Alzheimer's Research & Therapy最新文献

{"title":"Herpes simplex virus and kallikrein-related peptidases - a functional connection in Alzheimer's disease.","authors":"Oliver Goldhardt, Cinthia Mella Robles, Matthias Eberl, Tobias Dreyer, Antoninus Soosaipillai, Eleftherios P Diamandis, Josef Priller, Dieter Hoffmann, Jochen M Wettengel, Hianara Aracelly Bustamante, Paula Salazar, Markus Thaler, Carola Otth, Ingrid Pamela Ehrenfeld Slater, Timo Grimmer","doi":"10.1186/s13195-026-02204-3","DOIUrl":"10.1186/s13195-026-02204-3","url":null,"abstract":"<p><strong>Background: </strong>The viral hypothesis of Alzheimer's disease (AD) proposes that neurotropic pathogens may interact with amyloid and tau pathology, but the evidence remains controversial. We investigated whether cerebrospinal fluid (CSF) kallikrein-related peptidase 6 (KLK6) is associated with AD biomarkers and with an intrathecal anti-HSV immune response in patients with AD, and whether HSV-1 infection alters KLK6 expression in cell culture models.</p><p><strong>Methods: </strong>CSF KLKs and AD biomarkers were analyzed in patients with AD. HSV-1 serostatus and anti-HSV-1/2 CSF-to-serum antibody index (HSV-AI) were used as markers of previous or ongoing intrathecal anti-HSV immune response. In vitro, HSV-1 infection and KLK6 knockdown were examined in human cell models.</p><p><strong>Results: </strong>CSF-KLK6 correlated with tau and amyloid biomarkers. In HSV-1-seropositive patients, HSV-AI was associated with CSF-KLK6, although the effect size was modest and the association was strongly context-dependent on the Aβ42/40 ratio. In vitro, productive HSV-1 infection induced and stabilized KLK6 protein expression, and KLK6 knockdown reduced HSV-1 protein expression and infectious progeny in HaCaT cells.</p><p><strong>Conclusions: </strong>KLK6 is associated with AD biomarkers and with an intrathecal anti-HSV immune response in a subset of patients with AD. The in vitro data support a functional relationship between HSV-1 infection and KLK6, but the clinical findings are associative and do not demonstrate ongoing CNS HSV-1 replication or causality. These findings warrant independent validation. However, this research provides further evidence for a role of HSV-1 in the pathophysiology of AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149056824","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":"Enhancing Alzheimer's disease diagnosis in primary care through targeted screening of people at risk of developing dementia - study design and feasibility assessment of the PREDEM primary care study.","authors":"Sandar Aye, Signe Åhrberg, Axel C Carlsson, Jan Hasselström, Ibrahim Alshamani, Sara Wallen, Wobbie van den Hurk, Lena Lund, Alenka Jejcic, Sarah Thomas Broome, Adrià Duran Sidera, Lars Tjernberg, Linus Jönsson, Sophia Schedin-Weiss","doi":"10.1186/s13195-026-02162-w","DOIUrl":"10.1186/s13195-026-02162-w","url":null,"abstract":"<p><strong>Background: </strong>Timely detection of cognitive impairment due to Alzheimer's disease (AD) is increasingly important as disease modifying therapies become available. Current diagnostic pathways in primary health care (PHC) rely mainly on clinical assessment and brief cognitive screening tools, which lack sensitivity for early impairment. Blood-based biomarkers (BBMs) show promising diagnostic potential in research settings. Targeted screening of individuals with cognitive symptoms and dementia risk factors using sensitive cognitive tests and reliable biomarkers may improve early AD detection in PHC. The PREDEM primary care study evaluates a targeted screening strategy combining a multidomain digital cognitive test battery and BBMs in individuals having elevated risk of dementia. This pilot study assessed the feasibility of recruitment, digital cognitive testing, biomarker sampling, and data collection.</p><p><strong>Methods: </strong>This descriptive pilot study was conducted at two PHC centres in Stockholm (April-October 2024). Eligible individuals were aged ≥ 65 years with hypertension or type 2 diabetes and self-reported memory complaints. Participants completed a screening question, followed by a demographic questionnaire, a multidomain digital cognitive test battery (Mindmore), MMSE, and blood sampling for four BBMs (GFAP, NF‑L, total tau, pTau217). Feasibility metrics included recruitment yield, test completion rates, participant characteristics, cognitive performance, and biomarker distributions.</p><p><strong>Results: </strong>Of 548 identified individuals, 307 were invited and 40 were enrolled (13% participation). Among those enrolled, 37 completed all parts of the study. Digital home-based testing proved challenging: although 22 participants initially opted for home testing, only six completed it independently, and most required clinic-based support. Across cognitive tests, approximately one-third of participants scored below 1 standard deviation of normative performance, indicating detectable cognitive impairment. Non-native Swedish speakers (32%) showed significantly lower performance on verbally mediated tasks. Established cut-off values for pTau217 reflecting amyloid pathology showed pathological levels in 10-23% of participants depending on single or double cut-offs.</p><p><strong>Conclusions: </strong>This pilot study demonstrates the feasibility of the PREDEM primary care study design and data collection procedures. Targeted recruitment of older adults with cardiometabolic risk factors was able to identify a population relevant to the study aims. Key protocol refinements include removing the requirement for subjective memory complaints, conducting all cognitive testing at PHC, and optimization of cognitive test battery.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975431","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 self-reported hearing loss and tinnitus with brain structure and cognitive function: a population-based cross-sectional analysis from the Study of Health in Pomerania (SHIP).","authors":"Claudia Schwarz, Stefan Frenzel, Till Ittermann, Ulrike Grittner, Silke M Wortha, Tina Brzoska, Hans J Grabe, Agnes Flöel, Friedrich Ihler","doi":"10.1186/s13195-026-02166-6","DOIUrl":"10.1186/s13195-026-02166-6","url":null,"abstract":"<p><strong>Background: </strong>Hearing loss has been reported as a major, potentially modifiable risk factor for dementia and often co-occurs with tinnitus. Both conditions are prevalent and have been linked to brain health and cognitive decline. However, evidence from studies containing the whole age span of adults remains limited. Therefore, this study investigated associations of hearing loss and tinnitus with brain structure and cognitive performance in a large population-based cohort from northeastern Germany.</p><p><strong>Methods: </strong>Data from the baseline investigation of 4,420 participants (age 20-84 years) for the SHIP-TREND cohort was analysed. Thereof, 4,400 completed a self-assessment for hearing and 3,937 for tinnitus. Cognitive performance was assessed by tests on verbal memory and executive function. T1-weighted magnetic resonance imaging yielded data on global and regional volumes and cortical thickness for 2,144 participants. Multiple linear regression and mediation analyses were conducted, adjusted for age, sex, and further risk factors for dementia.</p><p><strong>Results: </strong>A total of 1,455 participants reported hearing loss, 679 thereof a clinically relevant degree while 874 participants reported tinnitus. Hearing loss was associated with worse memory performance and unfavourable brain measures, particularly along the central auditory pathway and in regions implicated in cognitive function and Alzheimer's Disease. Notably, white matter hypointensity volume partially mediated (8.8%) the association of self-reported hearing loss with immediate recall performance. Self-reported hearing loss was associated with tinnitus (odds ratio 7.5 [95%CI 6.0 to 9.3]; p < 0.001), but no relevant combined effects on cognitive performance or brain measures were observed, and tinnitus alone was not associated with cognition or adverse brain measures.</p><p><strong>Conclusions: </strong>This large cohort study not only confirmed independent associations of self-reported hearing loss with memory performance and structural brain measures but also suggested a pathophysiologic link between hearing loss and cerebrovascular disease. Our findings support an association between hearing loss, but not tinnitus, and cognitive decline as well as dementia-related brain changes, highlighting hearing loss as a potentially important target for early prevention strategies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13527976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863503","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 third-generation, high-affinity biparatopic anti-tau antibody inhibits intracellular tau aggregation seeded by Alzheimer's brain extracts.","authors":"Eric Hatterer, Lucile Broyer, Sara Pecoraro, Fabien Cusin, Naz Simsek, John J Breve, Mathieu Clavel, Kevin L Batenburg, Bart Klein, Thuur Zuidweg, Kristin Piché, Jeremie Bourguignon, Margot Bonnet-Gamard, Pauline Malinge, Franck Gueneau, Valery Moine, Nadia Anceriz, Krzysztof Masternak, Nicolas Fischer, Torleif Tollefsrud Gjølberg, Jenny Skjermo Telstad, Gaia Calamera, Simone Mester, Wiep Scheper, Wilma D J Van de Berg, Jean-Philippe Courade","doi":"10.1186/s13195-026-02155-9","DOIUrl":"10.1186/s13195-026-02155-9","url":null,"abstract":"<p><strong>Background: </strong>Tau immunotherapy has recently shown clinical promise but required high dosing. We developed NIDB-3101, a novel third-generation, high-affinity anti-tau biparatopic antibody designed for superior tau binding, aggregation inhibition, and extended half-life.</p><p><strong>Methods: </strong>NIDB-3101 binds tau's microtubule-binding region and C-terminal domains. Various binding and cellular functional assays using recombinants, but more importantly human AD extracts were used to assess NIDB-3101 benefits. Half-life mutations impact was assessed via FcRn binding and cellular assays recycling.</p><p><strong>Results: </strong>NIDB-3101 exhibited sub-nanomolar affinity, binding a broad spectrum of pathological tau species in AD homogenates, inhibited AD extracts-induced cellular effect compared to benchmark antibodies. Mutations enhanced hFcRn-mediated cellular recycling.</p><p><strong>Conclusions: </strong>NIDB-3101 captures a broad spectrum of pathological tau species leading to strong cellular efficacy using human AD extracts, supporting further clinical development as a potential disease-modifying therapy for AD and related tauopathies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886171","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 UNC13A cryptic exon associates with cognitive impairment in Alzheimer's disease.","authors":"Madison M Reeves, Sara Aviles Carpintero, Matteo Zanovello, Karen Jansen-West, Mei Yue, Anna Calliari, Yuping Song, Judith Dunmore, Candela Maroto Cidfuentes, Sophie Ball, Jennifer M Kachergus, Heather E Killeen, Bailey Rawlinson, Erica Engelberg-Cook, Michael DeTure, Gregory S Day, Neill R Graff-Radford, Bradley F Boeve, David S Knopman, Ronald C Petersen, Melissa Murray, Aubrey E Thompson, Dennis W Dickson, Pietro Fratta, Leonard Petrucelli, Keith A Josephs, Mercedes Prudencio","doi":"10.1186/s13195-026-02157-7","DOIUrl":"https://doi.org/10.1186/s13195-026-02157-7","url":null,"abstract":"<p><strong>Background: </strong>TAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer's disease (AD), where it co-occurs with amyloid β plaques and tau neurofibrillary tangles, and associates with accelerated cognitive decline and brain atrophy. TDP-43's function of repressing the inclusion of cryptic exons (CEs) during RNA splicing is compromised in AD. A single-nucleotide polymorphism (SNP) located within the CE in the UNC13A gene [rs12973192 (C > G)] is associated with higher disease risk and reduced survival in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) by weakening TDP-43 binding promoting CE inclusion.</p><p><strong>Objective: </strong>To investigate the influence of the rs12973192 UNC13A CE SNP and UNC13A cryptic splicing on TDP-43 pathology, survival and cognitive impairment in AD.</p><p><strong>Methods: </strong>We evaluated the UNC13A CE SNP in a cohort of 1,672 AD, including 643 AD brains with available cognitive measurements and 73 AD cases for which we measured cryptic RNA levels in the amygdala. We also evaluated a cohort of 466,517 from the UK Biobank to determine associations between the UNC13A CE SNP and dementia diagnosis.</p><p><strong>Results: </strong>In AD, the UNC13A CE SNP associated significantly with cognitive decline, but not with TDP-43 pathology or with survival. UNC13A cryptic RNA levels in the amygdala were a better predictor of cognitive decline than the UNC13A CE SNP itself, while STMN2-another well-known CE target-exhibited no such association.</p><p><strong>Conclusions: </strong>These findings point to UNC13A cryptic splicing as a specific driver of cognitive decline in AD, outperforming both genetic risk and other cryptic targets.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757139","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":"Semantic fluency predicts survival of memory clinic patients.","authors":"Lars Frings, Joachim Brumberg, Philipp T Meyer","doi":"10.1186/s13195-026-02152-y","DOIUrl":"10.1186/s13195-026-02152-y","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Semantic fluency is commonly assessed in the diagnostic work-up of individuals with suspected cognitive impairment due to neurodegenerative disease. Semantic fluency has a predictive value for survival in clinical AD and in healthy elderly individuals, but it is unknown if this also applies to biomarker-confirmed AD and non-AD memory clinic patients. Potential associations with and added value of imaging biomarkers of amyloid pathology and neurodegeneration have yet to be explored.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;From our clinical registry, we included patients who were assessed at a memory clinic with the neuropsychological assessment battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-NAB) and whose vital status could be retrieved in 07/2024. We tested the association of semantic fluency performance at first assessment and over time (and, for comparison, further CERAD-NAB subtest scores) with mortality risk using age-adjusted single-predictor Cox proportional hazard models. Amyloid status (positive vs negative on clinical PET reads) and global cognitive impairment (MMSE) were included as covariates. In addition, we explored associations between semantic fluency performance and both regional cortical glucose metabolism (FDG PET) and global amyloid load (centiloids; PiB PET). Finally, the predictive value of global amyloid load and glucose metabolism in comparison to and in combination with semantic fluency performance was assessed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;583 patients were included (age 68.9 ± 8.7, 45% female). 280 patients (48%) had died and 303 (52%) were alive after a median of 8.0 years [95% C.I. 7.7-8.4]. Better semantic fluency (age-, sex- and education adjusted Z score, based on normative data) was significantly associated with lower mortality risk (HR = 0.71 [0.63 - 0.80], Bonferroni-corrected p &lt; 0.001). Its predictive value was higher than that of all other CERAD-NAB subscores (e.g., memory, visuospatial abilities). Semantic fluency remained a significant predictor when amyloid status and global cognitive impairment were accounted for (HR = 0.75 [0.61 - 0.91], p = 0.0035). In patients with more than one assessment (N = 163), longitudinal change of semantic fluency (derived from a linear mixed effects model) was also a significant predictor (HR = 0.66 [0.53-0.83], p &lt; 0.001). In 218/583 patients who had received amyloid and FDG PET, worse semantic fluency was associated with decreased FDG uptake of left inferior and middle temporal, dorsolateral frontal, and posterior parietal cortical regions (Bonferroni-corrected p &lt; 0.05), but not with amyloid load. FDG uptake of the left IFG (pars opercularis) was itself a predictor of survival (HR = 0.68 [0.55 - 0.84], Bonferroni-corrected p &lt; 0.05), but to a lesser degree than semantic fluency (and MMSE, naming and figure drawing). Predictive accuracy of semantic fluency was further improved by including FDG uptake of the right a","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13452100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697003","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":"SuperAging is not the inverse of common-variant Alzheimer's risk: evidence across genetic ancestries.","authors":"Ignazio Stefano Piras, Ana Werneck Capuano, Amanda Cook Maher, Rhiana Schafer, Anna Bonfitto, Serena Song, Francis Taguinod, Felicia Goldstein, Angela Roberts, Ozioma Okonkwo, Adam Martersteck, Matt J Huentelman, Emily Rogalski","doi":"10.1186/s13195-026-02124-2","DOIUrl":"10.1186/s13195-026-02124-2","url":null,"abstract":"<p><strong>Background: </strong>As longevity increases and the population over age 65 expands, advancing age remains the most reliable predictor of cognitive decline, highlighting the need to identify biological mechanisms that support exceptional cognitive aging. We tested whether lower inherited risk of Alzheimer's disease (AD) dementia predicts SuperAger status (adults ≥ 80 years with episodic memory at least as good as middle-age adults) using prospectively enrolled SuperAgers and Cognitively Average Controls (Controls) from the multisite SuperAging Research Initiative.</p><p><strong>Methods: </strong>We studied 231 participants (SuperAgers n = 142; Controls n = 89). We confirmed that the genetic ancestry structure across groups was comparable. We evaluated whether APOE status (ε2, ε3, ε4) and three AD polygenic risk scores (PRS) derived from large contemporary Genome-Wide Association Studies (GWAS) (PRS_Lambert, PRS_Wightman, PRS_Bellenguez) predicted SuperAging status using logistic regression models adjusted for age, sex, and education, considering ancestry interactions.</p><p><strong>Results: </strong>APOE allele and genotype distributions did not differ between groups, and neither APOE nor any of the three PRS predicted SuperAger status. Results were unchanged when accounting for global non-European or African ancestry or principal components. In this well-characterized cohort, neither APOE nor contemporary PRS explained SuperAger status.</p><p><strong>Conclusions: </strong>These findings suggest that the exceptional late-life memory phenotype that is characteristic of SuperAging is not explained by common-variant AD genetic risk captured by APOE or contemporary AD PRS, motivating a deeper investigation of potential rare genetic variations and experiential factors contributing to exceptional cognitive aging.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576317","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":"Personalized non-invasive combined magnetic and electrical stimulation of the default mode network in mild AD patients (CMES-AD): a multicentric randomized sham-controlled trial protocol.","authors":"Sonia Bonnì, Romina Esposito, Lucia Mencarelli, Francesco Di Lorenzo, Francesco Ricci, Fulvia Di Iulio, Elena Savastano, Francesca Candeo, Francesca De Masi, Antonella Coletta, Andrea Carolina Vinci, Matteo Ferraresi, Marta Mancini, Elias Paolo Casula, Ilaria Borghi, Danny Adrian Spampinato, Michele Maiella, Alex Martino Cinnera, Martina Assogna, Matilde Bruno, Matteo Nocilli, Marica Ferrara, Marta Russo, Nevio Luigi Tagliamonte, Clarissa Ferrari, Salvatore Bertino, Rocco Salvatore Calabrò, Maria Grazia Maggio, Rosaria De Luca, Rachele Burrascano, Elvira Gjonaj, Alessio Mirabile, Paolo De Pasquale, Andrea d'Avella, Angelo Quartarone, Giacomo Koch","doi":"10.1186/s13195-026-02145-x","DOIUrl":"https://doi.org/10.1186/s13195-026-02145-x","url":null,"abstract":"<p><strong>Background: </strong>Patients with Alzheimer's disease (AD) exhibit early alterations in the Default Mode Network (DMN), a key brain network involved in episodic memory where the precuneus plays a central role. Precision-targeted, non-invasive brain stimulation represents a promising strategy to improve cognitive function in individuals with dementia. The DMN can be modulated through personalized non-invasive electromagnetic stimulation, a therapeutic approach that enhances neural plasticity and stabilizes network connectivity. This trial implements an innovative therapeutic protocol based on precision delivery of personalized electromagnetic stimulation targeting the precuneus, the main hub of the DMN.</p><p><strong>Methods: </strong>This phase 2 multicenter, randomized, double-blind, sham-controlled, three-arm trial evaluates the safety and efficacy of combined repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) targeting the precuneus in AD patients. rTMS will be applied using the intermittent theta burst stimulation (iTBS) protocol, while tACS will be delivered at gamma frequency (70 Hz). Personalization of iTBS-tACS treatment is established using neuronavigated TMS with electroencephalography (TMS-EEG). The 24-week intervention starts with a 2-week intensive course of daily combined treatment over the precuneus (5 sessions per week), followed by a 22-week maintenance phase with weekly stimulation. The primary outcome measure is the change in the integrated Alzheimer Disease Rating Scale (iADRS) between baseline and week 24. Secondary outcomes include score changes in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, Clinical Dementia Rating Scale-Sum of Boxes (CDR-SoB), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog₁₃), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Frontal Assessment Battery (FAB), the Face-Name Association Task (FNAT), the Neuropsychiatric Inventory (NPI), and the Apathy Motivation Index (AMI). Exploratory outcomes will include changes in cortical activity and connectivity (assessed through TMS-EEG, MRI), in blood based biomarkers of neurodegeneration, synaptic activity and neural inflammation, and sensorimotor functions in virtual environments. Evaluation at week 12 and a follow-up assessment at week 32 will be conducted to assess short-term and follow-up treatment effects, respectively.</p><p><strong>Significance: </strong>This trial aims to provide evidence that personalized combined electrical and magnetic stimulation of the DMN may slow functional and cognitive decline in AD patients, contributing to the development of personalized interventions for AD treatment.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT07075770, registered 10 July 2025.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547491","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":"Resting-state functional dynamics alterations relate to plasma amyloid markers and statistically explain memory impairments in the TgF344-AD model of Alzheimer's disease.","authors":"Alya Al-Awlaqi, Lori Berckmans, Sam De Waegenaere, Sarah Vanherle, Joseph Griffis, Ilse Dewachter, Marleen Verhoye, Mohit H Adhikari","doi":"10.1186/s13195-026-02146-w","DOIUrl":"10.1186/s13195-026-02146-w","url":null,"abstract":"<p><strong>Background: </strong>Resting-state functional MRI studies of Alzheimer's disease (AD) show lower functional connectivity (FC) of AD-relevant regions and resting-state networks in patients and transgenic rodent models at symptomatic stages. However, at early stages of the disease, both hyper and hypo connectivity has been reported. Traditional FC overlooks temporal fluctuations in connectivity and network dynamics at a short timescale captured by transient brain states such as co-activation patterns (CAPs). CAPs have been shown to be more sensitive than FC to detect early alterations in neurodegenerative diseases and therefore can shed light on hyper versus hypo connectivity observed at early stages. Moreover, how brain functional signatures of Alzheimer's disease are related to its behavioral and pathological markers and whether they have prognostic relevance remain scarcely investigated.</p><p><strong>Methods: </strong>We acquired high temporal resolution resting-state functional MRI data in the TgF344-AD model rats and age-matched wild-type animals at 4 and 10 months of age corresponding to the pre-plaque and plaque stages, respectively and delineated brain functional alterations using FC and CAPs in the model animals. We also assessed the levels of amyloid beta (Aβ) in blood and working and reference memory performance in the same animals at the plaque stage and investigated their statistical relationship with pre-plaque and plaque-stage changes in FC and CAPs.</p><p><strong>Results: </strong>TgF344-AD rats had significantly elevated blood Aβ levels, committed more working and reference memory errors and showed reduced hippocampal FC with the lateral cortical and default-mode-like network compared to wild-type animals at the plaque stage. FC at the pre-plaque stage did not differ between TgF344-AD and wild-type rats. TgF344-AD rats showed hyper- and hypo-activation in the default-mode-like-network and hippocampal regions at pre-plaque and plaque stages, respectively, in multiple CAPs. Blood Aβ levels were statistically explained more accurately by plaque-stage, than pre-plaque stage, FC values and CAP activations. CAP activations, especially at the pre-plaque stage, outperformed FC in accurate statistical explanation of memory impairments.</p><p><strong>Conclusion: </strong>Our findings demonstrate pre-plaque stage hyperconnectivity not in the traditional, static measure of functional connectivity but in transient, dynamic brain states and that these early brain functional signatures have prognostic relevance for memory deficits in a translational rat model of Alzheimer's disease.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468375","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":"Blood-based immunophenotyping of T cell profiles in patients with neurodegenerative disorders.","authors":"Frederika Malichova, Peter Swann, Stacey L Kigar, Natalia Savinykh Yarkoni, Julia Goddard, Kei Onn Lai, Leonidas Chouliaras, Ajenthan Surendranathan, Lorinda Turner, George Savulich, Richard Bevan-Jones, Nicholas J Ashton, Kaj Blennow, Henrik Zetterberg, Edward Needham, Joanne Jones, William A McEwan, James B Rowe, John T O'Brien, Maura Malpetti","doi":"10.1186/s13195-026-02144-y","DOIUrl":"10.1186/s13195-026-02144-y","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;There is increasing evidence for the role of central and peripheral inflammation across neurodegenerative disorders, with animal models and post-mortem studies identifying T-cell infiltration in the brain associated with pathology and neurodegeneration. Peripheral T-cell changes have been measured in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). This study examines a unique cohort of blood-based T-cell profiles across a range of neurodegenerative dementias including AD, DLB, FTD, corticobasal syndrome (CBS), PSP, and aged-matched healthy controls. Then it also explores their associations with dementia-relevant plasma biomarkers and clinical outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Freshly prepared peripheral blood mononuclear cells (PBMCs) from 174 participants (AD = 20, DLB = 24, FTD = 19, CBS = 18, PSP = 58, controls = 35) were studied using a flow-cytometry panel designed to analyse major T-cell subpopulations, including memory and T-helper subtypes. Neurodegeneration-relevant biomarkers (p-tau217, p-tau231, GFAP, NfL, and A-beta42/40) were measured in plasma samples. T-cell populations were compared between groups and in association with biomarkers, and principal components analysis (PCA) was used to identify T-cell profiles and their association with dementia-relevant biomarkers in diagnostic classification and survival prediction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;There was a significant reduction in the fraction of CD3+ cells in patients with DLB compared to other diagnostic groups, and an increase in relative Th1/17-like cell levels in patients with FTD compared to controls. This increase in Th1/17-like cells correlated with NfL and GFAP plasma levels in patients with FTD. PCA identified five components primarily representing CD4+ memory cell population subsets. After sex and age adjustments, component 4 marked by effector memory types including Th2-like, Th-like1 and Th1/17-like cells was a significant predictor of FTD, however was not as accurate as plasma NfL. Higher scores in specific T-cell components (1 and 3) were associated with reduced mortality across all diseases, with component 3 remaining a significant predictor even when controlling for traditional neurodegenerative biomarkers like NfL and p-tau217.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study provides evidence that T-cell dysregulation is not unified in patients with neurodegenerative diseases. We observe different involvement across different dementia types establishing adaptive immunity as a key contributor to disease heterogeneity. However, although plasma biomarkers such as NfL and p-tau217 exhibit superior diagnostic accuracy for clinical classification, peripheral T-cell signature were associated with survival outcomes across diagnostic groups, highlighting their promise for prognostic applications and disease monitoring. The characterisation of T-cell","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468381","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}