Alzheimer's Research & Therapy最新文献

{"title":"Correction: Influence of co-pathology on CSF and plasma synaptic markers SNAP25 and VAMP2 in Alzheimer's disease and Parkinson's disease.","authors":"Lorenzo Gaetani, Giovanni Bellomo, Davide Chiasserini, Charlotte De Rocker, Julie Goossens, Federico Paolini Paoletti, Eugeen Vanmechelen, Lucilla Parnetti","doi":"10.1186/s13195-026-02197-z","DOIUrl":"10.1186/s13195-026-02197-z","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149056778","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":"Fecal Aβ and tau aggregates are elevated in cognitive impairment and reveal peripheral proteopathic alterations.","authors":"Pelin Özdüzenciler, Laura Müller, Esra Kara, Maria-Christina Weber, Marlene Pils, Fabian Rehn, Oliver Bannach, Gereon R Fink, Dieter Willbold, Michael T Barbe, Oezguer A Onur, Gültekin Tamgüney","doi":"10.1186/s13195-026-02188-0","DOIUrl":"10.1186/s13195-026-02188-0","url":null,"abstract":"<p><strong>Background: </strong>Aggregation of amyloid-β (Aβ) and tau is central to Alzheimer's disease (AD) pathogenesis and forms the basis of established cerebrospinal fluid (CSF) and imaging biomarkers. However, increasing evidence suggests that AD involves systemic processes beyond the central nervous system. We previously demonstrated the presence of fecal Aβ aggregates. Here, we assessed the detectability of tau aggregates in human feces and examined the diagnostic value of combined fecal Aβ and tau quantification in cognitive impairment.</p><p><strong>Methods: </strong>Using surface-based fluorescence intensity distribution analysis (sFIDA), a single-particle assay selective for aggregated species, we quantified fecal Aβ and tau aggregates in individuals with cognitive impairment (dementia, MCI, SCD) and cognitively normal controls. Associations with CSF biomarkers were assessed, and classification performance was evaluated using cross-validated logistic regression models.</p><p><strong>Results: </strong>Tau aggregates were detectable in fecal samples. Both fecal Aβ and tau aggregate concentrations were significantly elevated in cognitively impaired individuals and remained independently associated with patient status after adjustment for age and sex. Fecal Aβ aggregates showed inverse associations with CSF tau biomarkers, particularly phosphorylated tau. In cross-validated models, fecal tau aggregates achieved stronger classification performance than fecal Aβ (AUC ~ 0.80 vs. ~ 0.68), and integration of fecal aggregates with demographic predictors improved discrimination to an AUC of 0.90.</p><p><strong>Conclusions: </strong>Detection of fecal tau aggregates extends previous observations on fecal Aβ and supports the concept that stool-based aggregate measurements capture systemic aspects of proteopathic biology associated with cognitive impairment. These findings suggest that fecal aggregate quantification may provide a minimally invasive biomarker approach that complements established CNS-based biomarkers and may be useful for patient stratification and monitoring in neurodegenerative disease.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13621666/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073470","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":"Correction: Higher phosphorylated tau levels predict cognitive decline and amyloid-related imaging abnormalities during lecanemab treatment: clinical practice data.","authors":"Moeko Noguchi-Shinohara, Takahiro Yoshinobu, Taro Ozaki, Daiki Muramatsu, Ayano Shima, Yasuhiro Sakashita, Yasutake Tada, Hiroki Yamaguchi, Junji Komatsu, Tokuhei Ikeda, Kenjiro Ono","doi":"10.1186/s13195-026-02196-0","DOIUrl":"10.1186/s13195-026-02196-0","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149056814","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":"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":"Data-driven mapping of known and novel fluid biomarker progression profiles in genetic frontotemporal lobar degeneration.","authors":"Julie F H De Houwer, Wenjie Kang, Renee van Buuren, Liset de Boer, Tine Swartenbroekx, Ana Rajicic, Arabella Bouzigues, Lucy L Russell, Phoebe H Foster, Eve Ferry-Bolder, John C van Swieten, Lize C Jiskoot, Raquel Sanchez-Valle, Robert Laforce, Caroline Graff, Daniela Galimberti, Rik Vandenberghe, Alexandre de Mendonça, Pietro Tiraboschi, Isabel Santana, Alexander Gerhard, Johannes Levin, Benedetta Nacmias, Markus Otto, Maxime Bertoux, Thibaud Lebouvier, Simon Ducharme, Chris R Butler, Isabelle Le Ber, Elizabeth Finger, Maria Carmela Tartaglia, Mario Masellis, James B Rowe, Matthis Synofzik, Fermin Moreno, Barbara Borroni, Henrik Zetterberg, Yolande A L Pijnenburg, Charlotte Teunissen, Jonathan D Rohrer, Stefan Klein, Elise G Dopper, Esther E Bron, Harro Seelaar","doi":"10.1186/s13195-026-02159-5","DOIUrl":"https://doi.org/10.1186/s13195-026-02159-5","url":null,"abstract":"<p><strong>Introduction: </strong>Recent proteomic studies have identified both established and novel proteins in genetic frontotemporal lobar degeneration (FTLD). However, it remains unclear at what point in the disease these proteins deviate from normal levels and how their trajectories relate to one another. Defining the temporal sequence of protein abnormalities could not only improve disease staging but also help identify biomarkers most sensitive to early disease activity in pathogenic variant carriers. We aimed to apply discriminative event-based modelling (DEBM) to characterize the progression profiles of proteins identified in a previous cross-sectional proteomic analysis.</p><p><strong>Methods: </strong>Building on our prior cross-sectional CSF proteomic analysis of genetic FTLD using a proximity extension assay, we selected the top ten significant proteins for each genetic group (C9orf72, GRN, MAPT). We then applied DEBM to characterize temporal dynamics of these proteins separately in each genetic group and evaluated their potential as early disease markers. To validate model performance, each individual was assigned a disease stage according to their position along the estimated disease timeline, based on protein levels and independent of clinical labels. Next, we assessed how well these stages discriminated symptomatic from presymptomatic carriers and non-carriers.</p><p><strong>Results: </strong>Across all genetic groups, NfL consistently became abnormal before TPM3, although the earliest abnormal proteins differed between groups. In C9orf72, ELAVL4 is the first protein to become abnormal; in GRN SEMA3G and GRN, and in MAPT MMP-10. Estimated individual-level disease stage effectively distinguished symptomatic carriers from presymptomatic carriers and non-carriers, demonstrating high diagnostic accuracy (range AUC 0.74-0.98).</p><p><strong>Conclusion: </strong>Our data-driven findings provide a temporal ordering of multiple CSF proteins, highlighting potential early biomarkers and disease dynamics in different forms of genetic FTLD. In addition, the model's accurate estimation of disease stages underscores the value of DEBM for patient stratification, offering a promising tool to support clinical trial design.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149369829","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":"MemTrax as a scalable digital triage tool for mild cognitive impairment screening: primary validation in Alzheimer's disease and exploratory analysis in Parkinson's disease.","authors":"Xinchong Shi, Haifan Kong, Weineng Chen, Lishan Lin, Kang Yuan, Fengjuan Su, Yating Wang, Ya Zhang, Jiayi Zhou, Xianbo Zhou, Curtis B Ashford, Feng Li, J Wesson Ashford, Michael F Bergeron, Zhong Pei, Yifan Zheng, Wenbiao Xian","doi":"10.1186/s13195-026-02153-x","DOIUrl":"10.1186/s13195-026-02153-x","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) and Parkinson's disease (PD) pose escalating global health challenges, with early detection of mild cognitive impairment (MCI) being critical for timely intervention. The 2023 Delphi consensus highlights the need for scalable tools suitable for primary care. This study aimed to validate the MemTrax as a rapid memory-focused triage tool against consensus-recommended cognitive assessments, including the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), for detecting MCI due to Alzheimer's disease (AD-MCI) as the primary objective, and to explore its performance in MCI due to Parkinson's disease (PD-MCI) as an exploratory aim, evaluating its utility as a rapid, accessible digital tool.</p><p><strong>Methods: </strong>We conducted a cross-sectional study enrolling 222 participants: 74 with AD-MCI, 73 healthy controls (HCs; primary cohort); 42 PD patients with normal cognition (PD-NC), 33 with PD-MCI (exploratory cohort). All participants underwent MMSE, MoCA and MemTrax testing. Diagnostic accuracy, optimal cut‑offs, and correlations between MemTrax parameters (percent correct [MTx‑%C], reaction time [MTx‑RT], composite score [MTx‑Cp]) and standard cognitive measures were evaluated.</p><p><strong>Results: </strong>In the primary AD cohort, MTx-%C showed an area under the curve (AUC) of 0.876 (95% CI: 0.813-0.926) for discriminating AD-MCI from HCs, comparable to MoCA (AUC = 0.879) and MMSE (AUC = 0.916). At a cut-off of ≤ 80%, MTx-%C achieved a sensitivity of 70.3% and specificity of 90.4%. In the exploratory PD cohort, MTx-%C (AUC = 0.808) showed similar discrimination to MMSE (AUC = 0.694) in differentiating PD-MCI from PD-NC (DeLong's test, p = 0.142). Multivariate analysis of MTx-%C, MTx-RT, and MTx-Cp demonstrated significant separation between MCI and cognitively normal groups in both the AD and PD cohorts. MTx-%C showed significant correlations with MMSE in AD (r = 0.709) and PD (r = 0.340), and with MoCA in AD (r = 0.601) and PD (r = 0.608). MemTrax metrics correlated significantly with distinct domain-level associations reflecting disease-specific cognitive profiles.</p><p><strong>Conclusions: </strong>MemTrax demonstrates good diagnostic accuracy comparable to established cognitive screening tools for AD-MCI (primary cohort), supporting its use as a rapid, scalable, and culturally neutral digital memory-focused triage tool. Exploratory findings in PD-MCI are promising but require confirmatory studies. Its brevity and automation support practical implementation in primary care and community settings, potentially facilitating earlier detection and stratification of cognitive impairment.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13733052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332119","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}