Alzheimer's Research & Therapy最新文献

{"title":"A systematic review and meta-analysis of the impact of transcranial direct current stimulation on cognitive function in older adults with cognitive impairments: the influence of dosage parameters.","authors":"Thatchaya Prathum, Thanwarat Chantanachai, Oranich Vimolratana, Chotica Laksanaphuk, Irin Apiworajirawit, Benchaporn Aneksan, Kanthika Latthirun, Cheng-Ta Yang, Wanalee Klomjai","doi":"10.1186/s13195-025-01677-y","DOIUrl":"10.1186/s13195-025-01677-y","url":null,"abstract":"<p><strong>Introduction: </strong>Numerous studies have demonstrated the effects of transcranial direct current stimulation (tDCS) on cognitive function in the older people. This study further explores the impact of tDCS and its dosage parameters on cognitive enhancement in older people with cognitive impairments.</p><p><strong>Methods: </strong>Randomized controlled trials (RCTs) published through November 2023 were retrieved from databases including PubMed, Scopus, EMBASE, EBSCO, and the Cochrane Library. Participants were older adults with cognitive impairments, including Alzheimer's disease (AD), mild cognitive impairment (MCI), and dementia. AD was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), or the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer' Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Dementia was diagnosed using the DSM-V or NINCDS-ADRDA criteria, while MCI was diagnosed using the DSM-V, the Petersen criteria, or assessments such as Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating (CDR). Standardized mean difference (SMD) values were analyzed to assess the effects.</p><p><strong>Results: </strong>A total of 19 RCTs were included. tDCS significantly improved the Mini-Mental State Examination score both immediately post-intervention (SMD = 0.51, p = 0.005) and at follow-up (SMD = 2.29, p = 0.0003). Significant effects were observed when tDCS was used alone (SMD = 0.39, p = 0.04), at current densities <math><mo>≤</mo></math> 0.06 mA/cm² (SMD = 0.25, p = 0.04), session durations exceeding 20 min (SMD = 0.89, p = 0.01), up to 15 sessions (SMD = 0.28, p = 0.009), and when an active electrode was placed over the temporal area (SMD = 0.33, p = 0.02). People with AD showed greater improvements compared to those with MCI or dementia (SMD = 0.91, p = 0.02). However, tDCS did not significantly improve memory or executive function.</p><p><strong>Conclusion: </strong>tDCS demonstrated efficacy in enhancing global cognition in older people with cognitive impairments, providing insight into optimal parameters for clinical application. However, no improvement were observed in memory or executive function.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"37"},"PeriodicalIF":7.9,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11796231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187926","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":"Multi-omics analyses identify gut microbiota-fecal metabolites-brain-cognition pathways in the Alzheimer's disease continuum.","authors":"Han Zhao, Xia Zhou, Yu Song, Wenming Zhao, Zhongwu Sun, Jiajia Zhu, Yongqiang Yu","doi":"10.1186/s13195-025-01683-0","DOIUrl":"10.1186/s13195-025-01683-0","url":null,"abstract":"<p><strong>Background: </strong>Gut microbiota dysbiosis is linked to Alzheimer's disease (AD), but our understanding of the molecular and neuropathological bases underlying such association remains fragmentary.</p><p><strong>Methods: </strong>Using 16S rDNA amplicon sequencing, untargeted metabolomics, and multi-modal magnetic resonance imaging, we examined group differences in gut microbiome, fecal metabolome, neuroimaging measures, and cognitive variables across 30 patients with AD, 75 individuals with mild cognitive impairment (MCI), and 61 healthy controls (HC). Furthermore, we assessed the associations between these multi-omics changes using correlation and mediation analyses.</p><p><strong>Results: </strong>There were significant group differences in gut microbial composition, which were driven by 8 microbial taxa (e.g., Staphylococcus and Bacillus) exhibiting a progressive increase in relative abundance from HC to MCI to AD, and 2 taxa (e.g., Anaerostipes) showing a gradual decrease. 26 fecal metabolites (e.g., Arachidonic, Adrenic, and Lithocholic acids) exhibited a progressive increase from HC to MCI to AD. We also observed progressive gray matter atrophy in broadly distributed gray matter regions and gradual micro-structural integrity damage in widespread white matter tracts along the AD continuum. Integration of these multi-omics changes revealed significant associations between microbiota, metabolites, neuroimaging, and cognition. More importantly, we identified two potential mediation pathways: (1) microbiota → metabolites → neuroimaging → cognition, and (2) microbiota → metabolites → cognition.</p><p><strong>Conclusion: </strong>Aside from elucidating the underlying mechanism whereby gut microbiota dysbiosis is linked to AD, our findings may contribute to groundwork for future interventions targeting the microbiota-metabolites-brain-cognition pathways as a therapeutic strategy in the AD continuum.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"36"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073347","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":"Effects of intensive lifestyle changes on the progression of mild cognitive impairment or early dementia due to Alzheimer's disease: the need for rigor.","authors":"Joshua D Grill, Daniel Gillen","doi":"10.1186/s13195-024-01621-6","DOIUrl":"10.1186/s13195-024-01621-6","url":null,"abstract":"<p><p>We consider the recent publication by Ornish and colleagues and the rigor expected for interventional clinical trials. We contend that lifestyle intervention trials should strive for the same rigor as drug trials and highlight opportunities to improve rigor in this example, particularly in design, data analysis, and publication of results for this and other lifestyle intervention studies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"32"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073341","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":"Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer's disease by regulating microglia homeostasis and inhibiting HMGB1 pathway.","authors":"Yuan Xu, Naiyuan Shao, Feng Zhi, Ronghua Chen, Yilin Yang, Jiahui Li, Ying Xia, Ya Peng","doi":"10.1186/s13195-025-01682-1","DOIUrl":"10.1186/s13195-025-01682-1","url":null,"abstract":"<p><strong>Background: </strong>Recent studies suggest that opioid receptor signaling may differentially affect Alzheimer's disease (AD) pathology and the relevant behavioral dysfunctions. However, the precise roles and mechanisms of opioid receptor subtypes in AD pathologies are still unclear with major controversies.</p><p><strong>Methods: </strong>We compared the delta-opioid receptor (DOR)- and mu-opioid receptor (MOR)-mediated effects on AD-associated cognitive deficits, pathologies, neuroinflammations, cell death using transgenic APP/PS1 mouse model and BV2 cell line at behavioral, molecular, and cellular levels. Unpaired t-test and one/two way analysis for variance (ANOVA) were used to analyze statistical significance of the data.</p><p><strong>Results: </strong>We show a distinct role of DOR and its major difference with MOR in AD injury in an APP/PS1 mouse model. DOR activation by UFP-512, but not MOR activation by DAMGO, attenuated cognitive impairment, reduced beta-amyloid (Aβ) production and aggregation, as well as protected the neurons from apoptosis in APP/PS1 mice. DOR and MOR also differentially modulated microglia in APP/PS1 mice and in vitro AD cell model with a DOR-mediated inhibition on the excessive activation of microglia and the release of pro-inflammatory cytokines in AD pathologies. Gene expression profiling further revealed that the alternations in DOR/MOR are closely associated with microglial homeostatic signatures and high mobility group protein B1 (HMGB1) in AD. DOR activation inhibited HMGB1 secretion and its translocation from nuclear to cytoplasm. Our in-vitro studies further confirmed that DOR overexpression mitigated microglial inflammatory response and rescued neurons from AD injury via HMGB1-NF-κB signaling pathway.</p><p><strong>Conclusions: </strong>These novel findings uncover previously unappreciated roles of DOR in neuroprotection against AD injury via modulating microglia-related inflammatory responses.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"35"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073338","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":"Retinal optical coherence tomography intensity spatial correlation features as new biomarkers for confirmed Alzheimer's disease.","authors":"Zi Jin, Xinmin Wang, Ying Lang, Yufeng Song, Huangxiong Zhan, Wuge Shama, Yingying Shen, Guihua Zeng, Faying Zhou, Hongjian Gao, Shuling Ye, Yanjiang Wang, Fan Lu, Meixiao Shen","doi":"10.1186/s13195-025-01676-z","DOIUrl":"10.1186/s13195-025-01676-z","url":null,"abstract":"<p><strong>Background: </strong>The nature and severity of Alzheimer's disease (AD) pathologies in the retina and brain correspond. However, retinal biomarkers need to be validated in clinical cohorts with confirmed AD biomarkers and optical coherence tomography (OCT). The main objective of this study was to investigate whether retinal metrics measured by OCT aid in the early screening and brain pathology monitoring for confirmed AD.</p><p><strong>Methods: </strong>This was a case-control study. All participants underwent retinal OCT imaging, and neurological examinations, including amyloid-β (Aβ) positron emission tomography. Participants were subdivided into cognitively normal (CN), mild cognitive impairment (MCI), and AD-derived dementia (ADD). Except retinal thickness, we developed the grey level co-occurrence matrix algorithm to extract retinal OCT intensity spatial correlation features (OCT-ISCF), including angular second matrix (ASM), correlation (COR), and homogeneity (HOM), one-way analysis of variance was used to compare the differences in retinal parameters among the groups, and to analyze the correlation with brain Aβ plaques and cognitive scores. The repeatability and robustness of OCT-ISCF were evaluated using experimental and simulation methods.</p><p><strong>Results: </strong>This study enrolled 82 participants, subdivided into 20 CN, 22 MCI, and 40 ADD. Compared with the CN, the thickness of retinal nerve fiber layer and myoid and ellipsoid zone were significantly thinner (P < 0.05), and ASM, COR, and HOM in several retinal sublayers changed significantly in the ADD (P < 0.05). Notably, the MCI showed significant differences in ASM and COR in the outer segment of photoreceptor compared with the CN (P < 0.05). The changing pattern of OCT-ISCF with interclass correlation coefficients above 0.8 differed from that caused by speckle noise, and was affected by OCT image quality index. Moreover, the retinal OCT-ISCF were more strongly correlated with brain Aβ plaque burden and MoCA scores than retinal thickness. The accuracy using retinal OCT-ISCF (AUC = 0.935, 0.830) was better than that using retinal thickness (AUC = 0.795, 0.705) in detecting ADD and MCI.</p><p><strong>Conclusions: </strong>The study demonstrates that retinal OCT-ISCF enhance the association and detection efficacy of AD pathology compared to retinal thickness, suggesting retinal OCT-ISCF have the potential to be new biomarkers for AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"33"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073425","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":"Rotation errors in path integration are associated with Alzheimer's disease tau pathology: a cross-sectional study.","authors":"Lise Colmant, Lisa Quenon, Lara Huyghe, Adrian Ivanoiu, Thomas Gérard, Renaud Lhommel, Pauline Coppens, Yasmine Salman, Vincent Malotaux, Laurence Dricot, Lukas Kunz, Nikolai Axmacher, Philippe Lefèvre, Bernard Hanseeuw","doi":"10.1186/s13195-025-01679-w","DOIUrl":"10.1186/s13195-025-01679-w","url":null,"abstract":"<p><strong>Background: </strong>Early Alzheimer's disease diagnosis is crucial for preventive therapy development. Standard neuropsychological evaluation does not identify clinically normal individuals with brain amyloidosis, the first stage of the pathology, defined as preclinical Alzheimer's disease. Spatial navigation assessment, in particular path integration, appears promising to detect preclinical symptoms, as the medial temporal lobe plays a key role in navigation and is the first cortical region affected by tau pathology.</p><p><strong>Methods: </strong>We have conducted a cross-sectional study. We related the path integration performance of 102 individuals without dementia, aged over 50, to amyloid and tau pathologies, measured using positron emission tomography. We included 75 clinically normal individuals (19 with brain amyloidosis, 56 without) and 27 individuals with mild cognitive impairment (18 with brain amyloidosis, 9 without). We fitted linear mixed models to predict the path integration performances according to amyloid status or tau pathology in the medial temporal lobal, adjusting for age, gender, cognitive status, education, and video game experience. We decomposed the error into rotation and distance errors.</p><p><strong>Results: </strong>We observed that clinically normal adults with brain amyloidosis (preclinical Alzheimer's disease) had spatial navigation deficits when relying only on self-motion cues. However, they were able to use a landmark to reduce their errors. Individuals with mild cognitive impairment had deficits in path integration that did not improve when a landmark was added in the environment. The amyloid status did not influence performance among individuals with mild cognitive impairment. Among all individuals, rotation, but not distance, errors increased with the level of tau pathology in the medial temporal lobe.</p><p><strong>Conclusion: </strong>Our results suggest that path integration performance in an environment without external cues allows identifying individuals with preclinical Alzheimer's disease, before overt episodic memory impairment is noticeable. Specifically, we demonstrated that poor angular estimation is an early cognitive marker of tau pathology, whereas distance estimation relates to older ages, not to Alzheimer's disease.</p><p><strong>Trial registration: </strong>Eudra-CT 2018-003473-94.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"34"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073427","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":"Glymphatic system clearance and Alzheimer's disease risk: a CSF proteome-wide study.","authors":"Natalia Cullell, Giovanni Caruana, Andrea Elias-Mas, Ariane Delgado-Sanchez, Cristina Artero, Maria Teresa Buongiorno, Marta Almería, Nicola J Ray, Sonia A L Correa, Jerzy Krupinski","doi":"10.1186/s13195-024-01612-7","DOIUrl":"10.1186/s13195-024-01612-7","url":null,"abstract":"<p><strong>Background: </strong>The emerging evidence of the role of the glymphatic system (GS) in Alzheimer's disease (AD) provides new opportunities for intervention from the earliest stages of the disease. The aim of the study is to evaluate the efficacy of GS in AD to identify new disease biomarkers.</p><p><strong>Methods: </strong>We performed a two-stage proteomic study to evaluate the GS health using intravenous gadolinium-based contrast agent (GBCA) with serial T1 3T magnetic resonance imaging (MRI) in individuals with amnestic mild cognitive impairment (aMCI). In Stage 1 (evaluated in the Cohort 1 of aMCI participants (n = 11)), we correlated the levels of 7K cerebrospinal fluid (CSF) proteins (estimated by SOMAscan) with GS health in 78 Freesurfer-segmented brain regions of interest (ROIs).</p><p><strong>Results: </strong>A total of seven different proteins were significantly associated with GS health (p-value < 6.4 × 10^-4). The stronger correlations were identified for NSUN6, GRAAK, OLFML3, ACTN2, RUXF, SHPS1 and TIM-4. A pathway enrichment analysis revealed that the proteins associated with GS health were mainly implicated in neurodegenerative processes, immunity and inflammation. In Stage 2, we validated these proteomic results in a new cohort of aMCI participants (with and without evidence of AD pathology in CSF (aMCI(-) and aMCI/AD( +); n = 22 and 7, respectively) and healthy controls (n = 10). Proteomic prediction models were generated in each ROI. These were compared with demographic-only models for identifying participants with aMCI(-) and aMCI/AD( +) vs controls. This analysis was repeated to determine if the models could identify those with aMCI/AD( +) from both aMCI(-) and controls. The proteomic models were found to outperform the demographic-only models.</p><p><strong>Conclusions: </strong>Our study identifies proteins linked with GS health and involved the immune system in aMCI participants.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"31"},"PeriodicalIF":7.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073346","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":"RADAR-AD: assessment of multiple remote monitoring technologies for early detection of Alzheimer's disease.","authors":"Manuel Lentzen, Srinivasan Vairavan, Marijn Muurling, Vasilis Alepopoulos, Alankar Atreya, Merce Boada, Casper de Boer, Pauline Conde, Jelena Curcic, Giovanni Frisoni, Samantha Galluzzi, Martha Therese Gjestsen, Mara Gkioka, Margarita Grammatikopoulou, Lucrezia Hausner, Chris Hinds, Ioulietta Lazarou, Alexandre de Mendonça, Spiros Nikolopoulos, Dorota Religa, Gaetano Scebba, Pieter Jelle Visser, Gayle Wittenberg, Vaibhav A Narayan, Neva Coello, Anna-Katharine Brem, Dag Aarsland, Holger Fröhlich","doi":"10.1186/s13195-025-01675-0","DOIUrl":"10.1186/s13195-025-01675-0","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, leading to cognitive and functional decline. Early detection and intervention are crucial for enhancing the quality of life of patients and their families. Remote Monitoring Technologies (RMTs) offer a promising solution for early detection by tracking changes in behavioral and cognitive functions, such as memory, language, and problem-solving skills. Timely detection of these symptoms can facilitate early intervention, potentially slowing disease progression and enabling appropriate treatment and care.</p><p><strong>Methods: </strong>The RADAR-AD study was designed to evaluate the accuracy and validity of multiple RMTs in detecting functional decline across various stages of AD in a real-world setting, compared to standard clinical rating scales. Our approach involved a univariate analysis using Analysis of Covariance (ANCOVA) to analyze individual features of six RMTs while adjusting for variables such as age, sex, years of education, clinical site, BMI and season. Additionally, we employed four machine learning classifiers - Logistic Regression, Decision Tree, Random Forest, and XGBoost - using a nested cross-validation approach to assess the discriminatory capabilities of the RMTs.</p><p><strong>Results: </strong>The ANCOVA results indicated significant differences between healthy and AD subjects regarding reduced physical activity, less REM sleep, altered gait patterns, and decreased cognitive functioning. The machine-learning-based analysis demonstrated that RMT-based models could identify subjects in the prodromal stage with an Area Under the ROC Curve of 73.0 %. In addition, our findings show that the Amsterdam iADL questionnaire has high discriminatory abilities.</p><p><strong>Conclusions: </strong>RMTs show promise in AD detection already in the prodromal stage. Using them could allow for earlier detection and intervention, thereby improving patients' quality of life. Furthermore, the Amsterdam iADL questionnaire holds high potential when employed remotely.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"29"},"PeriodicalIF":7.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045343","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":"The ABC transporter A7 modulates neuroinflammation via NLRP3 inflammasome in Alzheimer's disease mice.","authors":"Irene Santos-García, Pablo Bascuñana, Mirjam Brackhan, María Villa, Ivan Eiriz, Thomas Brüning, Jens Pahnke","doi":"10.1186/s13195-025-01673-2","DOIUrl":"10.1186/s13195-025-01673-2","url":null,"abstract":"<p><strong>Background: </strong>Specific genetic variants in the ATP-binding cassette transporter A7 locus (ABCA7) are associated with an increased risk of Alzheimer's disease (AD). ABCA7 transports lipids from/across cell membranes, regulates Aβ peptide processing and clearance, and modulates microglial and T-cell functions to maintain immune homeostasis in the brain. During AD pathogenesis, neuroinflammation is one of the key mechanisms involved. Therefore, we wanted to investigate the specific role of ABCA7 in microglial activation via the NLRP3 inflammasome.</p><p><strong>Methods: </strong>We developed the first humanized, Cre-inducible ABCA7^flx knock-in mouse model, crossbred it with the APPPS1-21 β-amyloidosis model, and generated constitutive ABCA7^ko and microglia Cx3cr1-specific conditional ABCA7^ko AD mice. The role of ABCA7 was analyzed using histological, biochemical, molecular and mass spectrometry methods.</p><p><strong>Results: </strong>Constitutive knockout of the Abca7 gene in APPPS1 mice increased the levels of Aβ42 and the number of IBA1+ (microglia) and GFAP+ (astrocytes) cells. Changes in the levels of astrocytes and microglia are associated with the activation of the NLRP3 inflammasome and increased levels of proinflammatory cytokines, such as IL1β and TNFα. Interestingly, microglia-specific ABCA7^ko restored Aβ₄₂ peptide levels and IBA1⁺ and GFAP⁺ and NLRP3-related gene expression to the original APPPS1 mouse levels. In primary glial cell cultures of APPPS1-hA7^ko microglia and APPPS1 astrocytes from newborn pups, we observed that conditioned media from LPS-stimulated microglia was able to induce NLRP3 inflammasome expression and proinflammatory cytokine release in astrocytes.</p><p><strong>Conclusions: </strong>Our data suggest that ABCA7 transporters regulate the communication between microglia and astrocytes through the NLRP3 inflammasome and the release of proinflammatory cytokines. This regulation implicates ABCA7 as a key driver ultimately involved in the persistence of the inflammatory response observed in AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"30"},"PeriodicalIF":7.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11773842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143050995","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":"Association of Alzheimer's and Lewy body disease pathology with basal forebrain volume and cognitive impairment.","authors":"Julia Schumacher, Stefan Teipel, Alexander Storch","doi":"10.1186/s13195-025-01678-x","DOIUrl":"10.1186/s13195-025-01678-x","url":null,"abstract":"<p><strong>Background: </strong>Degeneration of the basal forebrain cholinergic system is a hallmark feature shared by Alzheimer's disease (AD) and Lewy body disease (LBD) whereas hippocampus atrophy is more specifically related to AD. We aimed to investigate the relationship between basal forebrain and hippocampus atrophy, cognitive decline, and neuropathology in a large autopsy sample.</p><p><strong>Methods: </strong>Data were obtained from the National Alzheimer's Coordinating Center (NACC). Basal forebrain and hippocampus volumes were extracted using an established automated MRI volumetry approach. Associations of regional volumes with pathological markers (Braak stage, CERAD score, and McKeith criteria for LB pathology) and cognitive performance were assessed using Bayesian statistical methods.</p><p><strong>Results: </strong>We included people with autopsy-confirmed pure AD (N = 248), pure LBD (N = 22), and mixed AD/LBD (N = 185). Posterior basal forebrain atrophy was most severe in mixed AD/LB pathology compared to pure AD (Bayes factor against the null hypothesis BF₁₀ = 16.2) or pure LBD (BF₁₀ = 4.5). In contrast, hippocampal atrophy was primarily associated with AD pathology, independent of LB pathology (pure AD vs. pure LBD: BF₁₀ = 166, pure AD vs. mixed AD/LBD: BF₁₀ = 0.11, pure LBD vs. mixed AD/LBD: BF₁₀ = 350). Cognitive performance was more impaired in AD pathology groups, with Braak stage being the strongest predictor. Hippocampal volume partially mediated this relationship between tau pathology and cognitive impairment, while basal forebrain volume had a limited role in mediating the relationship between pathological burden and cognitive outcomes.</p><p><strong>Conclusion: </strong>In a heterogeneous autopsy sample, AD and LB pathology both contribute to cholinergic basal forebrain degeneration whereas hippocampus atrophy is more specifically related to AD pathology. Cognitive deficits are primarily associated with tau pathology which is partly mediated by hippocampus, but not basal forebrain atrophy.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"28"},"PeriodicalIF":7.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045377","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}