Alzheimer's & Dementia最新文献

{"title":"Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum: Evidence across two independent cohorts","authors":"Raffaele Cacciaglia,&nbsp;Carles Falcón,&nbsp;Gonzalo Sánchez Benavides,&nbsp;Anna Brugulat-Serrat,&nbsp;Marta Milà Alomà,&nbsp;Marc Suárez Calvet,&nbsp;José Luis Molinuevo,&nbsp;Karine Fauria,&nbsp;Carolina Minguillón,&nbsp;Gwendlyn Kollmorgen,&nbsp;Clara Quijano-Rubio,&nbsp;Kaj Blennow,&nbsp;Henrik Zetterberg,&nbsp;Luigi Lorenzini,&nbsp;Alle Meije Wink,&nbsp;Silvia Ingala,&nbsp;Frederik Barkhof,&nbsp;Craig W. Ritchie,&nbsp;Juan Domingo Gispert,&nbsp;for the ALFA study","doi":"10.1002/alz.14415","DOIUrl":"10.1002/alz.14415","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Identifying the link between early Alzheimer's disease (AD) pathological changes and neurodegeneration in asymptomatic individuals may lead to the discovery of preventive strategies. We assessed longitudinal brain atrophy and cognitive decline as a function of cerebrospinal fluid (CSF) AD biomarkers in two independent cohorts of cognitively unimpaired (CU) individuals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We used longitudinal voxel-based morphometry (VBM) in combination with hippocampal subfield segmentation. Changes in neuroimaging and cognitive variables were inspected using general linear models (GLMs) adjusting by age, sex, apolipoprotein E (<i>APOE)</i> status, follow-up time, and years of education.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>In both cohorts, baseline CSF amyloid beta (Aβ) biomarkers significantly predicted medial temporal lobe (MTL) atrophy rates and episodic memory (EM) decline independently of CSF phosphorylated tau (p-tau).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our data suggest that soluble Aβ dyshomeostasis triggers MTL longitudinal atrophy and EM decline independently of CSF p-tau. Our data underscore the need for secondary preventive strategies at the earliest stages of the AD pathological cascade.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>We assessed brain atrophy and cognitive decline in asymptomatic individuals.</li>\u0000 \u0000 <li>Aβ biomarkers predicted MTL atrophy independently of p-tau.</li>\u0000 \u0000 <li>Our results underscore the importance of undertaking Alzheimer's preclinical trials.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14415","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078409","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":"Dual sensory impairment: Global prevalence, future projections, and its association with cognitive decline","authors":"Brian Sheng Yep Yeo,&nbsp;Esther Yanxin Gao,&nbsp;Benjamin Kye Jyn Tan,&nbsp;Benedict Ding Chao Ong,&nbsp;Ryan Wei Yang Cho,&nbsp;Chee Yit Lim,&nbsp;Ryan Eyn Kidd Man,&nbsp;Eva K. Fenwick,&nbsp;Preeti Gupta,&nbsp;Christopher Li-Hsian Chen,&nbsp;Samuel Teong Huang Chew,&nbsp;Neville Wei Yang Teo,&nbsp;Song Tar Toh,&nbsp;Jia Hui Ng,&nbsp;Vanessa Yee Jueen Tan,&nbsp;Ecosse L. Lamoureux","doi":"10.1002/alz.14465","DOIUrl":"10.1002/alz.14465","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>There is rising public health concern surrounding dual sensory impairment (DSI), or comorbid hearing and vision impairments. Its global prevalence and the magnitude of its association with cognitive decline (CD) is unclear. Three databases were searched for epidemiological studies examining DSI prevalence or its association with CD. Independent reviewers selected studies, extracted data, and evaluated bias. Random-effects meta-analyses were performed. Projections were estimated using United Nations data. The population attributable fraction of DSI-associated CD was calculated. Among 43 studies with 5,246,796 participants, clinically assessed DSI prevalence was 5.50% (95% confidence interval [CI] = 2.88%–10.26%), with regional/ethnic/age variations. DSI prevalence is projected to increase by 27.2% from 2025 to 2050. Approximately 59.83% (95%CI = 41.03–76.12) of DSI patients had cognitive impairment. Baseline DSI was associated with incident CD (odds ratio [OR] = 1.72, 95%CI = 1.37–2.15). Globally, 3.81% (95%CI = 1.05–10.55) of incident CD may be attributed to DSI. DSI is globally prevalent, growing, and associated with CD, highlighting the need for better health policy and resource allocation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The global prevalence of DSI is 5.50%, with geographical, ethnical and age variations.</li>\u0000 \u0000 <li>The prevalence of DSI rises with age and is projected to increase by 27.2% by 2050.</li>\u0000 \u0000 <li>Approximately 60% of individuals with DSI may have measurable cognitive impairment.</li>\u0000 \u0000 <li>DSI was associated with a 72% greater longitudinal risk of incident CD.</li>\u0000 \u0000 <li>Globally, 3.81% of CD cases may be attributable to DSI.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14465","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056544","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":"Hippocampal neuronal loss and cognitive decline in LATE-NC and ADNC among community-dwelling older persons","authors":"Sonal Agrawal,&nbsp;Lei Yu,&nbsp;Sue E. Leurgans,&nbsp;Sukriti Nag,&nbsp;Lisa L Barnes,&nbsp;David A Bennett,&nbsp;Julie A Schneider","doi":"10.1002/alz.14500","DOIUrl":"10.1002/alz.14500","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>This study investigates the inter-related roles of hippocampal neuronal loss (HNL), limbic-predominant age-related TAR-DNA binding protein of 43 kDa (TDP-43) encephalopathy neuropathologic changes (LATE-NC), and Alzheimer's disease neuropathologic changes (ADNC) on cognitive decline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Participants underwent annual cognitive testing and autopsy. HNL, ADNC, LATE-NC, and other age-related pathologies were evaluated. Regression and mixed-effects models examined the association of HNL with ADNC and LATE-NC, and separately with cognitive decline. Path analyses examined the extent to which associations of LATE-NC and ADNC with cognitive decline were attributable to HNL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>LATE-NC was associated with more severe HNL, but ADNC was associated only after excluding subjects with hippocampal sclerosis (HS). HNL was associated with faster decline in global cognition and episodic, semantic, and working memory. In path analyses, about 61% of the association of LATE-NC with cognitive decline was attributable to HNL, whereas for ADNC it was mostly independent of HNL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>HNL has an independent contribution to cognitive decline and acts as a major step in LATE-NC-related cognitive decline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Hippocampal neuronal loss (HNL) is associated with cognitive decline.</li>\u0000 \u0000 <li>HNL is a prominent feature of limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) and less so with Alzheimer's disease neuropathologic changes (ADNC).</li>\u0000 \u0000 <li>HNL acts as a major pathway in cognitive decline for LATE-NC.</li>\u0000 \u0000 <li>Differential mechanisms in hippocampal degeneration are associated with LATE-NC versus ADNC.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14500","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056503","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 and p-tau217/Aβ1-42 are effective biomarkers for identifying CSF- and PET imaging-diagnosed Alzheimer's disease: Insights for research and clinical practice","authors":"Xiaomei Zhong,&nbsp;Qiang Wang,&nbsp;Mingfeng Yang,&nbsp;Gaohong Lin,&nbsp;Kexin Yao,&nbsp;Zhangying Wu,&nbsp;Danyan Xu,&nbsp;Huarong Zhou,&nbsp;Ben Chen,&nbsp;Haishan Shi,&nbsp;Min Zhang,&nbsp;Xiaolei Shi,&nbsp;Yijie Zeng,&nbsp;Jingyi Lao,&nbsp;Shuang Liang,&nbsp;JiaFu Li,&nbsp;Qin Liu,&nbsp;Huanmin Liu,&nbsp;Yunheng Chen,&nbsp;Yicheng Lin,&nbsp;Cong Ouyang,&nbsp;Jieqin Lv,&nbsp;Xiang Liang,&nbsp;Yuwang Cheng,&nbsp;Pengcheng Ran,&nbsp;Baoying Gong,&nbsp;Bin Zhang,&nbsp;Jianwen Guo,&nbsp;Hong Zhang,&nbsp;Sen Liu,&nbsp;Jihui Zhang,&nbsp;Haiying Liu,&nbsp;Yuping Ning","doi":"10.1002/alz.14536","DOIUrl":"10.1002/alz.14536","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;With the advancement of disease-modifying therapies for Alzheimer's disease (AD), validating plasma biomarkers against cerebrospinal fluid (CSF) and positron emission tomography (PET) standards is crucial in both research and real-world settings.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We measured plasma phosphorylated tau (p-tau)217, p-tau181, amyloid beta (Aβ)1-40, Aβ1-42, and neurofilament light chain in research and real-world cohorts. Participants were categorized by brain amyloid status using US Food and Drug Administration/European Medicines Agency–approved CSF or PET methods.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Plasma p-tau217 and p-tau217/Aβ1-42 demonstrated superior accuracy in detecting brain amyloid pathologies, with area under the curve from 0.94 to 0.97 in all cohorts. Specificity was lower in the real-world cohort but improved significantly by integrating demographic and clinical factors, aligning performance with research cohorts. Additionally, plasma biomarkers exhibited strong correlations with their CSF counterparts and PET standardized uptake value ratios, with significant associations in amyloid-positive participants.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Plasma p-tau217 and p-tau217/Aβ1-42 are effective diagnostic tools. However, patient demographics, apolipoprotein E ε4 status, and cognitive condition must be considered to improve specificity in the clinical practice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Plasma phosphorylated tau (p-tau)217 and p-tau217/amyloid beta (Aβ)1-42 demonstrated exceptional accuracy (area under the curve: 0.94–0.97) in detecting brain amyloid pathologies across both research (Southern China Aging Brain Initiative [SCABI]-1, SCABI-2) and real-world clinical practice (RCP) cohorts.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Incorporating patient-specific factors (sex, age, apolipoprotein E ε4, cognitive status) improved diagnostic specificity in the clinical RCP cohort, aligning its performance with that of research cohorts.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Plasma biomarkers, particularly p-tau217 and their ratios, showed robust correlations with cerebrospinal fluid biomarkers and positron emission tomography amyloid standardized uptake value ratios, underscoring their value as non-invasive diagnostic alternatives.&lt;/li&gt;\u0000 ","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14536","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056294","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":"Biomarker treatment effects in two phase 3 trials of gantenerumab","authors":"Tobias Bittner,&nbsp;Matteo Tonietto,&nbsp;Gregory Klein,&nbsp;Anton Belusov,&nbsp;Vittorio Illiano,&nbsp;Nicola Voyle,&nbsp;Paul Delmar,&nbsp;Marzia A. Scelsi,&nbsp;Susanna Gobbi,&nbsp;Erica Silvestri,&nbsp;Muhamed Barakovic,&nbsp;Antonio Napolitano,&nbsp;Christopher Galli,&nbsp;Maryam Abaei,&nbsp;Kaj Blennow,&nbsp;Frederik Barkhof","doi":"10.1002/alz.14414","DOIUrl":"10.1002/alz.14414","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We report biomarker treatment effects in the GRADUATE I and II phase 3 studies of gantenerumab in early Alzheimer's disease (AD).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Amyloid and tau positron emission tomography (PET), volumetric magnetic resonance imaging (vMRI), cerebrospinal fluid (CSF), and plasma biomarkers used to assess gantenerumab treatment related changes on neuropathology, neurodegeneration, and neuroinflammation over 116 weeks.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Gantenerumab reduced amyloid PET load, CSF biomarkers of amyloid beta (Aβ)40, total tau (t-tau), phosphorylated tau 181 (p-tau181), neurogranin, S100 calcium-binding protein B (S100B), neurofilament light (NfL), alpha-synuclein (α-syn), neuronal pentraxin-2 (NPTX2), and plasma biomarkers of t-tau, p-tau181, p-tau217, and glial fibrillary acidic protein (GFAP) while increasing plasma Aβ40, Aβ42. vMRI showed increased reduction in whole brain volume and increased ventricular expansion, while hippocampal volume was unaffected. Tau PET showed no treatment effect.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Robust treatment effects were observed for multiple biomarkers in GRADUATE I and II. Comparison across anti-amyloid antibodies indicates utility of p-tau and GFAP as biomarkers of amyloid plaque removal while NfL and tau PET seem unsuitable as consistent indicators of clinical efficacy. vMRI might be confounded by non-neurodegenerative brain volume changes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;p&gt;&lt;b&gt;TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV IDENTIFIER)&lt;/b&gt;:&lt;/p&gt;\u0000 \u0000 &lt;p&gt;NCT03444870 and NCT03443973.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Gantenerumab significantly reduced brain amyloid load.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Tau positron emission tomography showed no treatment effect in a small subset of participants.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Volumetric magnetic resonance imaging showed increased whole brain volume reduction under treatment while hippocampal volume was unaffected.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Robust treatment effects on cerebrospinal fluid and plasma biomarkers were found, despite lack of clinical efficacy.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 &lt;/div&gt;\u0000 ","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14414","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056958","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":"Predicting conversion in cognitively normal and mild cognitive impairment individuals with machine learning: Is the CSF status still relevant?","authors":"Mirella Russo,&nbsp;Davide Nardini,&nbsp;Sara Melchiorre,&nbsp;Consuelo Ciprietti,&nbsp;Gaetano Polito,&nbsp;Miriam Punzi,&nbsp;Fedele Dono,&nbsp;Matteo Santilli,&nbsp;Astrid Thomas,&nbsp;Stefano L. Sensi,&nbsp;the Alzheimer's Disease Neuroimaging Initiative","doi":"10.1002/alz.14398","DOIUrl":"10.1002/alz.14398","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Machine learning (ML) helps diagnose the mild cognitive impairment–Alzheimer's disease (MCI-AD) spectrum. However, ML is fed with data unavailable in standard clinical practice. Thus, we tested a novel multi-step ML approach to predict cognitive worsening.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We selected cognitively normal and MCI participants from the Alzheimer's Disease Neuroimaging Initiative dataset and categorized them on total tau/amyloid beta 1-42 ratios. ML was applied to predict the 3-year conversion with standard clinical data (SCD), assess the model's accuracy, and identify the role of cerebrospinal fluid (CSF) biomarkers in this approach. Shapley Additive Explanations (SHAP) analysis was carried out to explore the automated decisional process.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The model achieved 84% accuracy across the entire cohort, 86% in patients with negative CSF, and 88% in individuals with AD-like CSF. SHAP analysis identified differences between CSF-positive and -negative patients in predictors of conversion and cut-offs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> CONCLUSIONS</h3>\u0000 \u0000 <p>The approach yielded good prediction accuracy using SCD. However, CSF-based categorizations are needed to improve predictive accuracy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Machine learning algorithms can predict cognitive decline with standard and routinely used clinical data.</li>\u0000 \u0000 <li>Classification according to cerebrospinal fluid biomarkers enhances prediction accuracy.</li>\u0000 \u0000 <li>Different cut-offs could be applied to neuropsychological tests to predict conversion.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14398","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056501","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":"Cranial bone maneuver ameliorates Alzheimer's disease pathology via enhancing meningeal lymphatic drainage function","authors":"Xuan Lu,&nbsp;Shanshan Bai,&nbsp;Lu Feng,&nbsp;Xu Yan,&nbsp;Yuejun Lin,&nbsp;Junzhe Huang,&nbsp;Xulin Liao,&nbsp;Haixing Wang,&nbsp;Linlong Li,&nbsp;Zhengmeng Yang,&nbsp;Leo Yik Chun Yan,&nbsp;Boguang Yang,&nbsp;Ming Wang,&nbsp;Jiakang Jin,&nbsp;Zhixian Zong,&nbsp;Zhaowei Jiang,&nbsp;Chuiguo Huang,&nbsp;Chaoran Liu,&nbsp;Xiaoting Zhang,&nbsp;Han Su,&nbsp;Yaofeng Wang,&nbsp;Wayne Yuk-Wai Lee,&nbsp;Xiaohua Jiang,&nbsp;Micky D. Tortorella,&nbsp;Sien Lin,&nbsp;Ho Ko,&nbsp;Gang Li","doi":"10.1002/alz.14518","DOIUrl":"10.1002/alz.14518","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia. Recent research highlights meningeal lymphatics as key regulators in neurological diseases, suggesting that enhancing their drainage function could be a potential therapeutic strategy for AD. Our proof-of-concept study demonstrated that cranial bone transport can improve meningeal lymphatic drainage function and promote ischemic stroke recovery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>This study defined cranial bone maneuver (CBM) technique. After osteotomy, a small circular bone flap was made and attached to an external fixator for subsequent maneuver in a controlled fashion for a defined period using 5xFAD mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>CBM treatment improved memory functions, reduced amyloid deposits, and promoted meningeal lymphatic drainage function. CBM induced cascades of inflammatory and lymphangiogenic processes in skull and meninges. Meningeal lymphatics are indispensable elements for the therapeutic effects of CBM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>CBM might be a promising innovative therapy for AD management, warranting further clinical investigation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Cranial bone maneuver (CBM) alleviated memory deficits and amyloid depositions.</li>\u0000 \u0000 <li>CBM promoted meningeal lymphangiogenesis and lymphatic drainage function.</li>\u0000 \u0000 <li>The beneficial effects of CBM lasted for a long time following the CBM procedures.</li>\u0000 \u0000 <li>CBM induced cascades of inflammatory and lymphangiogenic processes in the meninges.</li>\u0000 \u0000 <li>Meningeal lymphatic vessels are indispensable elements for CBM therapeutic effects.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14518","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056504","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 proteomic characterization of motoric cognitive risk and mild cognitive impairment","authors":"Gabriela T. Gomez,&nbsp;Sanish Sathyan,&nbsp;Jingsha Chen,&nbsp;Myriam Fornage,&nbsp;Pascal Schlosser,&nbsp;Zhongsheng Peng,&nbsp;Jenifer Cordon,&nbsp;Priya Palta,&nbsp;Kevin J. Sullivan,&nbsp;Adrienne Tin,&nbsp;B. Gwen Windham,&nbsp;Rebecca F. Gottesman,&nbsp;Nir Barzilai,&nbsp;Sofiya Milman,&nbsp;Joe Verghese,&nbsp;Josef Coresh,&nbsp;Keenan A. Walker","doi":"10.1002/alz.14429","DOIUrl":"10.1002/alz.14429","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by mobility and cognitive dysfunction. This study conducted a proteome-wide study of MCR and compared the proteomic signatures of MCR to that of mild cognitive impairment (MCI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Participants were classified as MCR using a memory questionnaire and 4-meter walk. We measured 4877 plasma proteins collected during late-life and midlife. Multivariable logistic regression related each protein to late-life MCR/MCI. MCR-associated proteins were replicated internally at midlife and in an external cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Proteome-wide analysis (<i>n</i> = 4076) identified 25 MCR-associated proteins. Eight of these proteins remained associated with late-life MCR when measured during midlife. Two proteins (SVEP1 and TAGLN) were externally replicated. Compared to MCI, MCR had a distinct and much stronger proteomic signature enriched for cardiometabolic and immune pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our findings highlight the divergent biology underlying two pre-dementia syndromes. Metabolic and immune dysfunction may be a primary driver of MCR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>MCR is defined by concurrent cognitive and gait dysfunction.</li>\u0000 \u0000 <li>MCR protein biomarkers have key roles in cardiometabolic and vascular function.</li>\u0000 \u0000 <li>MCR biomarkers are also associated with cerebrovascular disease and dementia.</li>\u0000 \u0000 <li>MCR and MCI demonstrate overlapping but divergent proteomic signatures.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14429","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056749","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":"Variability of cognitive changes after donanemab treatment","authors":"Roger A. L. Dampney","doi":"10.1002/alz.14576","DOIUrl":"10.1002/alz.14576","url":null,"abstract":"&lt;p&gt;To The Editor&lt;/p&gt;&lt;p&gt;In an article in this journal published recently,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Drs. Daly, Kepp, and Imbimbo discussed the question as to whether the anti-amyloid beta monoclonal antibodies lecanemab and donanemab effectively modify the natural history of disease in patients with early Alzheimer's disease (AD). Based on their analysis of results obtained from two large clinical trials of these drugs carried out over an 18 -month period,&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; Daly, Kepp, and Imbimbo concluded that there is not yet strong evidence for claiming a modification of the natural history of the disease by these drugs. In particular, they point out that while both drugs greatly reduced brain amyloid plaques in patients with AD as well as led to statistically significant reductions in the rate of cognitive decline in patients treated with the drugs compared to the placebo group, these clinical benefits were modest. Furthermore, both drugs are associated with significant adverse effects. In particular, donanemab was associated with increased risks of amyloid-related imaging abnormalities and brain volume loss.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;A further question concerning the results of these clinical trials is the degree of individual variability in the observed changes in cognition in patients treated with either drug or placebo. In the case of the study by Sims et al.,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; the integrated Alzheimer's Disease Rating Scale (iADRS) score after 76 weeks of donanemab treatment decreased by a mean of 10.2 units in the 583 patients who completed the trial, with 95% confidence limits of 11.22 and 9.16. Given that 95% confidence limits are close to ± 2 standard errors of the mean (SEM), the SEM for this group is calculated as 0.53. Further, given an &lt;i&gt;n&lt;/i&gt; value of 583, the standard deviation (SD) is 12.69 (as calculated from the formula SEM = SD divided by the square root of &lt;i&gt;n&lt;/i&gt;). In the placebo group, the iADRS score after 76 weeks decreased by a mean of 13.1, with 95% confidence limits of 14.10 and 12.13. There were 653 patients in this group. By the same method as above, the SD for the placebo group is calculated as 12.84. As shown in Figure 1A, there is considerable overlap between the donanemab and placebo groups in the change in iADRS score after 76 weeks.&lt;/p&gt;&lt;p&gt;Given that the iADRS is a combination of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog, which itself is the sum of several components) and the Alzheimer's Disease Cooperative Study–instrumental Activities of Daily Living (ADCS-iADL), it is reasonable to assume that the change in iADRS is normally distributed. Based on this assumption, the distribution of this variate for the donanemab group would be as shown in Figure 1B (mean value −10.2, SD 12.69). The mean score for the placebo group (−13.1) is also shown in Figure 1B. From the properties of the normal distribution, it follows that 59.0% of patients in the donanemab group","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14576","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055311","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":"APP antisense oligonucleotides are effective in rescuing mitochondrial phenotypes in human iPSC-derived trisomy 21 astrocytes","authors":"Srishruthi Thirumalai,&nbsp;Frederick J. Livesey,&nbsp;Rickie Patani,&nbsp;Christy Hung","doi":"10.1002/alz.14560","DOIUrl":"10.1002/alz.14560","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Antisense oligonucleotides (ASOs) have shown promise in reducing amyloid precursor protein (APP) levels in neurons, but their effects in astrocytes, key contributors to neurodegenerative diseases, remain unclear. This study evaluates the efficacy of APP ASOs in astrocytes derived from an individual with Down syndrome (DS), a population at high risk for Alzheimer's disease (AD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Human induced pluripotent stem cells (hiPSCs) from a healthy individual and an individual with DS were differentiated into astrocytes. Astrocytes were treated with APP ASOs for 10 days, and APP levels were quantified. Mitochondrial morphology and superoxide production in DS astrocytes were analyzed using super-resolution and confocal microscopy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>APP ASOs significantly reduced APP levels in astrocytes from both control and DS individuals. In DS astrocytes, treatment restored mitochondrial health, increasing mitochondrial number and size while reducing superoxide production.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>APP ASOs effectively reduce APP levels and improve mitochondrial health in astrocytes, suggesting their potential as a therapeutic approach for DS and DS-related AD. Further in vivo studies are required to confirm these findings.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>APP ASOs reduce APP levels in human iPSC-derived astrocytes.</li>\u0000 \u0000 <li>APP ASO treatment rescues mitochondrial phenotypes in trisomy 21 astrocytes.</li>\u0000 \u0000 <li>This study supports ASOs as a potential therapy for Down syndrome-related Alzheimer's disease.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14560","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055306","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}