations, produces large increases in the genetic risk for disorder B and associated disorders in cases of A. However, if disorder B is closely genetically related to disorder A (as seen with MD/AD and DUD/AUD pairings), the pattern differs dramatically and produces a general moderate elevation across the genetic risk profile. These findings provide guidelines for future investigators and suggest caution when screening out comorbid disorders and when utilizing secondary ascertainment.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"32 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851070","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":"Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease","authors":"David Mengel, Ester Soter, Julia Maren Ott, Madeleine Wacker, Alejandra Leyva, Oliver Peters, Julian Hellmann-Regen, Luisa-Sophie Schneider, Xiao Wang, Josef Priller, Eike Spruth, Slawek Altenstein, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Niels Hansen, Ayda Rostamzadeh, Emra Düzel, Wenzel Glanz, Enise I. Incesoy, Katharina Buerger, Daniel Janowitz, Michael Ewers, Robert Perneczky, Boris Rauchmann, Stefan Teipel, Ingo Kilimann, Christoph Laske, Sebastian Sodenkamp, Annika Spottke, Johanna Brustkern, Frederic Brosseron, Michael Wagner, Melina Stark, Luca Kleineidam, Kai Shao, Falk Lüsebrink, Renat Yakupov, Matthias Schmid, Stefan Hetzer, Peter Dechent, Klaus Scheffler, David Berron, Frank Jessen, Matthis Synofzik","doi":"10.1038/s41380-025-03021-0","DOIUrl":"https://doi.org/10.1038/s41380-025-03021-0","url":null,"abstract":"<p>Subjective cognitive decline (SCD) is proposed as an indicator of transitional disease stage 2 in the Alzheimer’s disease (AD) continuum. However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A + SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1). NfL levels rose across A + CU, A + SCD, and amyloid-positive mild cognitive impairment (A + MCI, stage 3). In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"9 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847224","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}