Molecular Neurodegeneration最新文献

{"title":"Disassembly of mitochondrial cristae architecture drives neurodegeneration in Huntington’s disease","authors":"Yutong Shang,Rihua Wang,Di Hu,Kyle McGill Percy,Xiaoyan Sun,Xin Qi","doi":"10.1186/s13024-026-01005-4","DOIUrl":"https://doi.org/10.1186/s13024-026-01005-4","url":null,"abstract":"Abstract Background Mitochondrial dysfunction is a key feature of many neurodegenerative diseases, including Huntington’s disease (HD), yet the initiating cellular lesion that links the disease-causing protein, mutant huntingtin (mtHtt), to organelle failure and neuronal degeneration remains unclear. Methods Using complementary in vitro and in vivo models of HD, we investigated the molecular mechanisms by which mtHtt disrupts mitochondrial integrity and identified its mitochondrial target whose perturbation leads to cristae disorganization and subsequent neuronal degeneration. The pathogenic relevance of this pathway was further evaluated in HD patient iPSC-derived striatal neurons and HD knock-in mice through genetic manipulation, where behavioral assays, neuropathological analyses, and electron microscopy were employed to assess disease progression and mitochondrial ultrastructure. Results We show that mutant huntingtin (mtHtt) destabilizes mitochondrial membrane architecture through disruption of the mitochondrial contact site and cristae organizing system (MICOS). Across neuronal and mouse models HD, the MICOS complex is disassembled and its core scaffold protein mitofilin is depleted. Mechanistically, mtHtt accumulates at mitochondrial contact sites, associates with mitofilin, and recruits the AAA-ATPase VCP/p97, which drives ATPase-dependent extraction of mitofilin from MICOS, leading to cristae disorganization, respiratory impairment, and structural destabilization. Extracted mitofilin accumulates in insoluble assemblies with mtHtt and VCP, reducing the soluble pool required to maintain crista junctions. Blocking VCP mitochondrial recruitment or inhibiting its ATPase activity preserves MICOS integrity, while restoring mitofilin reconstitutes cristae architecture, improves mitochondrial and synaptic function in patient-derived neurons, and ameliorates neuropathology and motor deficits in HD mice. Conclusions These findings identify mitochondrial cristae architecture as a point of vulnerability in neurodegeneration and establish architectural destabilization of organelles as an upstream pathogenic mechanism linking disease proteins to neuronal degeneration.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"34 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208748","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":"SALL1 as a marker for distinguishing microglia from blood-derived myeloid cells in stroke brain scRNA-seq data.","authors":"Chu-Yan Zhang, Yi-Ming Lu, Heng Zhang, Yi-Sheng Li, Luo-Yi-Fan He, Yi-Yao Gao, Mu-Zhou Xue, Zi-Yu Wang, Zi-Bo Tang, Li-Li Feng, Jiali Wang, Yi-Xuan Zhang","doi":"10.1186/s13024-026-01003-6","DOIUrl":"10.1186/s13024-026-01003-6","url":null,"abstract":"<p><p>Distinguishing resident microglia from infiltrating myeloid cells in stroke scRNA-seq data remains challenging due to shared myeloid markers; SALL1 shows greater specificity for microglia compared with commonly used markers (e.g. TMEM119, CX3CR1, P2RY12), and combining SALL1 with these commonly used markers improves the ability to distinguish microglia from infiltrating myeloid populations in stroke‑associated scRNA‑seq datasets.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ICA1L stabilizes LRP1 to mitigate Aβ pathology in Alzheimer’s disease","authors":"Liang Chen,Kai Zhuang,Chenxi Cao,Shuzhong Wang,Yan Yan,Yameng Zheng,Yiming Ma,Rijin Lin,Xiaowen Cai,Bo Wu,Li Zhong,Jiechao Zhou,Weiwei Gao,Jie Zhang","doi":"10.1186/s13024-026-01006-3","DOIUrl":"https://doi.org/10.1186/s13024-026-01006-3","url":null,"abstract":"Abstract Background Genetic and proteomic studies have identified numerous candidate genes associated with Alzheimer’s disease (AD), yet the functional relevance of many remains unclear. Islet Cell Autoantigen 1 Like (ICA1L) has consistently emerged as a top-ranked locus in integrative genome-wide and proteome-wide association studies, but its mechanistic role in AD pathogenesis has not been defined. Methods ICA1L expression was examined in postmortem human AD brains and 5xFAD transgenic mice. Cognitive function and amyloid pathology were assessed using three independent ICA1L -deficient mouse models, including germline knockout, central nervous system-specific and excitatory neuron–specific knockouts. Hippocampal ICA1L overexpression was employed to evaluate the effects of enhanced ICA1L expression in vivo. ICA1L-interacting proteins were identified by immunoprecipitation followed by liquid chromatography–tandem mass spectrometry (LC-MS). Protein stability and degradation pathways were assessed using cycloheximide chase assays together with ubiquitination and inhibitor-based analyses. A structure-guided 30–amino acid ICA1L-derived peptide was engineered and evaluated for blood–brain barrier penetration and therapeutic efficacy in 5xFAD mice. Results ICA1L expression was significantly upregulated in the brains of AD patients and 5xFAD mice. Genetic ablation of ICA1L markedly exacerbated cognitive deficits and amyloid-β (Aβ) pathology, whereas hippocampal overexpression of ICA1L attenuated amyloid deposition and improved cognitive function. Interactomics analyses revealed that ICA1L physically interacts with low-density lipoprotein receptor-related protein 1 (LRP1). Loss of ICA1L accelerated LRP1 degradation via ubiquitin–proteasome pathways, resulting in increased BACE1 expression and enhanced Aβ production. Notably, a 30–amino acid synthetic peptide derived from ICA1L stabilized LRP1, alleviated Aβ pathology, and improved cognitive performance in 5xFAD mice. Conclusions These findings identify ICA1L as an endogenous neuroprotective regulator of AD pathology and uncover a previously unrecognized ICA1L–LRP1 axis that modulates Aβ homeostasis. Targeting ICA1L or its active peptide represents a promising therapeutic strategy for Alzheimer’s disease.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"52 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208749","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":"AI-assisted discovery of an ABCA1/ABCG1 activator for restoring mitophagy and mitigating Alzheimer’s pathology","authors":"Zhipeng Ling,Jun-Ping Pan,Xianglu Xiao,Wenfan Wu,Guisi Chen,Fang Shi,Zehuan Chen,Haiyi Zhang,Yuehao Huang,Qing Tang,Qiwei Cai,Shenglong Deng,Zhangming Niu,Shi-Qi Zhang,He-Ling Wang,Jianying Zhang,Xuefeng Zhou,Lipeng Mao,Junliang Li,Hongming Chen,Guang Lu,Guobing Chen,Evandro Fei Fang,Guang Yang,Guocai Wang,Fei Xiao,Yubo Zhang","doi":"10.1186/s13024-026-00998-2","DOIUrl":"https://doi.org/10.1186/s13024-026-00998-2","url":null,"abstract":"Abstract Defective mitophagy is a key pathological risk of Alzheimer’s disease (AD), yet available pharmacological agents capable of restoring mitophagy remain clinically limited, largely due to the lack of tools for drug screening and target identification. To address this, we introduce an integrated platform with three novel artificial intelligence (AI)-enabled approaches—the phenotype-based screening model ‘CellAutoFM’, the drug-likeness predictor ‘ADMET Ranker’, and the target deconvolution method ‘PROCAT’. Using this platform together with wet lab validation, Crassifolin A (JGX-1) is identified as a potent natural product-derived mitophagy inducer; structurally, JGX-1 directly binds to ATP-binding cassette sub-family A member 1 (ABCA1) and sub-family G member 1 (ABCG1), triggering enhanced cholesterol efflux which activates PINK1/Parkin-dependent mitophagy. In both in vitro and in vivo AD laboratory models, JGX-1 reduces amyloid-β and Tau pathologies in an autophagy/mitophagy-dependent manner as these benefits are dramatically blunted with key mitophagy genes knocked down. Collectively, we provide an open-access, reproducible AI-assisted platform for rapid compound screening, drug-likeness evaluation, and potential target prediction to advance drug discovery. Through this paradigm, we unveil modulating the ABCA1/ABCG1-mediated cholesterol-mitophagy pathway as a promising anti-AD strategy, with a novel drug candidate JGX-1 identified.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"178 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089000","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":"Beneficial vs. pathogenic microglia functions across aging, multiple sclerosis, and Alzheimer’s disease","authors":"Jonathan K. Monteiro,Véronique E. Miron","doi":"10.1186/s13024-026-01002-7","DOIUrl":"https://doi.org/10.1186/s13024-026-01002-7","url":null,"abstract":"Abstract Microglia are a population of central nervous system (CNS)-resident macrophages that play key roles in regulating CNS health. Emerging work has revealed a plethora of ways by which microglia monitor and regulate neuronal and glial function in homeostasis. In response to stressors, microglia lose these homeostatic functions to limit injury and promote regeneration. However, with aging and in neurodegenerative diseases such as multiple sclerosis and Alzheimer’s disease, loss of microglial homeostasis can persist, which can contribute to demyelination, failed remyelination, neurodegeneration, and consequent neurological dysfunction. Given the lack of effective therapies for the treatment of aging-related dysfunction or neurodegeneration, it is important to understand the mechanisms by which beneficial microglia functions give way to pathogenic ones to identify putative therapeutic strategies. In this review, we discuss recent work that has revealed novel roles for microglia in homeostasis, and how loss of homeostasis can either promote disease resolution or drive persistent damage and dysfunction in the CNS.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"17 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088996","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":"Nucleoporin 50 rescues hallmarks of TDP-43 proteinopathy in ALS/FTD disease models","authors":"Courtney L. Smith,Bilal Khalil,Alyssa C. Walker,Feilin Liu,Dmytro Morderer,Jorge García Morato,Caroline Hsieh,Christopher Altheim,Nikhil B. Ghayal,Richard J. Crook,Adrianna E. White,Evan Udine,Cyril Pottier,Prakruthi Vadakattu,Typhaine Comyn,Jannifer H. Lee,Anh M. Ly,Antonia Raffelhueschen,Emma G. Mason,Chih-Wei Tsai,Dennis W. Dickson,Rosa Rademakers,Marka van Blitterswijk,Sami J. Barmada,Wilfried Rossoll","doi":"10.1186/s13024-026-01001-8","DOIUrl":"https://doi.org/10.1186/s13024-026-01001-8","url":null,"abstract":"Abstract Nuclear depletion and cytoplasmic aggregation of RNA-binding protein TDP-43 are common neuropathological hallmarks of the amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) disease spectrum. Although defects in nucleocytoplasmic transport are well-documented in ALS/FTD disease models and patient tissue, and nuclear transport receptors have been shown to modulate TDP-43 pathology, the role of nucleoporins in TDP-43 mislocalization and cytoplasmic aggregation is not well understood. Here, we show that nucleoporin 50 (NUP50), which has been genetically linked to ALS risk, acts as a protective modifier of TDP-43 pathology in cellular models of ALS/FTD. NUP50 expression reduces detergent-insoluble TDP-43, visible TDP-43 aggregation, and pathological TDP-43 hyperphosphorylation. We show that its activity against TDP-43 aggregation depends on association with the nuclear pore complex (NPC) and identify a 41-amino-acid NUP50 fragment that is sufficient for both NPC association and reduction of pathological TDP-43 aggregation. We demonstrate that this active fragment reduces TDP-43 aggregation and neurotoxicity in primary neurons. We also characterize an ALS-linked NUP50 missense variant with impaired activity against TDP-43 aggregation and show that NUP50 partially co-localizes with pathological TDP-43 inclusions in human ALS/FTD brain tissue. Together, our results identify NUP50 as a modifier of TDP-43 aggregation and toxicity, support a model in which reduced NUP50 activity contributes to TDP-43 proteinopathy, and highlight NUP50 activity and its minimal active fragment as promising starting points for therapeutic development aimed at reducing TDP-43 aggregation and toxicity.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"151 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088995","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":"Oxidative stress-induced microglial CD22 upregulation impairs phagocytosis and exacerbates Huntington’s disease","authors":"Yan Hua Lee,Jian Jing Siew,Chia-Wei Lee,Hui-Mei Chen,Ya-Ting Lu,Deepa Sridharan,Po-Chun Jimmy Huang,Hua-Chien Chang,Shih-Yun Guu,Pao-Yuan Wang,Yi-Fu Wang,Suh-Yuen Liang,Feng-Lan Chiu,Hung-Chih Kuo,Kay-Hooi Khoo,Shih-Yu Chen,Takashi Angata,Yijuang Chern","doi":"10.1186/s13024-026-00996-4","DOIUrl":"https://doi.org/10.1186/s13024-026-00996-4","url":null,"abstract":"Abstract Background Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal polyglutamine expansion in mutant huntingtin (mHTT) and is characterized by movement dysfunction and neuronal loss. Siglecs, a family of sialic acid-binding proteins, are expressed on brain microglia and implicated in Alzheimer’s disease. Sialic acids are abundant in mammalian brains and cap the termini of the glycocalyx of various brain cells. Alterations in sialoglycans or Siglecs may affect interactions between microglia and other brain cells. However, the roles of Siglecs in HD have not been investigated. Methods We profiled Siglecs in postmortem caudate nucleus samples from HD subjects and in a mouse model of HD (R6/2) using RT-qPCR and mass cytometry analyses. CD22 functions in microglia were evaluated using a microglial cell line (BV2) and primary microglia. Native ligands for microglial CD22 were assessed via glycomic profiling and flow cytometry. Regulation of CD22 ligands in astrocytes was investigated in an astrocytic cell line (C8-D1A) and primary astrocytes. The role of CD22 in HD was examined by genetic deletion in HD mice, followed by behavioral analyses and pathological evaluation with immunofluorescence staining and MRI. Results Upregulation of CD22 in microglia, observed in the brains of patients and mice with HD, impairs microglial phagocytosis via ITIM-ITAM signaling crosstalk. This CD22 upregulation was driven by sustained oxidative stress, as antioxidant treatment (N-acetylcysteine) markedly normalized CD22 levels. CD22 ligand, α2,6-sialylated-6-sulfo-LacNAc, primarily expressed by astrocytes, was significantly reduced in HD mice. mHTT, but not wild-type HTT, suppressed ligand synthesis in astrocytes under elevated oxidative stress, allowing more CD22 on the microglial surface to inhibit phagocytosis. Treatment with a neutralizing antibody or ligand-enriched extracellular vesicles depleted surface CD22 and restored the phagocytic function of microglia. Genetic deletion of CD22 in HD mice improved rotarod performance, reduced mHTT inclusion burden, increased DARPP-32 expression, and alleviated brain atrophy, supporting the concept that CD22-mediated inhibition of microglial phagocytosis contributes to HD pathogenesis. Conclusion Our findings suggest that CD22 acts as a negative regulator of microglial phagocytosis and may contribute to HD progression when astrocyte-microglia communication is impaired, thereby identifying CD22 as a potential molecular target with relevance to HD pathology.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"51 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149089077","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":"In vivo detection of pathologic α- synuclein and TDP-43 in the skin and olfactory mucosa of a patient with Parkinson’s disease-like phenotype carrying the p.Thr272Serfs*10 GRN mutation","authors":"Paola Caroppo,Vittoria Aprea,Cristina Villa,Ilaria Linda Dellarole,Aurora Romeo,Giacomina Rossi,Arianna Ciullini,Anna Burato,Sara Prioni,Marina Grisoli,Giuseppe Legname,Giulia Simmini,Alessia Luppino,Samanta Mazzetti,Fabio Moda,Grazia Devigili","doi":"10.1186/s13024-026-01000-9","DOIUrl":"https://doi.org/10.1186/s13024-026-01000-9","url":null,"abstract":"Abstract We describe a patient carrying the GRN p.Thr272Serfs*10 mutation, who presented with parkinsonism at onset and later developed prodromal frontotemporal dementia, in whom seed amplification assay on olfactory mucosa and skin analyses suggest mixed TDP-43 and α-synuclein co-pathology, highlighting how combining these techniques could provide a comprehensive approach to investigate the underlying neuropathological process.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"42 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088362","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":"From mechanism to intervention: lipoproteins and Alzheimer’s disease","authors":"Tetiana Poliakova,Lizi Zhang,Cheryl L. Wellington","doi":"10.1186/s13024-026-00993-7","DOIUrl":"https://doi.org/10.1186/s13024-026-00993-7","url":null,"abstract":"Abstract Alzheimer’s disease (AD) is the leading global cause of dementia, characterized by memory impairment and neuropathological hallmarks of amyloid and tau deposition. Several cardiovascular risk factors, including hypertension, type II diabetes, and dyslipidemia, are modifiable risk factors of AD, especially during midlife, highlighting a close interplay between AD and vascular contributions to cognitive impairment and dementia (VCID). The objectives of this narrative review are to: (1) synthesize recent literature, mainly from 2024 to 2026, on how lipoproteins, namely apolipoprotein E (ApoE), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), influence risk of AD and related dementias (ADRD), (2) describe mechanisms by which lipoproteins may contribute to ADRD and VCID risk, and (3) highlight potential interventions that involve lipoprotein metabolism with a focus on cholesteryl ester transfer protein (CETP), which regulates LDL-C and HDL-C levels in humans. Interest in CETP as a potential therapeutic target in dementia is surging, as a new and well-tolerated CETP inhibitor obicetrapib was recently found to slow progression of plasma p-tau-217, an approved diagnostic biomarker of amyloid positivity, over 12 months of treatment in patients with atherosclerotic cardiovascular disease, with more pronounced effects in APOE4 carriers.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"31 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048981","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":"Dynamic [18F]PI-2620 recording facilitates prediction of β-amyloid positivity and simultaneous staging of tau and neurodegeneration","authors":"Johannes Gnörich,Julia Kusche-Palenga,Agnes Kling,Amir Dehsarvi,Angela Bronte,Lukas Frontzkowski,Artem Zatcepin,Mirlind Zaganjori,Florian Schöberl,Sebastian N. Roemer-Cassiano,Boris-Stephan Rauchmann,Carolin Kurz,Carla Palleis,Alexander M. Bernhardt,Alexander Jäck,Sabrina Katzdobler,Maximilian Scheifele,Theresa Bauer,Gérard N. Bischof,Thilo van Eimeren,Alexander Drzezga,Jan Häckert,Robert Perneczky,Michael Rullmann,Katharina Buerger,Rudolf A. Werner,Andreas Zwergal,Johannes Levin,Peter Bartenstein,Osama Sabri,Henryk Barthel,Sophia Stöcklein,Günter Höglinger,Nicolai Franzmeier,Matthias Brendel","doi":"10.1186/s13024-026-00997-3","DOIUrl":"https://doi.org/10.1186/s13024-026-00997-3","url":null,"abstract":"Abstract Background Patients with Alzheimer’s disease (AD) and clinically overlapping neurodegenerative diseases are classified molecularly using the A/T/N classification system. Apart from fluid biomarkers and structural MRI, A/T/N assessment incorporates β-amyloid-PET (A), tau-PET (T), and [ 18 F]FDG-PET (N). We evaluated if dynamic features of tau-PET with [ 18 F]PI-2620 allow prediction of β-amyloid positivity and simultaneous staging of tau and neurodegeneration in individual patients using a single imaging session. Methods We studied 129 patients with tauopathies, comprising 47 patients with β-amyloid-positive 3/4-repeat tauopathy and 82 patients with β-amyloid-negative primary 4-repeat tauopathies, alongside 17 healthy controls. Participants underwent 60-minute dynamic [ 18 F]PI-2620 tau-PET. Kinetic modelling simultaneously provided tracer efflux rate (K2a) as a predictor for β-amyloid status, distribution volume ratio (DVR) for regional tau burden, and relative perfusion (R1) as a marker of neurodegeneration. These parameters were validated against β-amyloid-PET, [ 18 F]FDG-PET, volumetric MRI, and cerebrospinal fluid biomarkers using receiver operating characteristic and correlation analyses and visual assessments. [ 18 F]PI-2620 K2a -based prediction of β-amyloid positivtiy was additionally tested in an independent, clinically heterogeneous validation cohort of 97 individuals. Results [ 18 F]PI-2620 K2a differentiated tau isoform compositions despite clinically overlapping presentations and tau-PET patterns, demonstrating reduced cortical tracer clearance in 3/4-repeat compared with 4-repeat tauopathies. [ 18 F]PI-2620 K2a remained sensitive in individuals with visually negative or low [ 18 F]PI-2620 DVR signals and outperformed both tau burden and perfusion for predicting β-amyloid status, achieving an area under the curve of 0.99, a positive predictive value of 91.5%, and a negative predictive value of 95.1%. Performance remained robust in the independent validation cohort, with an area under the curve of 0.98, a positive predictive value of 87.9%, and a negative predictive value of 95.3%. [ 18 F]PI-2620 DVR quantified regional tau patterns, with cortical predominance in 3/4-repeat tauopathy and subcortical involvement in 4-repeat tauopathies. [ 18 F]PI-2620 R1 exhibited strong quantitative and visual associations with established markers of neurodegeneration. Integration of K2a, DVR, and R1 in disease-specific composite regions enabled individualized three-dimensional A/T/N staging. Conclusions Dynamic [ 18 F]PI-2620 PET imaging facilitates assessment of the β-amyloid status and regional staging of tau and neurodegeneration during a single acquisition. This one-stop-shop approach may reduce radiation exposure, streamline diagnostic workflows, and facilitate personalized disease profiling.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"32 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048982","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}