Alzheimer's Research & Therapy最新文献

{"title":"Impact of sex differences on microglial function in Alzheimer's disease.","authors":"Emilly V Figueiredo, Caroline Vieira Azevedo, Arlete Rita Penitente, Vinicius R Pedrosa, Vinicius R Camilo da Silva, Beatriz Monteiro Longo","doi":"10.1186/s13195-026-02099-0","DOIUrl":"10.1186/s13195-026-02099-0","url":null,"abstract":"<p><p>Aging is the strongest risk factor for Alzheimer's disease (AD), a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau pathology (hyperphosphorylated tau and neurofibrillary tangles [NFTs]), and associated neuroinflammatory processes. Age-related cellular and molecular stressors, including mitochondrial dysfunction, genomic instability, and chronic low-grade inflammation, progressively increase vulnerability to neurodegeneration. In parallel, sex is increasingly recognized as a biological variable that shapes AD risk, clinical course, and neuropathological burden. Women account for roughly two-thirds of AD cases, a disparity not fully explained by longevity. Multiple factors likely contribute, including hormonal transitions across the lifespan (particularly menopausal estrogen decline), sex chromosome-linked immune regulation, sex-dependent interactions between genetic risk factors (e.g., APOE4 and TREM2) and brain aging, and differences in vascular risk, cognitive reserve, and sociocultural exposures that influence disease expression and detection. Microglia, the brain's resident immune cells, are sexually dimorphic, and respond to Aβ and tau pathology, modulating inflammatory signaling, synaptic remodeling, and neurovascular dysfunction implicated in AD. Emerging human and experimental evidence indicate that microglial activation states, immunometabolism, and functional responses differ between males and females and may contribute to sex-specific AD trajectories. Here, we synthesize current evidence supporting microglial sexual dimorphism across aging and AD, highlight possible candidates (hormonal signaling, immuno-aging, disease-associated microglial states, and immunometabolic remodeling), and discuss key knowledge gaps toward sex-informed precision approaches for prevention and treatment.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13532007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275629","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":"Transcranial pulse stimulation modulates spectral signatures of Alzheimer's disease in the 3×Tg-AD mouse model.","authors":"Irmak Gezginer, Maria Eleni Karakatsani, Prakruti Nanda, Pranati Chalasani, Diana Kindler, Rafael Storz, Markus Belau, Ruiqing Ni, Gerhard Schratt, Xosé Luís Deán-Ben, Daniel Razansky","doi":"10.1186/s13195-026-02109-1","DOIUrl":"10.1186/s13195-026-02109-1","url":null,"abstract":"<p><strong>Background: </strong>Large-scale brain network dysfunction is increasingly recognized as an important feature of Alzheimer's disease (AD), offering insight into disease mechanisms and opportunities for targeted therapeutic intervention. The spectral features of this dysfunction remain poorly understood, and how neuromodulatory interventions interact with and reshape these frequency-resolved network signatures has yet to be explored.</p><p><strong>Methods: </strong>Triple-transgenic (3×Tg-AD) mice underwent resting-state functional MRI to assess functional connectivity, signal power, and variance across frequency bands after acute and longitudinal transcranial pulse stimulation (TPS), a low-intensity single-pulse neuromodulatory intervention. Novel object recognition testing was used to evaluate exploratory drive and short-term recognition memory following repeated TPS or sham treatment.</p><p><strong>Results: </strong>AD mice exhibited widespread functional connectivity loss accompanied by reduced low-frequency resting-state power and variance, together with a redistribution of spectral energy from slow-5 (0.01-0.027 Hz) to slow-4 (0.027-0.073 Hz) activity. TPS modulated these abnormalities by increasing low-frequency power, rebalancing slow-5/slow-4 fractional power, and strengthening network coherence, with the most prominent effects in cingulate, insular, piriform, and striatal regions. TPS effects showed a non-linear, region-dependent emergence across stimulation trains, with the strongest and most consistent modulation appearing after repeated stimulation. Similar spectral rebalancing was observed both after acute and longitudinal stimulation, persisting for up to 5 days. In addition, hippocampal regions that showed minimal acute responses exhibited delayed spectral changes at 24 h, with further modulation at 120 h. TPS-treated 3×Tg-AD mice did not show the decline in object exploration observed in sham-treated animals and showed an exploration-adjusted increase in novel object preference.</p><p><strong>Conclusions: </strong>Frequency-specific neural dynamics are sensitive markers of AD-related dysfunction and may provide a useful framework for tracking disease-related network abnormalities. TPS selectively modulates low-frequency oscillatory activity and network coherence and is accompanied by preliminary behavioral changes, including preserved exploratory engagement and an exploration-adjusted increase in novel object preference in a separate behavioral cohort. This highlights the potential of combining neuromodulation with spectral network analysis to monitor disease-related network dysfunction and treatment-associated responses.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257007","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":"A small molecule modulating heterogeneous amyloid-β isoforms improves cognitive and pathological outcomes in acute and 5XFAD Alzheimer's disease models.","authors":"JiMin Kim, Dohui Ku, InWook Park, Suhyun Ye, Illhwan Cho, Minseol Park, Wonbin Seo, Sunhee Lee, Hye Yun Kim, Ikyon Kim, YoungSoo Kim","doi":"10.1186/s13195-026-02113-5","DOIUrl":"10.1186/s13195-026-02113-5","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is characterized by the pathological aggregation of amyloid-β (Aβ) peptides into neurotoxic assemblies. While recent antibody therapies targeting Aβ have shown clinical efficacy, they face limitations including specificity for particular Aβ species and accessibility challenges. The structural heterogeneity of Aβ isoforms, including Aβ₄₀, Aβ₄₂, and pyroglutamate-modified Aβ_pE3-42, necessitates therapeutic strategies with broad-spectrum activity.</p><p><strong>Methods: </strong>The effects of YIAD-1003, a dihydropyrrolo[1,2-a]pyrazine derivative, were evaluated in vitro using Thioflavin T fluorescence assays and A11 dot blot to assess fibrillization and dissociation of preformed aggregates across Aβ₄₀, Aβ₄₂, and Aβ_pE3-42. In vivo efficacy was examined in an acute Aβ₄₂-induced AD model and in 5XFAD transgenic mice. Cognitive performance was assessed using spatial and associative memory tests. Amyloid pathology, including soluble Aβ and fibrillar deposition, and neuroinflammation markers were quantified by biochemical and histological analyses.</p><p><strong>Results: </strong>YIAD-1003 inhibited fibril formation and promoted dissociation of preformed aggregates across multiple Aβ isoforms in vitro. In the acute model, co-administration of YIAD-1003 ameliorated Aβ₄₂-induced memory impairment. In 5XFAD mice, oral administration improved cognitive performance, reduced plaque burden and soluble Aβ levels, and attenuated pathological alterations associated with neuroinflammation.</p><p><strong>Conclusions: </strong>YIAD-1003, a dihydropyrrolo[1,2-a]pyrazine derivative, exhibits broad-spectrum intervention in Aβ assembly across multiple isoforms and confers functional and pathological benefits in AD mouse models. These findings support the development of multi-isoform small-molecule modulators as a possible AD therapeutic strategy.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262902","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":"Development and validation of a harmonized memory score for multicenter Alzheimer's disease and related dementia research.","authors":"Mark Sanderson-Cimino, Alden L Gross, Leslie S Gaynor, Emily W Paolillo, Rowan Saloner, Marilyn S Albert, Liana G Apostolova, Brooke Boersema, Adam L Boxer, Bradley F Boeve, Kaitlin B Casaletto, Hilary W Heuer, Leah K Forsberg, Savannah R Hallgarth, Valentina E Diaz, Lindsay R Clark, Ani Eloyan, Sarah Tomaszewski Farias, Pauline Maillard, Mitzi M Gonzales, Dustin B Hammers, Renaud La Joie, Yann Cobigo, Amy Wolf, Benjamin M Hampstead, Dawn Mechanic-Hamilton, Bruce L Miller, Gil D Rabinovici, John M Ringman, Lina M D'Orazio, Howie J Rosen, Sephira G Ryman, Jillian L Prestopnik, David P Salmon, Glenn E Smith, Charles DeCarli, Kumar B Rajan, Lee-Way Jin, Jason D Hinman, David K Johnson, Danielle J Harvey, Myriam Fornage, Maria C Carrillo, Bradford C Dickerson, Joel H Kramer, Adam M Staffaroni","doi":"10.1186/s13195-026-02100-w","DOIUrl":"10.1186/s13195-026-02100-w","url":null,"abstract":"<p><strong>Introduction: </strong>List-learning tasks (LLTs) are important for characterizing memory in Alzheimer's disease and related dementias. However, as the Uniform Data Set Neuropsychological Battery (UDS-NB) historically did not require a specific LLT, centers have administered different LLTs. The newest UDS version (v4.0) requires one of two LLTs. To support harmonized UDS memory research, we developed a memory composite incorporating UDS memory tests and multiple LLTs.</p><p><strong>Methods: </strong>Item-banking confirmatory factor analysis was applied to develop a memory composite in a diagnostically heterogeneous sample (n = 8716) that completed the UDS-NB and one of five LLTs. Construct validity was evaluated through associations with demographics, disease severity, cognitive tasks, brain volume, amyloid/tau PET positivity, and plasma phosphorylated tau. Analyses were replicated in a racially/ethnically diverse cohort (n = 839).</p><p><strong>Results: </strong>Psychometric properties were adequate. Expected associations with demographics and clinical measures within development and validation cohorts supported validity.</p><p><strong>Conclusions: </strong>This composite supports memory research across cohorts that administer the UDS and LLTs. A user-friendly UI is freely available to create the score in other datasets.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257017","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":"Cognitive, biomarker, and neuroimaging indices associated with traumatic encephalopathy syndrome across two independent athlete cohorts.","authors":"Brooke D Conway Kleven, Lung-Chang Chien, Dana Surwill, Michael L Alosco, Jennifer V Wethe, Yorghos Tripodis, Charles H Adler, Martha E Shenton, Ofer Pasternak, Douglas I Katz, Elaine Peskind, Laura J Balcer, Inga K Koerte, Jesse Mez, Eric M Reiman, Robert C Cantu, Robert A Stern, Henrik Zetterberg, Charles Bernick, Jeffrey L Cummings","doi":"10.1186/s13195-026-02110-8","DOIUrl":"10.1186/s13195-026-02110-8","url":null,"abstract":"<p><strong>Background: </strong>Traumatic encephalopathy syndrome (TES) is a clinical research construct used to identify individuals at risk for chronic traumatic encephalopathy (CTE) following exposure to repetitive head impacts (RHI). Adjudication of TES relies on clinical features such as progressive cognitive impairment and neurobehavioral dysregulation. Blood-based biomarkers and structural neuroimaging abnormalities have been associated with TES but are not part of the criteria. This study evaluated whether TES identification was associated with the combined contribution of cognitive performance, blood biomarkers, and structural neuroimaging measures across two well-characterized cohorts.</p><p><strong>Methods: </strong>Participants included 158 professional fighters from the Professional Athletes Brain Health Study and 149 former American football players from The DIAGNOSE CTE Research Project. Three indices were constructed representing complementary domains: a cognitive index reflecting cohort-specific cognitive features, a blood biomarker index including plasma neurofilament light chain, glial fibrillary acidic protein, total tau, tau phosphorylated at amino acid 231, and APOE-ε4 carrier status, and an imaging index comprising volumetric MRI measures of subcortical structures, ventricles, and corpus callosum subregions. Grouped weighted quantile sum regression models were estimated within each cohort to evaluate associations between these indices and TES while adjusting for age, race, competition status, and RHI exposure.</p><p><strong>Results: </strong>Multidomain models demonstrated improved model performance compared with single-domain models in both cohorts (PABHS: AUC = 0.91, PPV = 0.80; DIAGNOSE CTE: AUC = 0.84, PPV = 0.85). Biomarker and imaging indices contributed additional information across cohorts, although imaging contributions were more prominent in fighters whereas blood biomarker associations were stronger in football players.</p><p><strong>Conclusion: </strong>TES in RHI-exposed athletes was associated with a convergent clinicobiological profile observed across two independent cohorts with distinct exposure patterns. These findings support multidomain analytic frameworks for evaluating correlated biological signals in RHI-exposed populations and may inform future studies of TES and CTE.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13495526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148248746","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":"Estimation of positron emission tomography amyloid load and related biomarkers in Alzheimer's disease using evoked potential tomography EEG: development and internal validation in a cross-sectional cohort.","authors":"Boris-Stephan Rauchmann, James Hamet, Jesyin Lai, Homeira Kafi, Joe Rexwinkle, Matthias Brendel, Nicolai Franzmeier, Carolin Kurz, Oliver Pogarell, Johannes Levin, Günter Höglinger, Robert Perneczky","doi":"10.1186/s13195-026-02076-7","DOIUrl":"10.1186/s13195-026-02076-7","url":null,"abstract":"<p><strong>Background: </strong>Dementia affects over 50 million individuals globally, predominantly due to Alzheimer's disease (AD). Effective early detection and intervention remain clinical challenges, as there is a lack of unified, portable solutions to assess multiple biomarkers.</p><p><strong>Methods: </strong>We evaluated Evoked Potential Tomography (EPT), an EEG-based method using a novel visual evoked potential protocol. An automated pipeline for EEG preprocessing, ERP extraction, feature selection, optimization, and regression modeling was developed to estimate key AD biomarkers: PET-amyloid standardized uptake value ratio (SUVR), CSF phosphorylated tau (p-tau181), Free and Cued Selective Reminding Test (FCSRT), and Mini-Mental State Examination (MMSE) scores.</p><p><strong>Results: </strong>Regression models using ERP features from dementia participants demonstrated strong correlations (r = 0.8-0.94, p < 0.01) between predicted and true PET-amyloid SUVR, p-tau181, FCSRT, and MMSE values. In an independent external cohort, PET-amyloid SUVR predictions remained significantly associated with true values (r = 0.60, p < 0.01).</p><p><strong>Discussion: </strong>Despite limitations, these preliminary results support EPT's potential as a sensitive and non-invasive method for estimating AD-related biomarkers in a clinically enriched AD cohort. Further validation studies are ongoing.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148238503","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":"Shared genetic architecture between Alzheimer's disease and brain morphology.","authors":"Xiao Wu, Alexey Shadrin, Gabriëlla A M Blokland, Sinan Guloksuz, Ole A Andreassen, David E J Linden, Dennis van der Meer","doi":"10.1186/s13195-026-02105-5","DOIUrl":"10.1186/s13195-026-02105-5","url":null,"abstract":"<p><strong>Background: </strong>A hallmark of Late-onset Alzheimer's disease (LOAD) is brain tissue atrophy across multiple cortical and subcortical regions. However, studies report no significant genetic correlation between LOAD and brain morphology, indicating that the genetic drivers of neurodegeneration are complex. Resolving this shared genetic architecture is key to uncovering the biological mechanisms linking brain morphology to LOAD.</p><p><strong>Methods: </strong>We analyzed UK Biobank genotype data (n = 272,513; 57.1 ± 8.0 years; 54.6% female) alongside genome-wide association study summary statistics for LOAD and 89 brain morphological traits. We employed linkage disequilibrium score regression (LDSC), polygenic score (PGS), and Local Analysis of [co]Variant Association (LAVA) to evaluate genetic relationships at the whole-genome and locus level. The extent of polygenic overlap was quantified using bivariate causal mixture modeling (MiXeR), and specific shared loci were identified via conjunctional FDR. Identified loci were mapped to genes and followed by enrichment analyses to characterize the shared biological pathways.</p><p><strong>Results: </strong>LDSC and regression analyses revealed no significant global genetic correlations between LOAD and brain morphological traits and no associations between PGS and LOAD proxy scores. In contrast, LAVA identified significant local genetic correlations (both positive and negative) across all LOAD-brain trait pairs. MiXeR analysis further revealed a substantial number of shared genetic variants characterized by mixed effect directions, explaining the lack of global correlation. We identified 183 shared loci mapping to 80 distinct genes. Enrichment analyses indicated that these shared genes are involved in biological processes related to cell differentiation, development, and cellular component organization.</p><p><strong>Conclusions: </strong>Our findings provide evidence of extensive polygenic overlap between LOAD and brain morphology, revealing that the absence of global genetic correlation stems from mixed local effect directions. These shared genetic architectures implicate pathways in cellular development and differentiation, providing a molecular framework for understanding the link between brain morphology and LOAD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148215942","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":"Methodological approaches to account for assay changes in longitudinal biomarker analysis: insights from Alzheimer's blood biomarkers in the MEMENTO cohort.","authors":"Vincent Bouteloup, Cécile Proust-Lima, Isabelle Pellegrin, Andrea Boizard-Moracchini, Maëva Roy, Geneviève Chêne, Vincent Planche, Carole Dufouil","doi":"10.1186/s13195-026-02042-3","DOIUrl":"10.1186/s13195-026-02042-3","url":null,"abstract":"<p><strong>Background: </strong>Longitudinal studies allow the modelling of disease progression through repeated measurement of health outcomes, such as biomarkers. Changes in measurement tools over time, due to logistical or financial constraints, may challenge the statistical modeling of outcome trajectories. This study aims to compare two methods for managing changes in blood biomarkers assays over time, in the context of modeling their longitudinal trajectories.</p><p><strong>Methods: </strong>We analyzed data from 2299 individuals in the French MEMENTO cohort, focusing on two Alzheimer's disease blood biomarkers: 181-phosphorylated tau (p-tau181) and neurofilament light chain (NfL). Baseline blood samples were quantified using an initial assay kit in 2021, while samples collected at 2- and 4-year follow-ups with updated kits in 2023. Two approaches were applied to derive conversion equations for aligning measurements from the initial to the updated assay: (i) a bridging study, requiring biomarker quantification using both the initial and the updated assay in a subsample of individuals and (ii) Latent Process Models (LPM), which established links between the two assays as measures of the same latent process over age, using biomarker measurements available at the 3 timepoints. Prediction error rates were computed, and biomarker trajectories estimated with linear mixed models according to two variables of interest (education level, cognitive impairment).</p><p><strong>Results: </strong>Prediction error rates were slightly higher for LPM than for bridging for both NfL and p-tau181. While the two methods yielded similar predictions around the median, discrepancies were observed at the tails of the distribution of the observed values. Longitudinal trajectories showed consistent associations for the variables of interest at baseline and during follow-up for both biomarkers.</p><p><strong>Conclusions: </strong>LPM provide a feasible and efficient method for managing changes in biomarker quantification assays in longitudinal studies. LPM yields results comparable to traditional bridging studies without requiring additional sample analysis. This approach is particularly advantageous in studies with long-term follow-up, where changes in measurement tools cannot always be avoided, offering a straightforward and resource-efficient solution.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13377702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148209720","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":"Associations of plasma metabolites with protein biomarkers linked to Alzheimer's disease pathology in the Rotterdam Study.","authors":"Midas M Kuilman, Shahzad Ahmad, Amos C Pomp, Frank J Wolters, Rima Kaddurah-Daouk, M Arfan Ikram, Mohsen Ghanbari","doi":"10.1186/s13195-026-02108-2","DOIUrl":"10.1186/s13195-026-02108-2","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) and tau pathology, neuroaxonal damage, and neuroinflammation. While blood biomarkers, such as tau, neurofilament light chain (NfL), and Aβ isoforms, reflect AD pathology, the systemic metabolic alterations contributing to the disease remain poorly defined. This study aims to explore associations between plasma metabolites and key protein biomarkers linked to AD pathology in a large, population-based cohort.</p><p><strong>Methods: </strong>Plasma levels of Aβ40, Aβ42, total-tau (t-tau), and NfL were measured using the highly sensitive Simoa NF-light and N3PA assays (Quanterix platform) among over 3,000 participants from the Rotterdam Study. Plasma metabolites were quantified using the Nightingale NMR-based (n = 2,871) and Metabolon MS-based (n = 1,491) platforms. Multivariable linear regression models, adjusted for demographic, lifestyle, and genetic factors, were applied. Analyses were stratified by sex and APOE genotype. Sensitivity analyses excluded participants with dementia, stroke, or impaired kidney function.</p><p><strong>Results: </strong>Triglyceride-rich lipoproteins across VLDL, LDL, and HDL subclasses were positively associated with both Aβ isoforms. Among them, Triglyceride-rich lipoproteins in small VLDL showed the strongest association with Aβ40 (β = 0.168, FDR = 4.362e-16). Conversely, HDL cholesterol fractions showed inverse associations with Aβ. GlycA (β > 0.097, FDR < 2.092e-05) and creatinine (β > 0.253, FDR < 3.371e-24) were positively associated with all Alzheimer's disease biomarkers, while albumin was inversely related to tau (β = -0.094, FDR = 1.924e-04) and NfL (β = -0.079, FDR = 4.210e-05). On the Metabolon platform, S-adenosylhomocysteine (β > 0.206, FDR < 1.303e-09) was positively associated with all biomarkers, while uridine and 2'-deoxyuridine showed inverse associations with Aβ40, t-tau, and NfL. Stratified analyses indicated stronger GlycA-tau associations in APOE ε2 carriers and sex-specific effects for amino acids and ApoA1.</p><p><strong>Conclusions: </strong>Our findings highlight metabolites involved in lipid transport, inflammation, amino acid metabolism, and methylation as being linked to AD-related protein biomarkers. These results provide novel insights into systemic metabolic pathways underlying AD and suggest that certain metabolites may serve as potential biomarkers for early detection and risk stratification in AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148209693","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":"Chronic central-targeted Interleukin-6 overexpression promotes hippocampal and cortical neuropathology in the Tg2576 mouse model of Alzheimer's disease.","authors":"Carla Canal, Kevin Aguilar, Gemma Comes, Elisenda Sanz, Mercedes Giralt, Paula Sanchis, Juan Hidalgo","doi":"10.1186/s13195-026-02101-9","DOIUrl":"10.1186/s13195-026-02101-9","url":null,"abstract":"<p><strong>Background: </strong>Interleukin-6 (IL-6) is a cytokine detected in the brains and peripheral fluids of both Alzheimer's disease (AD) patients and mouse models, where its levels correlate with amyloid-beta (Aβ) burden and plaque deposition. Interestingly, IL-6 deficiency ameliorates cognitive deficits and attenuates hippocampal neuroinflammation, whereas astrocyte-targeted IL-6 signaling via its soluble receptor accentuates pathological features in AD mouse models. These findings suggest that central IL-6 overexpression may actively drive disease manifestations. However, because IL-6 can also signal through its classical membrane-bound receptor pathway, the overall impact of central IL-6 on AD pathophysiology is still not fully elucidated.</p><p><strong>Main text: </strong>To explore the contribution of central IL-6 overexpression in modulating AD-related mortality, metabolic, behavioral and neuroinflammatory changes in the hippocampus and cortex, we crossed a transgenic mouse model (Tg2576) of Aβ-driven amyloidosis with mice expressing IL-6 under the Glial Fibrillary Acidic Protein promoter (GFAP-IL6), which predominantly targets astrocytes. Chronic IL-6 overexpression reduced inguinal white adiposity in both males and females and decreased body weight in females. Early behavioral alterations were observed in Tg2576 mice, with central-targeted IL-6 overexpression regulating behavior in an age- and sex-dependent manner. Increased cortical and hippocampal Aβ42/Aβ40 ratios, along with gliosis, were observed in aged female and male Tg2576 mice. Interestingly, chronic central-targeted IL-6 overexpression increased cortical and hippocampal Aβ42/Aβ40 ratios while inducing a differential distribution and/or reactivity of astrocytes and microglia in aged Tg2576 mice. In particular, central-targeted IL-6 overexpression resulted in increased overall gliosis in the cortical and hippocampal parenchyma but reduced gliosis in the vicinity of cortical and hippocampal amyloid plaques. Finally, cortical transcriptomic profiling in Tg2576 mice revealed widespread changes in immune, synaptic, and stress response pathways in response to chronic IL-6 overexpression, with cortical neuroinflammatory and neurotransmission-associated gene networks showing sex-dependent differences.</p><p><strong>Conclusions: </strong>Our findings emphasize that chronic central-targeted IL-6 overexpression shapes the cortical and hippocampal molecular landscape underlying amyloidosis in both male and female Tg2576 mice. Thereby, we propose IL-6 as a potential target for future AD therapeutic strategies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13595659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148203737","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}