Alzheimer's Research & Therapy最新文献

{"title":"Anti-tau VHH therapy against PHF6: a safe approach to slowing the phenotype of tau pathology.","authors":"Raphaelle Caillierez, Clémence Leboullenger, Sarah Leclercq, Mélanie Besegher, Séverine Bégard, Florent Auger, Claude-Alain Maurage, Bertrand Accart, Justine Mortelecque, Elian Dupré, Clément Danis, Isabelle Landrieu, Luc Buée, Morvane Colin","doi":"10.1186/s13195-025-01823-6","DOIUrl":"10.1186/s13195-025-01823-6","url":null,"abstract":"<p><strong>Background: </strong>Tauopathies share common features, including tau aggregation, which plays a central role in neurodegeneration. However, these disorders are highly heterogeneous, particularly in the spread of pathological tau species between cells. In Alzheimer's disease, intracellular tau aggregation is followed by a propagation between cells leading to a hierarchical pathway of neurodegeneration, whereas in other tauopathies, such as progressive supranuclear palsy (PSP), pathological tau remains largely confined within neurons and exhibits more limited spread. This variability raises the question of whether tailored treatments for each tauopathy might offer more therapeutic benefit. Hence, we designed two different immunological approaches using single domain antibody fragments, also called VHHs, to target intracellular and extracellular tau. This study aims to first evaluate the safety of these immunological tools on physiological tau and then their potential to slow disease progression.</p><p><strong>Methods: </strong>We selected the pro-aggregative tau hexapeptide PHF6 as a common target for the VHHs. These VHHs were cloned in viral vectors allowing to compare two different expression systems: 1) intracytosolic expression to prevent tau accumulation (intraVHH) and 2) secretion into the interstitial fluid, to prevent tau spreading (extraVHH). By stereotactic injection of viral vectors, these VHHs were expressed in the brain of transgenic or wild-type mice and three readouts were studied: behavior, brain imaging and tau lesions.</p><p><strong>Results: </strong>We validated the correct addressing of intra- and extraVHHs. These two constructs were not associated with adverse effects, even in the absence of tau overexpression, in wild-type mice. Their efficacy was demonstrated in transgenic mouse tau models, either chronic long-term or in acute seeding with injections of human brain homogenates from Alzheimer's disease patients. They both can slow down several pathological effects (i.e. cognitive deficits, cerebral atrophy and neuronal hyperphosphorylation of tau).</p><p><strong>Conclusions: </strong>This study is a proof of concept demonstrating that VHHs can be engineered to reduce both intra- and extracellular tau pathologies without major adverse effects, making them of interest for therapeutic applications.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"221"},"PeriodicalIF":7.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243625","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":"Sex differences in dementia risk: considering underlying medical conditions.","authors":"Anat Rotstein, Arad Kodesh, Michal Schnaider Beeri, Stephen Z Levine","doi":"10.1186/s13195-025-01843-2","DOIUrl":"10.1186/s13195-025-01843-2","url":null,"abstract":"<p><strong>Background: </strong>Underlying medical conditions may explain inconsistent reports of the association between sex and dementia risk. The current study aimed to explore the association between sex and the risk of incident dementia, considering a broad range of medical conditions.</p><p><strong>Methods: </strong>This prospective national birth cohort study consisted of 53,224 members of a nonprofit health maintenance organization. Participants were born between 1922 and 1946 and entered the cohort on January 1, 2002, aged 55 to 80, without a dementia diagnosis. The cohort was followed up for 18 years to January 1, 2020. Dementia was ascertained based on medical diagnoses. Cox regression models were fitted to quantify the association between sex and the risk of incident dementia with hazard ratios (HR) and their 95% confidence intervals (CI), unadjusted and, in the primary model, adjusted for background demographic factors and 33 medical conditions, classified as ten medical domains. Complementary analyses examined adjustment for each medical domain, and sensitivity analyses provided sex-specific estimates for each demographic or medical domain.</p><p><strong>Results: </strong>The analytic cohort of 53,224 participants had a mean (SD) age at cohort entry of 64.3 (7.08) years (Males: N = 24,489; 46.01%; M=63.47 (6.39); Females: N = 28,735; 53.99%; M=64.35 (6.78)). During follow-up, 8,373 participants (15.73%) were diagnosed with dementia (Females: 17.36%; N = 4,987; Males: 13.83%; N = 3,386). Sex differences in the risk of dementia were null after adjustment for demographic factors and medical conditions (unadjusted HR = 1.08 [95% CI = 1.03-1.13, P = 0.001]; adjusted HR = 1.02 [95% CI, 0.97-1.08; p = 0.38]). Complementary analyses showed that when accounting for some conditions (i.e., circulatory, respiratory, metabolic, digestive, or nervous system diseases; cancer; and injuries), females were at an elevated dementia risk compared to males. However, after accounting for rheumatic and genitourinary diseases, the association between sex and dementia was attenuated to null, and when accounting for psychiatric disorders, males were at greater risk.</p><p><strong>Conclusions: </strong>In this prospective birth cohort, the association between sex and the risk of incident dementia changed when background medical conditions were considered, possibly explaining previous inconsistent reports. Future dementia risk and prevention studies may wish to adequately explore sex differences in medical history.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"219"},"PeriodicalIF":7.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237655","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":"Regional tau PET patterns predict prospective domain-specific cognitive decline in early symptomatic Alzheimer's disease.","authors":"Maura Malpetti, Saima Rathore, Leonardo Iaccarino, Renaud La Joie, Giulia Tronchin, Alette M Wessels, John R Sims, Michael J Pontecorvo, Sergey Shcherbinin, Gil D Rabinovici","doi":"10.1186/s13195-025-01868-7","DOIUrl":"10.1186/s13195-025-01868-7","url":null,"abstract":"<p><strong>Background: </strong>Tau-PET binding patterns are heterogenous, with regional binding showing strong cross-sectional correlations with domain-specific cognitive performance and longitudinal correlations with prospective neurodegeneration. Here we evaluated whether regional patterns of baseline tau-PET predict prospective longitudinal decline in specific cognitive domains in early symptomatic Alzheimer's disease (AD), including participants from clinical trial cohorts.</p><p><strong>Methods: </strong>731 amyloid-positive participants with a clinical diagnosis of mild cognitive impairment (MCI) or mild AD dementia underwent a flortaucipir F 18 PET (FTP-PET), structural MRI, and neuropsychological testing with the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Cognitive assessment was repeated after 9-18 or 12-24 months. Sub-scale annualized w-scores at each time point were combined as composite scores according to domains, including episodic memory, semantic memory, executive function, language and praxis. Latent growth curve models were applied to longitudinal composite scores to estimate the rate of annual decline (slope) in each participant. Standardized uptake value ratio (SUVR) images were created using cerebellar crus as the reference region. Regional and voxel-wise correlation analyses were implemented to identify baseline FTP-PET patterns and MRI grey matter volumes associated with longitudinal changes in each cognitive domain, and to evaluate whether MRI mediates the association between FTP-PET and cognitive decline.</p><p><strong>Results: </strong>Differential FTP-PET signal patterns showed significant negative associations with domain-specific annual rates of decline. Higher temporo-parietal FTP-PET SUVR was associated with faster decline in episodic memory, while higher left anterior temporal SUVR was associated with faster decline in semantic memory. FTP-PET signal in a left-dominant fronto-temporal pattern was associated with faster decline in language, while FTP-PET signal in a right-dominant fronto-parietal pattern was associated with faster decline in praxis. Executive decline showed limited spatial associations with FTP-PET. Overall, regional and voxel-wise analyses identified similar pairwise associations between FTP-PET signal and domain-specific longitudinal decline. Baseline MRI showed weaker associations with domain-specific cognitive decline than FTP-PET, and did not mediate the predictive effect of the latter.</p><p><strong>Conclusion: </strong>Differential regional tau-PET signal patterns were associated with domain-specific cognitive decline in MCI and early AD dementia. Tau-PET may be a useful precision medicine tool to support individualized predictions of cognitive decline trajectories in early symptomatic AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"220"},"PeriodicalIF":7.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12502172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237538","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":"Usability and feasibility of ADappt: a digital toolkit to support communication on diagnosis and prognosis in memory clinics.","authors":"Heleen M A Hendriksen, Tanja J de Rijke, Aniek M van Gils, Marlijn H de Beer, Femke H Bouwman, Ana Diaz, Tjeerd Fluitman, Liesbeth Hempenius, Ingrid S van Maurik, Ruth E Pel-Littel, Hanneke F M Rhodius-Meester, Gerwin Roks, Ellen M A Smets, Wiesje M van der Flier, Leonie N C Visser","doi":"10.1186/s13195-025-01847-y","DOIUrl":"10.1186/s13195-025-01847-y","url":null,"abstract":"<p><strong>Background: </strong>ADappt is a digital toolkit for both memory clinic professionals and patients to support communication on diagnosis and prognosis in memory clinics. We aimed to evaluate ADappt's usability and feasibility in clinical practice.</p><p><strong>Methods: </strong>In this mixed-methods study, we first assessed usability via think-aloud sessions with ten memory clinic professionals from eight memory clinics, six patients, and one care partner. Think-aloud comments were deductively categorized into: content, navigation, and design. Second, we conducted a feasibility study in four memory clinics. Eight memory clinic professionals recruited 21 patients and 21 care partners. Professionals were instructed to integrate the ADappt-toolkit in their routine. Before their visit, patients received information about the ADappt-patient tools: two video-animations and a question prompt list (QPL). Participants completed questionnaires on usability, satisfaction, and feasibility either after the first consultation (n = 14 patients; n = 15 care partners), after the disclosure consultation (n = 4 patients; n = 5 care partners), or after both consultations (n = 3 patients; n = 1 care partner). Interviews with professionals were conducted and analyzed using thematic content analysis. Third, together with Alzheimer Europe, we co-organized a patient and public involvement (PPI) session with citizens, patients, and care partners to further improve the patient tools.</p><p><strong>Results: </strong>Professionals found ADappt relevant, easy-to-navigate, and visually appealing. Most think-aloud comments focused on content and navigation, especially regarding the risk calculation tool. Patients indicated the patient tools to be helpful in preparing for consultations. After use in practice, professionals reported acceptable usability (68 ± 14, scale 0-100) and satisfaction (71 ± 10, scale 0-100) with ADappt. Professionals most often used the tool that provides an overview of diagnostic tests with pros and cons (in 15/24(63%) consultations), which they also deemed most helpful (median(IQR): 4(3.75-4), scale 1-5). About half to two-thirds of patients and care partners reported to have received the patient tools (video-animations: n = 23/46(50%)); QPL: n = 30/46(65%)), of whom a majority used (video-animations: n = 16/23(70%)); QPL: n = 21/30(70%)) and would recommend them (video-animations: n = 15/16(94%); QPL: n = 20/21(95%)). The tools helped to express themselves more effectively. The PPI session highlighted the importance of widespread dissemination of the patient tools and through multiple channels.</p><p><strong>Conclusions: </strong>Our study demonstrates the potential of digital tools to improve medical communication in memory clinics. Taking feedback into account, ADappt is further improved and steps towards implementation are being taken.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"218"},"PeriodicalIF":7.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12492680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211413","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":"Micro infarcts are associated with cognitive impairment in neurofibrillary tangle predominant decedents: evidence from the NACC autopsy cohort.","authors":"Nicko Martinez, Krishna L Bharani, Saadia Hasan, Cellas A Hayes","doi":"10.1186/s13195-025-01863-y","DOIUrl":"10.1186/s13195-025-01863-y","url":null,"abstract":"<p><strong>Background: </strong>A subset of older adults develops high neurofibrillary tangle burden with minimal amyloid, a biomarker profile consistent with suspected non-Alzheimer's pathophysiology or primary age-related tauopathy. Yet its cognitive correlates are unclear, particularly when vascular neuropathologies coexist. We examined whether vascular neuropathologies are linked to cognitive impairment proximate to death and pre-mortem cognitive decline among decedents with intermediate-to-high Braak stage (III-VI) and absent/low neuritic plaques.</p><p><strong>Methods: </strong>In 579 autopsied participants from the National Alzheimer's Coordinating Center cohort (Braak III-VI; CERAD C0-C1), we evaluated arteriolosclerosis, atherosclerosis of the circle of Willis, cerebral amyloid angiopathy, gross infarcts/lacunes, and microinfarcts effect on harmonized memory, executive function, and language z-scores proximate to death using multivariable linear regression (adjusted for age, sex, education, APOE ε4 status). Linear mixed-effects models assessed interactions between each vascular neuropathology and years-to-death on pre-mortem longitudinal decline.</p><p><strong>Results: </strong>At the last assessment, microinfarcts were associated with lower memory (β=-0.28, 95% CI - 0.51 - - 0.05; p = 0.02), executive function (β=-0.24, 95% CI - 0.44 - - 0.04; p = 0.02), and language (β=-0.21, 95% CI - 0.38 - - 0.04; p = 0.02). These associations remained after controlling for cardiovascular risk, neuritic plaques and Braak stage, last assessment and death interval, and co-existing vascular neuropathologies. Microinfarcts were not associated with the rates of pre-mortem cognitive decline.</p><p><strong>Conclusions: </strong>Microinfarcts are contributors to domain-specific cognitive deficits in tangle-predominant, low-amyloid older adults. These findings underscore a vascular-neurodegenerative pathway distinct from classic Alzheimer's disease. Thus, targeting microvascular injury may mitigate impairment in this underrecognized phenotype.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"216"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12486553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205503","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":"Dissecting real-world memory clinical cohort heterogeneity: analysis of neuroanatomical subtypes using HYDRA.","authors":"Gordon Zhaoqi An, Yunchang Xie, Tammie L S Benzinger, Brian A Gordon, Aristeidis Sotiras","doi":"10.1186/s13195-025-01850-3","DOIUrl":"10.1186/s13195-025-01850-3","url":null,"abstract":"<p><strong>Background: </strong>There is significant evidence for neuroanatomical heterogeneity in neurodegenerative disorders, which has been demonstrated predominantly through analyses of well-characterized research cohorts. Despite the known diversity in clinical presentations among patients attending memory clinics, studies exploring neuroanatomical heterogeneity in such clinically diverse groups remain sparse.</p><p><strong>Methods: </strong>To address this gap, we applied the semi-supervised Heterogeneity through Discriminative Analysis (HYDRA) (Neuroimage 145:346-364 2017) machine learning method to magnetic resonance imaging (MRI) data from the Open Access Series of Imaging Studies (OASIS) (NeuroImage 26:102248 2020) to uncover patterns of neurostructural heterogeneity in memory clinic attendees. Cross-validation was used to assess clustering stability via the Adjusted Rand Index (ARI), Silhouette Score, and Calinski-Harabasz Index (CHI). We performed survival analyses using Kaplan-Meier curves and mixed-effects models for longitudinal cognitive data (e.g., memory, executive function, and language assessments) to examine differences in disease progression.</p><p><strong>Results: </strong>Cross-validation analyses indicated two highly stable subtypes of cognitively impaired individuals (ARI = 0.552), exhibiting significant neuroanatomical differences. Subtype 1, termed the Temporal-Sparing Atrophy (TSA) Subtype, was defined by relatively mild atrophy, especially in temporal areas, with slower cognitive decline and preserved Function across most domains. Subtype 2, termed the Temporal-Parietal Predominated Atrophy (TPPA) Subtype, was marked by notable alterations in areas critically affected in neurodegenerative disorders. These included key areas critical for executive function and memory, such as the frontal, temporal, and parietal cortices including the precuneus. Longitudinal analysis of neuroimaging and cognitive data revealed contrasting trajectories. The TSA Subtype demonstrated a gradual decline in cognitive functions over time, particularly in the assessments that are memory-focused tests. Conversely, the TPPA Subtype exhibited a more severe decline in these functions.</p><p><strong>Conclusions: </strong>This research illustrates that neurodegenerative diseases present a spectrum of structural brain changes rather than uniform pathology, suggesting that future research may benefit from stratified therapeutic approaches and targeted recruitment strategies for clinical trials. By leveraging detailed clinical assessments and longitudinal data, including uncertain diagnoses and Clinical Dementia Rating (CDR) scores, this study contributes to better understanding/characterizing memory clinic populations, which could help with optimizing interventions.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"215"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205375","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":"Population intervention models of racial ethnic disparities in cognitive outcomes from cardiometabolic risk factors - HABS-HD.","authors":"Cellas A Hayes, Lubnaa Abdullah, Joshua Gills, Michelle C Odden","doi":"10.1186/s13195-025-01866-9","DOIUrl":"10.1186/s13195-025-01866-9","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease and related dementias are major public health challenges, with the apolipoprotein (APOE) ε4 allele being a significant genetic risk factor. Cardiometabolic risk factors such as diabetes, hypertension, dyslipidemia, obesity, and tobacco use are also linked to cognitive impairment. The objective of this study was to (1) characterize both independent and interactive associations of racial/ethnic group (Non-Hispanic White (NHW), Non-Hispanic Black (NHB) and Hispanic), APOE ε4 genotype, and multiple cardiometabolic risk factors with performance across four cognitive domains. Secondarily, we aimed to quantify the hypothetical population-level cognitive gains that could result from eliminating each modifiable risk factor within each racial/ethnic group.</p><p><strong>Methods: </strong>We analyzed baseline data from 3,833 HABS-HD participants (1,348 NHW; 1,065 NHB; 1,420 Hispanic; mean age 65.3 ± 8.6 years; 62.0% female). APOE genotype, consensus-determined cardiometabolic status, and harmonized cognitive domain scores (episodic memory, executive function, processing speed, language) were obtained. Multivariable linear regressions assessed independent effects of race/ethnicity, APOE ε4 carriage, and each cardiometabolic factor on domain-specific z-scores, adjusting for age, sex, and education (Bonferroni-corrected). Interaction terms tested effect modification by race/ethnicity. Counterfactual population intervention models estimated the mean cognitive gain from hypothetically eliminating each modifiable risk factor within each racial/ethnic group.</p><p><strong>Results: </strong>NHB Hispanic, and NHW participants prevalences were APOE ε4 (32.2%, 27.4%, 17.6%), diabetes (26.1%, 35.0%, 13.9%), hypertension (79.0%, 63.6%, 58.2%), obesity (56.8%, 50.3%, 38.5%), and tobacco dependence (12.9%, 7.5%, 3.9%). In adjusted models, NHB and Hispanic ethnicity, APOE ε4, diabetes, hypertension, and tobacco dependence each independently predicted lower performance across all four cognitive domains (adjusted p < .001), whereas obesity showed domain-specific positive associations. No race × risk-factor interactions remained significant after correction. In intervention models, hypothetically eliminating diabetes and hypertension yielded the largest predicted improvements, especially in executive function and language, with the greatest gains projected among NHB and Hispanic racial ethnic group.</p><p><strong>Conclusions: </strong>Cardiometabolic health markedly contributes to racial ethnic differences in cognitive aging beyond APOE ε4 effects. Population-level interventions targeting diabetes and hypertension could narrow NHB and Hispanic cognitive deficits, informing precision public-health strategies for dementia prevention.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"217"},"PeriodicalIF":7.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12487193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205513","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":"Centiloid values from deep learning-based CT parcellation: a valid alternative to freesurfer.","authors":"Yeo Jun Yoon, Seungbeom Seo, Sangwon Lee, Hyunkeong Lim, Kyobin Choo, Daesung Kim, Hyunkyung Han, Minjae So, Hosung Kang, Seongjin Kang, Dongwoo Kim, Young-Gun Lee, Dongho Shin, Tae Joo Jeon, Mijin Yun","doi":"10.1186/s13195-025-01860-1","DOIUrl":"10.1186/s13195-025-01860-1","url":null,"abstract":"<p><strong>Background: </strong>Amyloid PET/CT is essential for quantifying amyloid-beta (Aβ) deposition in Alzheimer's disease (AD), with the Centiloid (CL) scale standardizing measurements across imaging centers. However, MRI-based CL pipelines face challenges: high cost, contraindications, and patient burden. To address these challenges, we developed a deep learning-based CT parcellation pipeline calibrated to the standard CL scale using CT images from PET/CT scans and evaluated its performance relative to standard pipelines.</p><p><strong>Methods: </strong>A total of 306 participants (23 young controls [YCs] and 283 patients) underwent 18 F-florbetaben (FBB) PET/CT and MRI. Based on visual assessment, 207 patients were classified as Aβ-positive and 76 as Aβ-negative. PET images were processed using the CT parcellation pipeline and compared to FreeSurfer (FS) and standard pipelines. Agreement was assessed via regression analyses. Effect size, variance, and ROC analyses were used to compare pipelines and determine the optimal CL threshold relative to visual Aβ assessment.</p><p><strong>Results: </strong>The CT parcellation showed high concordance with the FS and provided reliable CL quantification (R² = 0.99). Both pipelines demonstrated similar variance in YCs and effect sizes between YCs and ADCI. ROC analyses confirmed comparable accuracy and similar CL thresholds, supporting CT parcellation as a viable MRI-free alternative.</p><p><strong>Conclusions: </strong>Our findings indicate that the CT parcellation pipeline achieves a level of accuracy similar to FS in CL quantification, demonstrating its reliability as an MRI-free alternative. In PET/CT, CT and PET are acquired sequentially within the same session on a shared bed and headrest, which helps maintain consistent positioning and adequate spatial alignment, reducing registration errors and supporting more reliable and precise quantification.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"212"},"PeriodicalIF":7.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197600","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":"IRF1 ameliorates synaptic dysfunction through the modulation of O-GlcNAcylation on GluN1 subunit of NMDAR.","authors":"Xing Fan, Hao Wang, Cuiping Guo, Shijia Huang, Liye Xia, Zheng Zhou, Ran Tao, Mingzhe Li, Xiaochuan Wang, Wei Qian","doi":"10.1186/s13195-025-01857-w","DOIUrl":"10.1186/s13195-025-01857-w","url":null,"abstract":"<p><strong>Background: </strong>Synaptic dysfunction, which occurs before the formation of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs), is strongly associated with cognitive deficits and represents major early clinical features of Alzheimer's disease (AD). Abnormal NMDAR signaling emerges as a noticeable feature of synaptic dysfunctions in AD. Nonetheless, the underlying mechanisms of NMDAR dysfunctions remain unclear.</p><p><strong>Methods: </strong>3xTg-AD mice were injected with AAV-IRF1. Cognitive function was assessed using behavioral tests, while biochemical and immunofluorescence analyses were conducted to evaluate the protein levels of IRF-1, OGA, subunits of NMDAR, O-GlcNAcylation of NMDAR subunits, and internalization of NMDA receptors. Synaptic alterations in the hippocampus were detected by electrophysiology and Golgi staining.</p><p><strong>Results: </strong>In the present study, we demonstrate that Interferon Regulatory Factor-1 (IRF-1), which is deficient in the brain of individuals with Alzheimer's disease (AD), negatively regulates the O-GlcNAcylation levels of GluN1 through transcriptional regulation of the human OGA gene. Furthermore, IRF-1 may influence trafficking of NMDARs, thereby affecting dendritic spine density and synaptic plasticity, and ultimately improving the learning and memory of 3xTg-AD mice.</p><p><strong>Conclusion: </strong>Our results indicate that IRF1 can improve the cognitive function of 3xTg-AD mice by regulating the O-GlcNAcylation of GluN1, offering evidence that IRF-1 could serve as a novel therapeutic target for treating synaptic dysfunction in Alzheimer's diseases.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"205"},"PeriodicalIF":7.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel electric field approach for improving cognitive function through ameliorating cell-specific pathology in P301S tauopathy mice.","authors":"Jinyun Zhou, Yan Zhong, Chentao Jin, La Dong, Rui Zhou, Yuxing Wang, Zhengbo Fan, Xuesheng Zheng, Xiaoqing Xing, Jing Wang, Mei Tian, Hong Zhang","doi":"10.1186/s13195-025-01859-8","DOIUrl":"10.1186/s13195-025-01859-8","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a devastating neurodegenerative disorder, with no effective treatment currently available. Recently, non-pharmacological therapy, especially gamma frequency stimulation has shown promising therapeutic effects in Alzheimer's disease (AD) mouse models. Electric field (EF) is a non-invasive biophysical approach for neuronal protection. However, whether EF is beneficial in AD neuropathology remains unknown. In this study, we exposed the P301S tauopathy mouse model to EF at gamma frequency on the head. We demonstrated that EF treatment significantly improved the cognitive impairments in the P301S mice. This was accompanied by reduced tau pathologies, suppressed microglial activation, neuroinflammation and oxidative stress in the tauopathy mouse brain. Moreover, EF treatment induced cell-specific responses in neural cells, with neurons being more susceptible, followed by microglia and oligodendrocytes. EF also had favorable effects on synaptic protein in neurons, inflammatory response and complement signaling in microglia, and myelination in oligodendrocytes. This study provides strong evidence that EF at gamma frequency may have great potential to be a novel therapeutic intervention for P301S by attenuating neuropathology and offering neuroprotection.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"210"},"PeriodicalIF":7.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481757/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197470","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}