Alzheimer's Research & Therapy最新文献

{"title":"Deuteration may reduce the efficacy of dextromethorphan in treating agitation in Alzheimer's disease.","authors":"Anton Bespalov, Jina Swartz, Nadine Knowles, Hans J Moebius","doi":"10.1186/s13195-025-01780-0","DOIUrl":"10.1186/s13195-025-01780-0","url":null,"abstract":"<p><p>Agitation is one of the most prevalent neuropsychiatric symptoms leading to institutionalization in individuals with Alzheimer's disease (AD) dementia. It is associated with poor outcomes, including reduced functional ability, reduced quality of life, accelerated disease progression, increased mortality, and significant economic burden. Following an initial report demonstrating the strong efficacy of a combination of dextromethorphan and the CYP2D6 inhibitor quinidine, several follow-up development efforts have explored this approach. Axsome Therapeutics has reported positive results in three out of four clinical trials evaluating AXS-05, a combination of dextromethorphan with another CYP2D6 inhibitor, bupropion. In contrast, Otsuka's AVP-786, a combination of deuterated dextromethorphan and quinidine, has yielded predominantly negative results. It is widely believed that deuteration alters a molecule's pharmacokinetic properties without affecting its pharmacodynamics. However, in our patch-clamp experiments, deuteration resulted in a 16-fold increase in IC50 for dextrorphan and about two-fold increase for dextromethorphan at NMDA receptors containing the NR2D subunit. Thus, based on both clinical data and emerging pharmacological evidence, we hypothesize that AVP-786 failed to demonstrate efficacy in treating agitation in AD dementia due to the negative impact of deuteration on dextromethorphan's pharmacodynamic properties.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"133"},"PeriodicalIF":7.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257103","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":"AP2A1 activates Rab7 to promote axonal autophagosome transport and slow the progression of Alzheimer's disease.","authors":"Yangyang Wang, Siyu Li, Xiao Liang, Jianing Fan, Shijie Li, Fanlin Zhou, Xiaoju Li, Mengmeng Lai, Dianmao Feng, Yu Li","doi":"10.1186/s13195-025-01771-1","DOIUrl":"10.1186/s13195-025-01771-1","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"132"},"PeriodicalIF":7.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12147321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257102","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 biomarkers for early detection of alzheimer's disease: a cross-sectional study in a Japanese cohort.","authors":"Masahito Kubota, Shogyoku Bun, Keisuke Takahata, Shin Kurose, Yuki Momota, Yu Iwabuchi, Toshiki Tezuka, Hajime Tabuchi, Morinobu Seki, Yasuharu Yamamoto, Ryo Shikimoto, Yu Mimura, Takayuki Hoshino, Sho Shimohama, Natsumi Suzuki, Ayaka Morimoto, Azusa Oosumi, Yuka Hoshino, Kenji Tai, Hirofumi Aoyagi, Yoshiaki Sato, Junro Kuromitsu, Jin Nakahara, Masaru Mimura, Daisuke Ito","doi":"10.1186/s13195-025-01778-8","DOIUrl":"10.1186/s13195-025-01778-8","url":null,"abstract":"<p><strong>Background: </strong>Plasma biomarkers offer a promising alternative to amyloid beta (Aβ) positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers for diagnosing Alzheimer's disease (AD). This cross-sectional study assessed the utility of multiple plasma biomarkers for diagnosing and staging AD in a Japanese cohort.</p><p><strong>Methods: </strong>The assessed plasma biomarkers included Aβ42/40, phosphorylated tau (p-tau181 and p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), individually and in combination. Aβ42/40 was measured using the HISCL^® platform, while all other biomarkers were measured using the Simoa^® platform. Participants were classified based on Aβ PET imaging and neuropsychological testing into healthy controls (HC), AD continuum (preclinical AD, mild cognitive impairment [AD-MCI], and mild dementia [AD-D]), and non-AD cognitive impairment (CI) groups. Receiver operating characteristic analyses were performed to predict the Aβ PET status, correlation with Centiloid (CL) values and cognitive scores, and biomarker comparisons across AD stages.</p><p><strong>Results: </strong>Sixty-nine HC, 13 preclinical AD, 38 AD-MCI, 44 AD-D, and 79 non-AD CI participants were included. The area under the curves (AUCs) for predicting Aβ PET status were 0.937 (Aβ42/40), 0.926 (p-tau217), and 0.946 (p-tau217/Aβ42); results of pair-wise DeLong tests revealed no significant differences among these three metrics (all p > 0.05). In the cognitively normal group, the AUCs were 0.968 (Aβ42/40), 0.958 (p-tau217), and 0.979 (p-tau217/Aβ42), while in the cognitively impaired group, they were 0.919 (Aβ42/40), 0.893 (p-tau217), and 0.923 (p-tau217/Aβ42). Among HC and AD continuum participants, CL correlations were - 0.74 (Aβ42/40), 0.81 (p-tau217), and 0.83 (p-tau217/Aβ42). In the HC and AD continuum, Aβ42/40 levels showed a bimodal distribution (cutoff = 0.096), with a shift from high to low occurring at 19.3 CL, compared to the PET positivity threshold of 32.9 CL. P-tau217 exhibited a linear increase with disease progression. All biomarkers correlated strongly with logical memory scores.</p><p><strong>Conclusions: </strong>Plasma biomarkers, Aβ42/40 and p-tau217, and particularly their ratio (p-tau217/Aβ42), show strong potential as Aβ PET alternatives for AD diagnosis. HISCL-based plasma Aβ42/40 detects Aβ accumulation earlier than Aβ PET visual reading threshold, underscoring its utility as an early diagnostic marker.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"131"},"PeriodicalIF":7.9,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245773","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":"Revisiting the therapeutic landscape of tauopathies: assessing the current pipeline and clinical trials.","authors":"Glenn A Harris, Lauren R Hirschfeld, M Isabel Gonzalez, Martyn C Pritchard, Patrick C May","doi":"10.1186/s13195-025-01775-x","DOIUrl":"10.1186/s13195-025-01775-x","url":null,"abstract":"<p><p>Microtubule associated protein tau (MAPT) is a naturally occurring protein that plays a significant role in stabilizing microtubules, which are essential for the transport of nutrients and other materials within neurons. In tauopathies, tau protein assembles into mis-folded multimers ranging from soluble oligomers to insoluble aggregates, known as neurofibrillary tangles, neuropil threads and are components of neuritic plaques. These abnormal tau assemblies collectively are thought to disrupt the normal function of neurons and lead to their death. Tauopathies are a leading cause of neurodegeneration, and there are no approved disease modifying therapies targeting the tau pathology for any tauopathy. This review is a two-year update to an initial review of preclinical, clinical, and recently discontinued therapeutic programs in development focused on ameliorating tau pathology. This review outlines the landscape of therapeutic drugs indexed through January 1, 2025. Currently, there are 170 drugs monitored in the pipeline, one less than in the previous period. In the clinic, there are five candidates in phase 3 trials, 15 in phase 2 trials, and 12 in phase 1 trials. In total, there are four less candidates in clinical trials during this review period than the last. New to this review is the inclusion of the clinical development of tau positron emission tomography (PET) ligands which undergo regulatory oversite. In addition to the one FDA-approved tau PET ligand Tauvid™ (flortaucipir), there are six additional tau PET ligands currently in active clinical trials.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"129"},"PeriodicalIF":7.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214645","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":"Potential role of Amyloid-β on the association between Orexin-A and blood-brain barrier leakage of globus pallidus in Alzheimer's disease and dementia with lewy bodies.","authors":"Jinghuan Gan, Ziming Xu, Chen Wen, Hao Wu, Zhichao Chen, Zhihong Shi, Hao Lu, Yajie Wang, Shuai Liu, Yong Ji","doi":"10.1186/s13195-025-01770-2","DOIUrl":"10.1186/s13195-025-01770-2","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence indicates that globus pallidus (GP) function can be modulated by orexin-A in movement disorders, while its role in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) remains unclear. We have ever found the increased blood-brain barrier (BBB) permeability in GP and plasma orexin-A level were respectively correlated with plasma amyloid-β (Aβ) levels in AD and DLB. However, the interplay among these factors and their underlying mechanisms is poorly understood.</p><p><strong>Methods: </strong>In this study, we measured plasma orexin-A, Aβ1-40, and Aβ1-42 levels, along with BBB permeability in GP via dynamic contrast-enhanced MRI, in 20 healthy controls (HC), 25 patients with AD, and 16 patients with DLB from December 2020 to April 2022. Demographic, clinical, and neuropsychological data were collected. The mediation analysis models were used to calculate the mediating effect of Aβ on the associations between orexin-A and BBB permeability in GP (reflected by K^trans or Vp values).</p><p><strong>Results: </strong>Patients with AD had significantly higher plasma orexin-A than DLB (p = 0.047) and HC (p < 0.001), while DLB showed elevated Aβ1-40 and Aβ1-42 versus AD and HC (all p < 0.05). HC had higher Vp values of right GP than AD (p = 0.037). Patients with AD displayed higher K^trans for left GP and average left-right K^trans than both HC and DLB (all p < 0.05). K^trans and Vp values for GP correlated with MoCA, CDR, HAMD, and NPI scores in patients with AD and DLB, and with plasma orexin-A, Aβ1-40, and Aβ1-42 in HC. After adjusting for confounders, Aβ1-40 (Beta = -0.864, p = 0.021) and Aβ1-42 (Beta = -0.875, p = 0.039) partially mediated the link between orexin-A and K^trans for left GP in HC. Aβ1-40 (Beta = -1.845, p = 0.042) partially mediated the link between orexin-A and K^trans for right GP in DLB. No significant mediation was found in AD or across all participants.</p><p><strong>Conclusion: </strong>This study elucidates the clinical role of BBB permeability in GP in AD and DLB, highlights the partial mediating effect of Aβ on the association between orexin-A and BBB leakage. These findings provide mechanistic insights into BBB dysfunction during aging and neurodegeneration.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"128"},"PeriodicalIF":7.9,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207381","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":"Hampered AMPK-ULK1 cascade in Alzheimer's disease (AD) instigates mitochondria dysfunctions and AD-related alterations which are alleviated by metformin.","authors":"Arnaud Mary, Samantha Barale, Fanny Eysert, Audrey Valverde, Sandra Lacas-Gervais, Charlotte Bauer, Sabiha Eddarkaoui, Luc Buée, Valérie Buée-Scherrer, Frédéric Checler, Mounia Chami","doi":"10.1186/s13195-025-01772-0","DOIUrl":"10.1186/s13195-025-01772-0","url":null,"abstract":"<p><p>The adenosine monophosphate-activated protein kinase (AMPK) and its downstream effector Unc-51 like autophagy activating kinase 1 (ULK1) represent a key cellular signaling node, the alteration of which likely contribute to AD development. This study investigated the AMPK-ULK1 pathway activation state in AD and the impact of its modulation on mitochondria structure and function as well as on AD-related alterations. We show in human sporadic AD and 3xTgAD mice brains a defective activating phosphorylation of ULK1 despite the active phosphorylation of AMPK. In addition, we reported defective p-AMPK and p-ULK1 in cells expressing the amyloid precursor protein with the familial Swedish mutation. We then show that the antidiabetic metformin (Met) drug-mediated AMPK-ULK1 cascade activation alleviates structural and functional mitochondrial abnormalities in AD cells and mice brains. Furthermore, in the 3xTgAD brains, it reduces the early accumulation of APP C-terminal fragments (APP-CTFs) as well as amyloid beta (Aβ) burden, microgliosis and astrogliosis occurring at a later disease stage. AMPK-ULK1 activation increases the localization of APP-CTFs within cathepsin D-positive lysosomal compartments and the recruitment of Iba1⁺ cells to Aβ plaques in vivo and enhances cathepsin D activity and phagocytic activity of microglia in vitro. Additionally, AMPK-ULK1 activation normalizes dendritic spine morphology in organotypic hippocampal slice cultures modeling AD and alleviates learning deficit in symptomatic 3xTgAD mice. Our study demonstrates potential therapeutic benefits of targeting AMPK-ULK1 cascade to reverse both early and late AD-related alterations, deserving further investigation in fundamental research and in human clinical studies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"127"},"PeriodicalIF":7.9,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207380","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":"Towards a national registry for Alzheimer's disease and related dementias: rationale, design, and initial observations of the ABOARD cohort.","authors":"Casper de Boer, Hanneke F M Rhodius-Meester, Sophie M van der Landen, Jurgen Claassen, Romy de Haan, Janne M Papma, Harro Seelaar, Marleen Kloppenburg-Lagendijk, Barbara van Munster, Marjolein de Vugt, Derk Arts, Marco Blom, Tanja J de Rijke, Miriam Beusink, Robbert Huijsman, Evert-Ben van Veen, Argonde van Harten, Jort Vijverberg, Marissa Zwan, Henk-Jan Mutsaerts, Sven J van der Lee, Wiesje M van der Flier","doi":"10.1186/s13195-025-01725-7","DOIUrl":"10.1186/s13195-025-01725-7","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease and related dementias (ADRD) take 20 to 30 years to develop, yet setting up studies or registries that take into account the entire disease trajectory is difficult and time consuming. Moreover, prediction models are often based on selected research populations and their outcomes may not be most relevant to patients' daily lives. To address these gaps we set up the ABOARD Cohort, a national data collection infrastructure to (i) study the disease trajectory using patient reported outcome measures (PROMs) and medical data, (ii) link to available data sources, and (iii) serve as central platform to facilitate research, roll out healthcare innovations, and accommodate nationwide disease registration. Here, we describe the design of the project and characteristics of the first 10,275 participants.</p><p><strong>Method: </strong>The ABOARD Cohort is an ongoing, participant-centered data-collection, taking PROMs and a minimal case report form (CRF) with relevant medical data as starting point, supplemented with linkage to existing data sources. Eligible participants with or at-risk of ADRD a and their study partners are recruited directly-to-participant, i.e. without the need for a doctor to sign informed consent. Informed consent and annual collection of PROMs are fully online. Relevant stakeholders are involved in decisions on project development through a participants panel and on data usage through a data access committee.</p><p><strong>Results: </strong>The ABOARD Cohort has been fully operational since January 2023. As of October 2024, 10,275 participants (mean age 66.1 (9.2) years, 70% female) and 1,383 study partners signed up, and received an invitation to fill in online questionnaires and complete a digital cognitive test. Over 90% of participants gave consent to link their data to existing data sources. Participants who had consulted a doctor for memory problems (N = 1,128), reported worse outcomes on PROMs assessing mental health and cognition, quality of life and lifestyle, compared to those who had not.</p><p><strong>Conclusion: </strong>The ABOARD Cohort has been set up as a national infrastructure to study ADRD disease trajectories, linking data-sources, with the participant at the steering wheel. This infrastructure has the potential to serve as a registry to advance research and roll out healthcare innovations on a national level.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"123"},"PeriodicalIF":7.9,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186230","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":"Digital twins and non-invasive recordings enable early diagnosis of Alzheimer's disease.","authors":"Lorenzo Gaetano Amato, Michael Lassi, Alberto Arturo Vergani, Jacopo Carpaneto, Salvatore Mazzeo, Valentina Moschini, Rachele Burali, Giovanni Salvestrini, Carlo Fabbiani, Giulia Giacomucci, Giulia Galdo, Carmen Morinelli, Filippo Emiliani, Maenia Scarpino, Sonia Padiglioni, Benedetta Nacmias, Sandro Sorbi, Antonello Grippo, Valentina Bessi, Alberto Mazzoni","doi":"10.1186/s13195-025-01765-z","DOIUrl":"10.1186/s13195-025-01765-z","url":null,"abstract":"<p><strong>Background: </strong>The diagnosis of Alzheimer's disease (AD) in its preclinical stages, such as subjective cognitive decline (SCD), is crucial for a timely management of the condition. However, current early diagnostic methods are unsuitable for preclinical screenings due to limited availability and diagnostic reliability. Additionally, reliance on invasive and scarcely available methods exacerbates the underdiagnosis of AD in its preclinical forms.</p><p><strong>Methods: </strong>We introduce an early diagnostic pipeline based on the Digital Alzheimer's Disease Diagnosis (DADD) digital twin model, which derives personalized AD biomarkers from non-invasive electroencephalographic (EEG) recordings. These biomarkers reconstruct patient-specific neurodegeneration, capturing synaptic and connectivity degeneration mechanisms. Digital biomarkers were used to predict cerebrospinal fluid (CSF) biomarker positivity for AD and clinical conversions at follow-up in 124 participants with varying degrees of cognitive decline, including a control group of 19 healthy subjects.</p><p><strong>Results: </strong>Digital biomarkers derived from the DADD model: i) Robustly distinguished SCD from healthy participants, improving classification accuracy by 7% compared to standard EEG biomarkers; ii) Identified patients positive for CSF biomarkers of AD with 88% accuracy (significantly outperforming standard EEG biomarkers, which achieved 58% accuracy); iii) Predicted follow-up conversions to clinical cognitive decline with 87% accuracy (compared to 54% accuracy for standard EEG biomarkers).</p><p><strong>Conclusions: </strong>The DADD model provided robust digital AD biomarkers with strong diagnostic and prognostic value for preclinical AD, enabling the prediction of CSF biomarkers and clinical conversions using only non-invasive EEG recordings. This is particularly important as preclinical patients, such as those with SCD, are often excluded from diagnostic procedures like lumbar puncture. Predicting CSF biomarkers by combining digital twins with non-invasive recordings could revolutionize AD diagnosis in its early stages, paving the way for the clinical application of digital twins in AD diagnostics.</p><p><strong>Trial registration: </strong>Clinical Trial identifier: NCT05569083 (submitted 2022-08-24).</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"125"},"PeriodicalIF":7.9,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations between platelet indices and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study.","authors":"Shi-Yin Xiong, Yong-Li Zhao, Yan Fu, Qiong-Yao Li, Quan Hao, Dan-Dan Zhang, Min Liu, Shan Yin, Lan-Yang Wang, Yong-Chang Wang, Shu-Dong Qiu, Zi-Qi Zhang, Lan Tan","doi":"10.1186/s13195-025-01755-1","DOIUrl":"10.1186/s13195-025-01755-1","url":null,"abstract":"<p><strong>Introduction: </strong>Although previous studies have shown that specific platelet indices had correlations with cognitive impairment, the associations between platelet indices and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology remain unclear.</p><p><strong>Methods: </strong>Our study included 1,047 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. The total participants had an average age of 58.33 years, a female proportion of 41.5% and average educational attainment of 9.58 years. Multiple linear regression models were used to analyze the associations of five platelet indices (plateletcrit [PCT], platelet count [PLT], mean platelet volume [MPV], platelet distribution width [PDW], and platelet large cell ratio [PLCR]) with CSF AD biomarkers after adjusting for age, gender, education and APOE ε4 allele status. Furthermore, the interactive, stratified and sensitivity analyses were further conducted to verify their relationships.</p><p><strong>Results: </strong>In the total participants, we found higher PCT levels were significantly correlated with higher CSF P-tau/Aβ42 (β = 0.102, P = 0.008) and T-tau/Aβ42 (β = 0.102, P = 0.008), as well as lower CSF Aβ42 (β = -0.089, P = 0.018) and Aβ42/Aβ40 (β = -0.093, P = 0.018). Moreover, other four platelet indices (PLT, MPV, PDW, PLCR) demonstrated moderate correlations with CSF AD biomarkers. The interaction analyses revealed that age affected the correlations between PCT and PLT with CSF Aβ42. Importantly, the associations between PCT and the aforementioned CSF AD biomarkers became more significant in the late-life group, but turned non-significant in the mid-life group. Besides, sensitivity analyses confirmed the robustness of our findings.</p><p><strong>Conclusions: </strong>Our study provided preliminary evidence suggesting potential associations between platelet indices (especially PCT) and CSF AD biomarkers in cognitively intact adults. Nonetheless, more studies are needed to further validate these findings.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"124"},"PeriodicalIF":7.9,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191269","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":"Deep-learning based multi-modal models for brain age, cognition and amyloid pathology prediction.","authors":"Chenxi Wang, Weiwei Zhang, Ming Ni, Qiong Wang, Chang Liu, Linbin Dai, Mengguo Zhang, Yong Shen, Feng Gao","doi":"10.1186/s13195-025-01773-z","DOIUrl":"10.1186/s13195-025-01773-z","url":null,"abstract":"<p><strong>Background: </strong>Magnetic resonance imaging (MRI), combined with artificial intelligence techniques, has improved our understanding of brain structural change and enabled the estimation of brain age. Neurodegenerative disorders, such as Alzheimer's disease (AD), have been linked to accelerated brain aging. In this study, we aimed to develop a deep-learning framework that processes and integrates MRI images to more accurately predict brain age, cognitive function, and amyloid pathology.</p><p><strong>Methods: </strong>In this study, we aimed to develop a deep-learning framework that processes and integrates MRI images to more accurately predict brain age, cognitive function, and amyloid pathology.We collected over 10,000 T1-weighted MRI scans from more than 7,000 individuals across six cohorts. We designed a multi-modal deep-learning framework that employs 3D convolutional neural networks to analyze MRI and additional neural networks to evaluate demographic data. Our initial model focused on predicting brain age, serving as a foundational model from which we developed separate models for cognition function and amyloid plaque prediction through transfer learning.</p><p><strong>Results: </strong>The brain age prediction model achieved the mean absolute error (MAE) for cognitive normal population in the ADNI (test) datasets of 3.302 years. The gap between predicted brain age and chronological age significantly increases while cognition declines. The cognition prediction model exhibited a root mean square error (RMSE) of 0.334 for the Clinical Dementia Rating (CDR) regression task, achieving an area under the curve (AUC) of approximately 0.95 in identifying ing dementia patients. Dementia related brain regions, such as the medial temporal lobe, were identified by our model. Finally, amyloid plaque prediction model was trained to predict amyloid plaque, and achieved an AUC about 0.8 for dementia patients.</p><p><strong>Conclusions: </strong>These findings indicate that the present predictive models can identify subtle changes in brain structure, enabling precise estimates of brain age, cognitive status, and amyloid pathology. Such models could facilitate the use of MRI as a non-invasive diagnostic tool for neurodegenerative diseases, including AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"126"},"PeriodicalIF":7.9,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191270","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}