Acta Neuropathologica Communications最新文献

{"title":"Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.","authors":"Sandra Harjuhaahto, Manu Jokela, Jayasimman Rajendran, Minea Rokka, Bowen Hu, Jouni Kvist, Fuping Zhang, Tomáš Zárybnický, Kimmo Haimilahti, Liliya Euro, Eija Pirinen, Nadine Huber, Sanna-Kaisa Herukka, Annakaisa Haapasalo, Emilia Kuuluvainen, Swetha Gopalakrishnan, Pekka Katajisto, Ville Hietakangas, Thibaut Burg, Ludo Van Den Bosch, Xiaoping Huang, Derek P Narendra, Satu Kuure, Emil Ylikallio, Henna Tyynismaa","doi":"10.1186/s40478-025-02039-3","DOIUrl":"10.1186/s40478-025-02039-3","url":null,"abstract":"<p><p>Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant are less clear. Here we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ. We demonstrate that the amount of the mutant CHCHD10 is reduced, but the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state. Novel knock-in mouse model recapitulates the dose-dependent reduction of mutant CHCHD10 protein and the slow disease progression of SMAJ. With metabolome analysis of patients' primary fibroblasts and patient-specific motor neurons, we show that CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"111"},"PeriodicalIF":6.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct characteristics of brain metastasis in lung adenocarcinoma: development of high-confidence cell lines.","authors":"Jintao He, Zen-Ichi Tanei, Dao-Sian Wu, Lei Wang, Yoshitaka Oda, Masumi Tsuda, Shinya Tanaka","doi":"10.1186/s40478-025-02038-4","DOIUrl":"10.1186/s40478-025-02038-4","url":null,"abstract":"<p><p>Lung cancer is a leading cause of cancer-related deaths worldwide, with brain metastasis occurring in approximately 30-55% of patients, particularly in lung adenocarcinoma. Due to the challenges in obtaining genuine brain metastasis tumor cells, researchers commonly use nude mouse models to establish brain metastasis cell lines, though traditional methods have limitations such as high costs, lengthy timeframes, and the need for specialized imaging equipment. To address these issues, we developed an improved approach by performing low cell number circulating intracranial injections (500-4000 cells) in nude mice, successfully establishing the H1975-BM1, BM2, and BM3 cell lines. Through RNA sequencing and bioinformatics analyses, we identified transcriptomic differences among these cell lines, revealing that H1975-BM1 cells primarily exhibit stem cell function and migration characteristics, while H1975-BM3 cells display enhanced chemotaxis, cell adhesion, and cytokine secretion associated with interactions. Experimental validation, including Transwell assays, CCK8, cell adhesion assays, and subcutaneous tumor implantation in nude mice, further confirmed these findings, with H1975-BM3 forming larger tumors and a more pronounced secretion cystic cavity. In conclusion, our improved methodology successfully established high-confidence brain metastasis lung adenocarcinoma cell lines, elucidating distinct transcriptomic and functional characteristics at different stages of brain metastasis progression.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"109"},"PeriodicalIF":6.2,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12093710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain.","authors":"Francesco Catapano, Reem Alkharji, Darren Chambers, Simran Singh, Artadokht Aghaeipour, Jyoti Malhotra, Patrizia Ferretti, Rahul Phadke, Francesco Muntoni","doi":"10.1186/s40478-025-01996-z","DOIUrl":"10.1186/s40478-025-01996-z","url":null,"abstract":"<p><p>Mutations in the dystrophin gene (DMD) cause the severe muscle-wasting disease Duchenne muscular dystrophy (DMD). Additionally, there is a high incidence of intellectual disability and neurobehavioural comorbidities in individuals with DMD. Similar behavioural abnormalities are found in mdx dystrophic mouse models. Unlike muscle, several dystrophin isoforms are expressed in the human brain, but a detailed map of regional and cellular localisation of dystrophin isoforms is missing. This is crucial in understanding the neuropathology of DMD individuals, and for evaluating the translatability of pre-clinical findings in DMD mouse models receiving genetic therapy interventions. Here, we provide a comprehensive dystrophin expression profile in human brains from early development to adulthood. We reveal expression of dp427p2, dp427c, dp427m and dp40 isoforms in human embryonic brains, not previously reported. We also detected dp427p2 expression and developmental regulation in human brain across the lifespan. In addition we showed by in situ hybridisation that dp140 was greatly downregulated in adult brains. Importantly, our data also demonstrate expression of DMD transcripts in human motor neurons and co-expression of different dystrophin isoforms within single neurons in both developing and adult brains. Finally, we show localisation of DMD transcripts with GAD1+ GABAergic-associated transcripts in neurons including cerebellar Purkinje cells and interneurons, as well as in the majority of neocortical and hippocampal SLC17A7+ glutamatergic neurons, suggesting a role for dystrophin in signalling at the neuronal inhibitory and excitatory synapses.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"110"},"PeriodicalIF":6.2,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial repopulation reverses radiation-induced cognitive dysfunction by restoring medial prefrontal cortex activity and modulating leukotriene-C4 synthesis.","authors":"Yubo Hu, Zhe Li, Yafeng Zhu, Mengdan Xing, Xiaoru Xie, Panwu Zhao, Xin Cheng, Chuan Xiao, Yuting Xia, Jingru Wu, Yuan Luo, Ho Ko, Yamei Tang, Xiaojing Ye, Wei-Jye Lin","doi":"10.1186/s40478-025-02026-8","DOIUrl":"10.1186/s40478-025-02026-8","url":null,"abstract":"<p><p>Cranial radiotherapy and environmental radiation exposure are associated with increased risk of cognitive dysfunction, including memory deficits and mood disorders, yet the underlying mechanisms remain poorly understood. In this study, we demonstrate that cranial irradiation induces hypoactivity in the medial prefrontal cortex (mPFC) of mice, leading to anxiety-like behaviors and memory impairments, which can be prevented by optogenetic activation of mPFC excitatory neurons. Radiaiton exposure also causes a significant reduction in microglial density within the mPFC, accompanied by morphological and transcriptional alterations in the remaining microglia. Notably, microglial repopulation, achieved through CSF1R antagonist-mediated depletion prior to irradiation and subsequent repopulation, restores mPFC neuronal acitivity and reverses cognitive and behavioral deficits. Integrated bulk RNA sequencing and microglial proteomic analysis of the mPFC reveal that microglial repopulation specifically modulates the leukotriene-C4 biosynthesis pathway, without significant changes in canonical pro-inflammatory cytokines or chemokines. Importantly, pharmacological inhibition of leukotriene-C4 synthase ameliorates radiation-induced anxiety and memory impairments. These findings identify leukotriene-C4 signaling as a critical mechanism underlying radiation-induced cognitive dysfunction and suggest that microglial repopulation and targted inhibition of leukotriene-C4 represent potential therapeutic strategies for mitigating radiation-associated cognitive disorders.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"105"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Small molecule treatment alleviates photoreceptor cilia defects in LCA5-deficient human retinal organoids.","authors":"Dimitra Athanasiou, Tess A V Afanasyeva, Niuzheng Chai, Kalliopi Ziaka, Katarina Jovanovic, Rosellina Guarascio, Karsten Boldt, Julio C Corral-Serrano, Naheed Kanuga, Ronald Roepman, Rob W J Collin, Michael E Cheetham","doi":"10.1186/s40478-025-02010-2","DOIUrl":"10.1186/s40478-025-02010-2","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"104"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histomorphological variations in progressive multifocal leukoencephalopathy correlated with JCV replication in brain lesions: insights from 91 patients.","authors":"Kenta Takahashi, Yuko Sato, Hideki Hasegawa, Harutaka Katano, Tadaki Suzuki","doi":"10.1186/s40478-025-02027-7","DOIUrl":"10.1186/s40478-025-02027-7","url":null,"abstract":"<p><p>Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by JC polyomavirus (JCV). The histopathology of PML is morphologically diverse and characterized by the classical triad of demyelination, enlarged oligodendroglial nuclei, and bizarre astrocytes. Pathological diagnostic criteria for PML require both the classical triad and viral detection in brain tissue. However, the frequency of this triad in surgical pathology specimens and its correlation with disease progression and viral loads remain unclear. In this study, 117 brain tissues from 91 pathologically confirmed PML patients were investigated. PML histopathology was found to be spatially and temporally pleomorphic, and not all brain tissues exhibited the complete classical triad. The sensitivity of quantitative PCR for detecting JCV in brain tissues was 100%, whereas that of immunohistochemistry (IHC) was 83.5-87.8%. Viral loads in biopsy samples were significantly higher than those in autopsy samples and decreased over time after disease onset. To systematically characterize PML lesions from the outer border to the demyelinated center, we developed a histological classification based on the classical triad and macrophage infiltration. This classification correlated with viral loads, with subtypes characterized by abundant enlarged oligodendroglial nuclei at the demyelination border exhibiting the highest levels of JCV DNA. Pathological variability was influenced by spatial and temporal factors rather than by underlying diseases, although PML associated with acquired immunodeficiency syndrome exhibited more severe demyelination. In conclusion, histomorphological variability in PML reflects viral replication activity, emphasizing the importance of comprehensive pathological evaluation. Combining histomorphology, tissue-based PCR for viral DNA detection, and IHC for viral antigens is crucial for assessing disease progression. Early brain biopsy from the demyelination border offers the best opportunity for a definitive diagnosis of PML and may guide therapy targeting active lesions.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"106"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond the brain: exploring the impact of animal models of leptomeningeal disease from solid tumors.","authors":"Jillyn R Turunen, Priya Kumthekar, Atique U Ahmed","doi":"10.1186/s40478-025-01959-4","DOIUrl":"10.1186/s40478-025-01959-4","url":null,"abstract":"<p><p>Leptomeningeal disease (LMD) is a devastating manifestation of late-stage cancer which currently suffers from a lack of effective therapeutics. Unfortunately, a significant obstacle preventing the widespread development and testing of therapeutics for LMD is the lack of biologically accurate animal models. We provide overviews of six types of animal models of leptomeningeal metastasis from solid tumors: injection of tumor cells into the cerebrospinal fluid (CSF), blood, or brain parenchyma; subcutaneous or mammary fat pad injection of tumor cells; the LeptoM/LM-phenotype model; and genetic manipulation. We identify the pros and cons of each model and suggest broad areas of future research that could improve each model in terms of its similarity to human LMD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"103"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial transcriptomics reveal PI3K-AKT and metabolic alterations in aggressive, treatment-resistant lactotroph pituitary neuroendocrine tumors.","authors":"Florencia Martinez-Mendoza, Sergio Andonegui-Elguera, Ernesto Sosa-Eroza, Erick Gomez-Apo, Aurea Escobar-España, Carolina Gonzalez-Torres, Javier Gaytan-Cervantes, Alam Palma-Guzman, Hugo Torres-Flores, Alberto Moscona-Nissan, Silvia Hinojosa-Alvarez, Jesús Hernandez-Perez, Roció A Chavez-Santoscoy, Gerardo Guinto, Gerardo Y Guinto-Nishimura, Blas E Lopez-Felix, Erick U Zepeda-Fernandez, Erick M Estrada-Estrada, Victor Correa-Correa, Pedro A Gonzalez-Zavala, Marco A Asenscio-Montiel, Miguel A Garcia-Vargas, Emmanuel Cantu-Chavez, Rocio L Arreola-Rosales, Keiko Taniguchi-Ponciano, Daniel Marrero-Rodriguez, Moisés Mercado","doi":"10.1186/s40478-025-02025-9","DOIUrl":"10.1186/s40478-025-02025-9","url":null,"abstract":"<p><p>Clinically aggressive lactotroph pituitary neuroendocrine tumors (PitNET) are invasive tumors with an unusually rapid growth rate despite maximally tolerated doses of dopamine agonist (DA). We aimed to unravel the molecular heterogeneity of lactotroph PitNET and to identify biomarkers of aggressiveness and resistance to pharmacological treatment. A total of 13 patients harboring DA-resistant lactotroph PitNET were included in this study. Visium Spatial Transcriptomics (ST), whole transcriptome sequencing (WTS), and whole exome sequencing (WES) were performed in tumors from 4 of these patients; WTS and WES was carried out in 5; tumors from two patients underwent ST and WES and tumors from two other patients underwent only ST. Tumors were classified as null or partial responders according to their response to DA treatment. The eight PitNET analyzed by ST exhibited significant intratumoral heterogeneity, with clones showing alterations in PI3K/AKT and lipid metabolism pathways, particularly inositol phosphate, glycerophospholipid, and sphingolipid metabolism. The cell-cell communication analysis showed FGF-FGFR ligand receptor interaction whilst the transcription factors RXRA and CREM showed participation in both groups. A trajectory exploration was performed by including all PitNET together in a single analysis to determine whether there was a tendency or molecular pathway showing a differentiation pattern that would guide the transition from a partially responsive PitNET to a completely unresponsive one. We did not observe any such pattern. All of these findings were corroborated in the cohort of DA-resistant PitNETs in which only bulk WTS and WES were performed. The bulk WTS corroborated lipid metabolism and PI3K-AKT pathway alteration in PitNET, whereas the WES showed only SF3β1 and TP53 variants in one tumor each. Our work suggests that the PI3K/AKT pathway may constitute a molecular target at which to aim therapeutic strategies designed to treat aggressive and DA-resistant lactotroph PitNET.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"107"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation.","authors":"Ian Weidling, Christina N Preiss, Sarah E Chancellor, Gyan Srivastava, Lauren Gibilisco, Gen Lin, Melanie Shackett Brennan, Janice Lee, Lindsay M Roth, Olga Morozova, Kyong Nyon Nam, Nehal R Patel, Qing Liu, J K Thomas, Peter Reinhardt, Ruven Wilkens, Dagmar E Ehrnhoefer, Andreas Striebinger, Stefan Barghorn, Christina Xanthopoulos, Marie-Theres Weil, Sandra Biesinger, Miroslav Cik, Nandini Romanul, Kiran Yanamandra, Alessandra M Welker, Jessica Wu, Laura Gasparini, Jan Stöhr, Xavier Langlois, Justine D Manos","doi":"10.1186/s40478-025-02000-4","DOIUrl":"10.1186/s40478-025-02000-4","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized by the accumulation and spread of Tau intraneuronal inclusions throughout most of the telencephalon, leaving hindbrain regions like the cerebellum and spinal cord largely spared. These neuropathological observations, along with the identification of specific vulnerable sub-populations from AD brain-derived single nuclei transcriptomics, suggest that a subset of brain regions and neuronal subtypes possess a selective vulnerability to Tau pathology. Given the inability to culture neurons from patient brains, a disease-relevant in vitro model which recapitulates these features would serve as a critical tool to validate modulators of vulnerability and resilience. Using our recently established platform for inducing endogenous Tau aggregation in human induced pluripotent stem cell (hiPSC)-derived cortical excitatory neurons via application of AD brain-derived exogenous Tau aggregates, we explored whether Tau aggregates preferentially induce aggregation in specific neuronal subtypes. We compared Tau seeding in hiPSC-derived neuron subtypes representing regional identities across the forebrain, midbrain, and hindbrain. Higher susceptibility (i.e. more Tau aggregation) was consistently observed among cortical neuron subtypes, with CTIP2-positive, somatostatin (SST)-positive cortical inhibitory neurons showing the greatest aggregation levels across hiPSC lines from multiple donors. hiPSC-neurons also delineated between the disease-specific vulnerabilities of different protein aggregates, as α-synuclein preformed fibrils showed an increased propensity to induce aggregates in midbrain dopaminergic (mDA)-like neurons, mimicking Parkinson's disease (PD)-specific susceptibility. Aggregate uptake and degradation rates were insufficient to explain differential susceptibility. The absence of a consistent transcriptional response following aggregate seeding further indicated that intrinsic neuronal subtype-specific properties could drive susceptibility. The present data provides evidence that hiPSC-neurons exhibit features of selective neuronal vulnerability which manifest in a cell autonomous manner, suggesting that mining intrinsic (or basal) transcriptomic signatures of more vulnerable compared to more resilient hiPSC-neurons could uncover the molecular underpinnings of differential susceptibility to protein aggregation found in a variety of neurodegenerative diseases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"108"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-dependent interactions of APOE isoform 4 and Alzheimer's disease neuropathology: findings from the NACC.","authors":"Cellas A Hayes, Roland J Thorpe, Michelle C Odden","doi":"10.1186/s40478-025-02012-0","DOIUrl":"10.1186/s40478-025-02012-0","url":null,"abstract":"<p><p>Alzheimer's disease related pathologies, neurodegenerative pathologies, and vascular neuropathologies are common in older adults at death. Previous studies using the National Alzheimer's Coordinating Center (NACC) have not investigated the association between age at death and apolipoprotein E (APOE) ε4 and the prevalence of neuropathologies found at autopsy. We used autopsy confirmed neuropathology data from the NACC to examine the interactive effects of age and APOE ε4 on various neuropathologies (N = 5,843) using modified Poisson regression to estimate the prevalence ratios. Significant interactions between APOE ε4 and age at death were observed for neuritic plaques, Braak staging, diffuse neuritic plaques, and Lewy body disease pathology, with the effect of APOE ε4 decreasing at older ages. In contrast, a significant positive interaction was found for hemorrhages/microbleeds, indicating that the association between APOE ε4 and microbleeds strengthens with increasing age. These findings suggest that future therapeutic strategies should consider both genetic risk and age to effectively target AD progression.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"102"},"PeriodicalIF":6.2,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}