Alzheimer's Research & Therapy最新文献

{"title":"A clinically feasible framework to estimate tau pathology and clinical-biological discordance in the Alzheimer's disease spectrum.","authors":"Jung-Lung Hsu, Shao-Yi Huang, Hsiu-Chuan Wu, Kun-Ju Lin, Kuo-Lun Huang, Chin-Chang Huang, SangYun Kim, Ing-Tsung Hsiao","doi":"10.1186/s13195-026-02083-8","DOIUrl":"10.1186/s13195-026-02083-8","url":null,"abstract":"<p><strong>Background: </strong>Tau positron emission tomography (PET) is critical for biological staging and treatment stratification in Alzheimer's disease (AD), particularly in the era of anti-amyloid therapies where lower tau burden predicts greater clinical benefit. However, tau PET remains costly and inaccessible in many clinical settings. We aimed to develop and validate a clinically feasible framework to estimate global and regional tau burden using routinely available amyloid PET and clinical measures, aligned with the 2024 Alzheimer's Association (AA-2024) diagnostic framework, and to characterize clinical-biological discordance across the AD continuum.</p><p><strong>Methods: </strong>We conducted a cross-sectional study of 229 individuals spanning cognitively unimpaired, mild cognitive impairment, and dementia stages who underwent [¹⁸F]florbetapir amyloid PET, [¹⁸F]florzolotau tau PET, structural MRI, and cognitive assessment. Amyloid burden was quantified using the Centiloid (CL) scale (A+ defined as CL > 20). Tracer-specific tau thresholds for global and Braak-stage volumes were derived using two-component Gaussian mixture modeling. Logistic regression models incorporating CL, age, Mini-Mental State Examination (MMSE), and medial temporal lobe (MTL) volume were developed to classify high global tau burden and neocortical tau involvement. Among amyloid-positive individuals, biological staging was compared with clinical stage to assess discordance patterns.</p><p><strong>Results: </strong>Global and regional tau burden increased stepwise across clinical severity and amyloid strata. High global tau burden was uncommon in individuals with CL 21-60 (6.1%) but increased in CL 61-100 (22.6%) and > 100 (36.2%). A multivariable model integrating CL, age, MMSE, and relative MTL volume demonstrated good discrimination for high global tau burden (AUC = 0.87) and neocortical involvement (AUC = 0.84). Model robustness was confirmed by bootstrap resampling. Among amyloid-positive participants, 53.1% exhibited clinical-predominant AD, characterized by older age and higher cardiovascular risk despite relatively modest tau burden, indicating substantial clinical-biological discordance.</p><p><strong>Conclusion: </strong>Routinely obtainable amyloid PET and clinical measures can approximate global and topographical tau burden with good accuracy and identify frequent clinical-biological discordance within the AD spectrum. This scalable framework provides a practical surrogate for tau PET in resource-limited settings and may support biological staging, therapeutic eligibility assessment, and precision treatment decision-making.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980046","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":"Plasma p-tau217, p-tau181, and Aβ42 predict amyloid PET positivity in cognitively unimpaired adults.","authors":"Rui Bao, Wanying Shi, Hongbo Bao, Tonghua Zhang, Xueying Li, Wencai Ding","doi":"10.1186/s13195-026-02080-x","DOIUrl":"10.1186/s13195-026-02080-x","url":null,"abstract":"<p><strong>Background: </strong>Early detection of Alzheimer's disease (AD) pathology in cognitively unimpaired individuals is critical for preclinical intervention. Plasma biomarkers, especially phosphorylated tau217 (p-tau217), are promising predictors of amyloid-β (Aβ) accumulation.</p><p><strong>Methods: </strong>In this cohort study, we analyzed data from cognitively unimpaired older adults in the A4 and LEARN studies (n = 1,407), comprising 452 participants with Aβ positron emission tomography (PET)-negative status and 955 participants with Aβ PET-positive status. We evaluated the accuracy of plasma biomarkers (p-tau217, p-tau181, Aβ42/40 ratio, and others) in predicting Aβ PET positivity using receiver operating characteristic analysis, comparing covariate-adjusted individual biomarker and biomarker-ratio models with a multivariable combined model integrating plasma biomarkers and covariates. (age, sex, apolipoprotein E [APOE] ε4 genotype).</p><p><strong>Results: </strong>Plasma p-tau217 showed the strongest individual association with Aβ PET status (area under the curve [AUC], 0.85). A combined model integrating p-tau217, p-tau181, Aβ42, age, sex, and APOE ε4 achieved the highest overall discrimination (AUC, 0.87), although the improvement over the covariate-adjusted p-tau217 model was modest.</p><p><strong>Conclusions: </strong>Plasma p-tau217 showed the strongest individual performance for predicting Aβ PET positivity in cognitively unimpaired older adults. Adding other plasma biomarkers and clinical covariates provided a modest incremental improvement in classification performance. These findings support blood-based prescreening as a potential enrichment approach, while indicating that confirmatory amyloid assessment remains necessary when definitive Aβ status is required.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13227887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980049","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: Comorbidities predict institutionalization and mortality in biomarker-confirmed alzheimer's disease.","authors":"Xin Xia, Alice Clark, Niels Juul Brogaard, Alex Mourer, Anna Areovimata, Maria Eriksdotter, Henrik Zetterberg, Silke Kern, Tobias Skillbäck, Linus Jönsson","doi":"10.1186/s13195-026-02072-x","DOIUrl":"10.1186/s13195-026-02072-x","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13188552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147980004","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":"Metabolic parameter variability, brain structure, perfusion, and cognition: a population-based study.","authors":"Xiaoshuai Li, Xuejia Li, Mengmeng Bai, Ling Yang, Jing Chen, Jiacheng Fan, Huijing Shi, Rui Li, Xiaoliang Liang, Shun Zhang, Pengfei Zhao, Jing Li, Han Lv, Shuohua Chen, Zhenghan Yang, Zhenjian Yu, Yuntao Wu, Ying Hui, Shouling Wu, Zhenchang Wang","doi":"10.1186/s13195-026-02074-9","DOIUrl":"10.1186/s13195-026-02074-9","url":null,"abstract":"<p><strong>Background: </strong>Metabolic instability can affect cognitive function, but the mechanisms are largely unknown. To address this, we investigated the association between metabolic parameter variability, brain volume, cerebral blood flow (CBF), and cognitive performance, and evaluated whether CBF and brain volume mediate this relationship.</p><p><strong>Methods: </strong>Participants were prospectively included from the Kailuan study. Between 2006 and 2020, the variability in metabolic parameters such as systolic blood pressure, fasting blood glucose, low-density lipoprotein cholesterol, and body mass index was evaluated using the coefficient of variation (CV). Starting in 2020, brain MRI and the Montreal Cognitive Assessment (MoCA) were performed continuously as part of the seventh follow-up visit and subsequent assessments. Generalized linear regression models were used to analyze the associations between metabolic variability, CBF, brain volume, and cognitive performance. Mediation analysis was performed to evaluate the mediation effects of CBF or brain volume.</p><p><strong>Results: </strong>A total of 1894 participants (mean age, 55.4 ± 10.9 years; 51.8% male) were included. High variability scores of metabolic parameters were associated with lower CBF in total brain (β [95% confidence interval]: -2.02 [-3.73, -0.30]), total white matter (WM) (-3.04 [-4.72, -1.37]), temporal lobe (-1.82 [-3.60, -0.03]), and hippocampus (-1.91 [-3.65, -0.17]), as well as decreased volume in both total gray matter (GM) (-5.64 [-11.24, -0.04]) and temporal lobe (-1.70 [-3.16, -0.25]). High variability in metabolic parameters was associated with reduced MoCA scores (-0.98 [-1.75, -0.20]). After multiple comparison correction, the association with total WM CBF remained significant. Decreased brain volume and CBF were associated with reduced MoCA scores (P < 0.05). Mediation analysis revealed that the association between variability in metabolic parameters and MoCA scores was mediated by total WM CBF, total GM volume, and temporal lobe volume, accounting for 7.518%, 5.619%, and 6.864% of the effect, respectively.</p><p><strong>Conclusion: </strong>Reduced total WM CBF, GM volume, and temporal lobe volume mediated the association between elevated metabolic variability and cognitive decline, with total WM CBF showing the most robust mediating effect.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13360039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969675","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":"Clarifying comparative claims in digital cognitive assessment: a matters arising on multimodal detection of cognitive impairment and amyloid positivity.","authors":"Paul W Estes","doi":"10.1186/s13195-026-02057-w","DOIUrl":"10.1186/s13195-026-02057-w","url":null,"abstract":"<p><p>Digital cognitive assessments represent an important and rapidly evolving approach to detecting cognitive impairment and Alzheimer's disease-related pathology. Jannati et al. report promising findings using a multimodal digital clock and recall assessment to identify cognitive impairment and amyloid positivity. While this contribution is welcomed, several comparative statements regarding Cognivue^® rely on historical regulatory data and do not reflect the contemporaneous peer-reviewed evidence base available at the time of manuscript preparation. This Matters Arising article clarifies the limitations of cross-study performance comparisons, addresses selective citation of a single early Cognivue publication, and summarizes subsequent peer-reviewed findings demonstrating Cognivue's psychometric validity, biomarker associations, and generalizability across diverse populations. These considerations highlight the importance of harmonized, contemporaneous comparisons when asserting relative performance among digital cognitive assessment tools.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13188380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969495","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":"Re: Clarifying comparative claims in digital cognitive assessment: Assessing concurrent validity in a shared cohort.","authors":"Ali Jannati, Sean Tobyne, Alvaro Pascual-Leone","doi":"10.1186/s13195-026-01987-9","DOIUrl":"10.1186/s13195-026-01987-9","url":null,"abstract":"<p><p>In response to correspondence from Cognivue, Inc. regarding our publication (Jannati et al., 2025), we clarify that our analysis employed a rigorous paired-sample design using the same 930 participants from the Bio-Hermes-001 study for both the Digital Clock and Recall^® (DCR) and Cognivue Clarity^® assessments. The assertion that our findings rely on \"nonequivalent cohorts\" or \"outdated regulatory data\" is factually incorrect; performance metrics were calculated de novo using the harmonized study dataset. Furthermore, we address the omission of the Cognivue Amyloid Risk Measure (CARM), noting that comparing a cross-validated predictive model (DCR) with a post hoc metric derived from the same dataset (CARM) would introduce significant bias due to overfitting. We conclude by highlighting how head-to-head comparisons in diverse cohorts align with the recently published Global CEO Initiative on Alzheimer's Disease (CEOi) recommendations for digital cognitive assessment standards.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13188391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969498","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":"Safety, tolerability and immunogenicity of vaccine ALZ-101 in patients with early Alzheimer's disease: randomised, controlled trial.","authors":"Zsófia Lovró, Anders Sandberg, Henrik Zetterberg, Stefan Pierrou, Riitta Parkkola, Niclas Sjögren, Mika Scheinin, Juha O Rinne","doi":"10.1186/s13195-026-02082-9","DOIUrl":"10.1186/s13195-026-02082-9","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;ALZ-101 is a therapeutic vaccine comprised of a stabilised oligomeric derivative of amyloid-β42 (Aβ42), denoted Aβ42CC, that elicits antibodies targeting a low-abundance, neurotoxic Aβ oligomer species. This first-in-human, single-center Phase 1b trial evaluated the safety, tolerability, and immunogenicity of ALZ-101, with exploratory biomarker and clinical outcomes, in participants with early Alzheimer's disease (AD).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Thirty‑two participants with biomarker‑confirmed early AD (mean age ∼69 years, ∼30% female, Mini‑Mental State Examination ∼24, Alzheimer's Disease Composite Score [ADCOMS] ∼0.55, Clinical Dementia Rating-Sum of Boxes ∼3.0, ∼70% APOE ε4 carriers) were enrolled in a randomised, double‑blind, placebo‑controlled main study (Part A1) and a semi‑blinded extension (Part B). In Part A1, participants received intramuscular ALZ‑101 125 µg (n = 10) or 250 µg (n = 10) or placebo (n = 6) at Weeks 0, 4, 8, and 16. After ≥ 14 weeks of follow‑up, eligible participants (n = 23) entered Part B and received two or four additional 250 µg doses of ALZ‑101 with partial blinding of original allocation. An open‑label arm (Part A2) explored ALZ‑101 400 µg (n = 6) on the same schedule as Part A1. Primary endpoints were safety and tolerability. Secondary and exploratory endpoints included Aβ‑specific antibody responses, cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive/functional scales.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;ALZ-101 was not associated with any clear safety signals, and no serious adverse drug reactions were observed. Sixteen asymptomatic ARIA‑H events, including two superficial siderosis events, occurred in nine participants (two initially on placebo, six on 125 µg, one on 250 µg), and one asymptomatic ARIA‑E occurred in the extension phase in a participant originally randomised to placebo; no ARIA was observed in the 400 µg arm. ALZ‑101 induced robust Aβ‑specific IgG responses in nearly all vaccinated participants, with classical primary/booster kinetics and high responder rates at all dose levels. No statistically significant between‑group differences were detected for pre‑specified CSF biomarkers or cognitive and functional outcomes versus placebo in the randomised phase. Over longer follow‑up in Part B, participants initially randomised to ALZ‑101 showed numerically smaller increases in CSF neurofilament light chain (NfL) and tau and a flatter ADCOMS trajectory than those initially on placebo, but these differences were not statistically significant. For CSF tau, attenuation of the increase seemed to be present already in Part A1, whereas for the more slowly changing NfL, potential attenuation emerged only over the longer Part B.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;In this small Phase 1 study in early AD, ALZ‑101 was not associated with clear safety signals and elicited strong, durable Aβ‑specific antibody responses. Exploratory biomarker and ADCOMS findings are compat","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13545801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969670","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":"TNF inhibition differentially impacts regional Abeta immunotherapy efficacy in the humanized hAb^SAA mouse model.","authors":"Katelynn E Krick, Jessica L Chalk, Joshua T Lykins, Hsin-Pei Wang, Chloe A Ferguson, Syed Salman Shahid, Erica M Weekman, Donna M Wilcock","doi":"10.1186/s13195-026-02084-7","DOIUrl":"10.1186/s13195-026-02084-7","url":null,"abstract":"<p><strong>Background: </strong>The FDA approval of amyloid beta (Aβ) targeting immunotherapies offered the first opportunity to clinically modify Alzheimer's disease progression and give patients back precious months in the course of disease progression. The administration of these therapeutics has uncovered a common side effect called Amyloid Related Imaging Abnormalities (ARIA). While often asymptomatic, these adverse events have potential to escalate, and their commonality has encouraged further studies to mitigate their incidence. Increases in immune activation are important in immunotherapy action, though heightened release of cytokines have also been shown in ARIA development. TNF has been shown in early studies to increase with immunotherapy administration and subsequent ARIA development and TNF itself has been implicated in blood brain barrier dysfunction which could contribute to hemorrhagic ARIA (ARIA-H) development.</p><p><strong>Methods: </strong>This study assessed hemorrhage outcomes in an aged mouse model using MRI and Prussian blue histology, explored transcriptomic and protein changes with NanoString nCounter and Meso Scale Discovery, and we performed immunohistochemical stains for microglia/macrophages, astrocytes, and pericyte changes.</p><p><strong>Results: </strong>In this study, we established ARIA-H pathology in a humanized mouse model (hAβ^SAA) via chronic Aβ immunotherapy administration. We saw significant hemorrhagic lesions in our model, despite low levels of cortical cerebral amyloid angiopathy (CAA) suggesting a role for CAA as a risk factor for ARIA but potentially not its driver. We also explored the role of TNF in ARIA progression by inhibiting soluble TNF alongside immunotherapy administration as a potential combination therapeutic to address ARIA. With TNF inhibition, we saw a reduction of hemorrhages in the hippocampus, but not in the cortex, suggesting a regional effect. Further, we saw additional regional differences between the cortex and hippocampus with TNF inhibition including macrophage activation markers and amyloid levels, suggesting a differential role for TNF signaling in these areas and a potential heterogeneity of cellular responses in each region.</p><p><strong>Conclusion: </strong>We induced ARIA without significant cortical CAA pathology and identified regional differences with TNF inhibition including a potential benefit of treatment in the hippocampus and possible detriment to pathology in the cortex.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13360540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969640","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":"Willingness and barriers to blood-based biomarker testing of Alzheimer's disease in the general population in the Czech Republic.","authors":"Eva Skácelíková, Martin Vyhnálek, Filip Děchtěrenko, Tomáš Nikolai, Kateřina Veverová","doi":"10.1186/s13195-026-02070-z","DOIUrl":"10.1186/s13195-026-02070-z","url":null,"abstract":"<p><strong>Background: </strong>Blood-based biomarkers (BBBM) for Alzheimer's disease (AD) are entering clinical practice with new clinical practice guidelines and the first FDA-approved blood test. Their implementation will depend not only on assay performance but also on public willingness, trust, and understanding of probabilistic results. We examined attitudes towards BBBM in the general population and psychosocial factors that may facilitate or hinder uptake.</p><p><strong>Methods: </strong>We conducted an online cross-sectional survey among adults aged ≥ 35 years (M = 51.08, SD = 9.79) in the Czech Republic (N = 666). The survey assessed willingness to undergo BBBM testing, sociodemographic characteristics, experience with AD, depressive symptoms (Patient Health Questionnaire, PHQ-9), concerns about developing AD, and medical distrust (Medical Distrust Index, MDI). Logistic regression models (unweighted and weighted for gender and region) were estimated to examine the association with willingness. Open-ended responses were analyzed thematically to identify motivators and barriers.</p><p><strong>Results: </strong>Overall, 92.8% of participants reported that they would undergo BBBM testing. Greater concern about developing AD was the strongest facilitator (OR = 1.59-2.34). Having AD in a close family member was associated with lower willingness (OR = 0.31-0.43), as was higher medical distrust (MDI OR = 0.79 in the fully weighted model). Education, age, gender, depressive symptoms, and AD knowledge were not significantly associated with willingness. Qualitative analyses showed that participants viewed BBBM as a way to \"take action in time\", \"know one's health status\" and \"prepare for the future\", whereas fear of AD, preference \"not to know\", perceived lack of treatment, test uncertainty/\"only probability\", and privacy concerns were common barriers.</p><p><strong>Conclusions: </strong>Public willingness to undergo BBBM testing is high, but psychosocial barriers, particularly familial experience of AD and medical distrust, may limit real-world uptake. Addressing these barriers through targeted education, probabilistic risk communication, and trusted primary-care pathways will be essential for the responsible implementation of BBBM in clinical practice.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13359417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969579","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":"Plasma extracellular vesicle proteins biomarker for cerebral small vessel disease related cognitive impairment.","authors":"Dan Yang, Pinyi Liu, Mengxi Han, Zhihong Ke, Yi Tan, Linjie Yu, Zheqi Hu, Chenglu Mao, Yue Cheng, Hao Zhang, Yun Zhang, Xiaolei Zhu, Yun Xu","doi":"10.1186/s13195-026-02078-5","DOIUrl":"10.1186/s13195-026-02078-5","url":null,"abstract":"<p><strong>Background: </strong>Cerebral small vessel disease (CSVD) is a major contributor to vascular dementia. Given the absence of effective treatments, the development of blood-based biomarkers for early diagnosis and prediction is paramount to facilitate targeted clinical interventions. We aimed to identified blood-based extracellular vesicle (EV) biomarkers for screening CSVD with normal cognition (CSVD-NC) or cognitive impairment (CSVD-CI), and predicting disease progression.</p><p><strong>Methods: </strong>We conducted a multi-center cross-sectional and longitudinal study involving patients with CSVD-NC and CSVD-CI, healthy controls (HCs), and patients with CI due to Alzheimer's disease (AD-CI). Plasma EV proteomics were profiled using LC-MS/MS in a discovery set. Candidate EV biomarkers identified in this phase were subsequently validated in a larger independent set using parallel reaction monitoring. Machine learning was applied to develop and optimize diagnostic combinations for identifying CSVD and predicting disease progression.</p><p><strong>Results: </strong>Plasma EV proteins exhibiting progressive changes during CSVD progression were predominantly enriched in immune-inflammatory and ribosomal dysfunction. Three plasma EV proteins (ATP6V1F, HNRNPU, and RPL38) demonstrated robust, cross-dataset consistency from HC to CSVD-NC to CSVD-CI continuum, and displayed distinct expression patterns between CSVD-CI and AD-CI (P < 0.001). These EV biomarkers demonstrated high diagnostic accuracy for CSVD with or without CI (AUC = 0.849-0.897), and effectively stratified high-risk versus low-risk populations for CSVD cognitive progression (P = 0.005). Moreover, they were associated with CSVD-related structural injury and specific cognitive functions: EV ATP6V1F with hippocampal atrophy, language, and memory; EV RPL38 with WMH burden and white matter integrity; and EV HNRNPU with visuospatial function and executive function.</p><p><strong>Conclusion: </strong>The identified plasma EV biomarkers reliably reflect CSVD-related vascular injury and cognitive decline, and hold promise as minimally invasive tools for early screening and risk stratification of CSVD-related CI, especially in community settings.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13343569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925571","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}