Alzheimer's Research & Therapy最新文献

{"title":"Semantic fluency predicts survival of memory clinic patients.","authors":"Lars Frings, Joachim Brumberg, Philipp T Meyer","doi":"10.1186/s13195-026-02152-y","DOIUrl":"10.1186/s13195-026-02152-y","url":null,"abstract":"<p><strong>Background: </strong>Semantic fluency is commonly assessed in the diagnostic work-up of individuals with suspected cognitive impairment due to neurodegenerative disease. Semantic fluency has a predictive value for survival in clinical AD and in healthy elderly individuals, but it is unknown if this also applies to biomarker-confirmed AD and non-AD memory clinic patients. Potential associations with and added value of imaging biomarkers of amyloid pathology and neurodegeneration have yet to be explored.</p><p><strong>Methods: </strong>From our clinical registry, we included patients who were assessed at a memory clinic with the neuropsychological assessment battery of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-NAB) and whose vital status could be retrieved in 07/2024. We tested the association of semantic fluency performance at first assessment and over time (and, for comparison, further CERAD-NAB subtest scores) with mortality risk using age-adjusted single-predictor Cox proportional hazard models. Amyloid status (positive vs negative on clinical PET reads) and global cognitive impairment (MMSE) were included as covariates. In addition, we explored associations between semantic fluency performance and both regional cortical glucose metabolism (FDG PET) and global amyloid load (centiloids; PiB PET). Finally, the predictive value of global amyloid load and glucose metabolism in comparison to and in combination with semantic fluency performance was assessed.</p><p><strong>Results: </strong>583 patients were included (age 68.9 ± 8.7, 45% female). 280 patients (48%) had died and 303 (52%) were alive after a median of 8.0 years [95% C.I. 7.7-8.4]. Better semantic fluency (age-, sex- and education adjusted Z score, based on normative data) was significantly associated with lower mortality risk (HR = 0.71 [0.63 - 0.80], Bonferroni-corrected p < 0.001). Its predictive value was higher than that of all other CERAD-NAB subscores (e.g., memory, visuospatial abilities). Semantic fluency remained a significant predictor when amyloid status and global cognitive impairment were accounted for (HR = 0.75 [0.61 - 0.91], p = 0.0035). In patients with more than one assessment (N = 163), longitudinal change of semantic fluency (derived from a linear mixed effects model) was also a significant predictor (HR = 0.66 [0.53-0.83], p < 0.001). In 218/583 patients who had received amyloid and FDG PET, worse semantic fluency was associated with decreased FDG uptake of left inferior and middle temporal, dorsolateral frontal, and posterior parietal cortical regions (Bonferroni-corrected p < 0.05), but not with amyloid load. FDG uptake of the left IFG (pars opercularis) was itself a predictor of survival (HR = 0.68 [0.55 - 0.84], Bonferroni-corrected p < 0.05), but to a lesser degree than semantic fluency (and MMSE, naming and figure drawing). Predictive accuracy of semantic fluency was further improved by including FDG uptake of the right a","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13452100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697003","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":"Neuropathological and vascular determinants of cerebral amyloid angiopathy risk: evidence from the NACC cohort.","authors":"Liwei Ma, Yihan Wang, Benjamin Goudey, Liang Jin, Yijun Pan","doi":"10.1186/s13195-026-02064-x","DOIUrl":"10.1186/s13195-026-02064-x","url":null,"abstract":"<p><strong>Background: </strong>Cerebral amyloid angiopathy (CAA) is strongly associated with Alzheimer's disease neuropathologic changes (ADNC), but its links with other brain pathologies remain unclear.</p><p><strong>Methods: </strong>We conducted a clinicopathological study of 3,267 participants from the National Alzheimer's Coordinating Center (NACC) cohort. Neuropathological evaluations included potential risk factors for CAA, such as ADNC, Lewy body pathology (LBP), frontotemporal lobar degeneration (FTLD), and other neuropathologies.</p><p><strong>Results: </strong>We found that ADNC and LBP were associated with increased odds of CAA, with the risk increasing according to ADNC severity and in cases of limbic/amygdala-predominant LBP. In contrast, FTLD, particularly the FTLD-TDP subtype, was inversely associated with CAA. Among other neuropathologies, CAA was positively associated with microinfarcts, arteriolosclerosis, white matter rarefaction, and hippocampus/cortical atrophy, but inversely associated with lobar atrophy and higher brain weight. In addition, APOE ε4 carriers with mixed ADNC, LBP, and FTLD exhibited the highest risk. Stronger associations between ADNC and CAA were observed in participants aged < 80 years and in males, whereas females demonstrated greater vulnerability to vascular- and atrophy-related correlates. Several neuropathology-CAA associations were also more pronounced among APOE ε4 carriers.</p><p><strong>Conclusion: </strong>These findings highlight the interplay of neurodegenerative, vascular, sex, and APOE ε4 in CAA susceptibility, with implications for risk stratification.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13721479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149294131","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":"Neuropsychological profiles and behavioural correlates in individuals exposed to repetitive head impacts: findings from the NEwTON study.","authors":"Suzie Kamps, Esmé H J Habraken, Suzan van Amerongen, Dirk N van Paassen, Sterre C M de Boer, Emma M Coomans, Sietske A M Sikkes, Philip Scheltens, Rik Ossenkoppele, Everard G B Vijverberg","doi":"10.1186/s13195-026-02122-4","DOIUrl":"10.1186/s13195-026-02122-4","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Repetitive head impacts (RHI) are associated with an increased risk of neurodegenerative disease, most notably chronic traumatic encephalopathy (CTE). This study characterized neuropsychological profiles of RHI-exposed individuals compared to unexposed controls. To investigate whether cognitive dysfunction is linked to behavioural symptoms in RHI, we examined associations between executive functioning, social cognition and behavioural disinhibition.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We included RHI-exposed individuals (N = 72, 90.4% male, mean age 53.84 ± 12.45) and unexposed, cognitively healthy controls (N = 40, 82.5% male, mean age 54.55 ± 12.12) from the \"Neurodegeneration: Traumatic brain injury as the Origin of Neuropathology\" (NEwTON) study from Amsterdam UMC. Neurocognitive functioning was assessed through a comprehensive test battery covering episodic memory, attention and processing speed, executive functioning, visuospatial abilities, language and semantic memory, and social cognition. Behavioural disinhibition was measured in the RHI group using informant-based questionnaires (the positive items of the Frontal Behavioural Inventory (FBI) and the Neuropsychiatric Inventory (NPI)). Group differences in cognitive domains were assessed with analysis of covariance (ANCOVA) corrected for age, sex and education. The RHI-exposed group was evaluated for Traumatic Encephalopathy Syndrome (TES) criteria (No TES, Suggestive of CTE, Possible CTE, Probable CTE), TES subgroups were exploratively compared on cognitive performance. Associations between behavioural disinhibition and executive functioning or social cognition were assessed with regression analyses.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;RHI-exposed individuals performed worse on episodic memory (η&lt;sup&gt;2&lt;/sup&gt; = 0.12, p&lt;sub&gt;FDR&lt;/sub&gt; ≤ .001), language and semantic memory (η&lt;sup&gt;2&lt;/sup&gt; = 0.10, p&lt;sub&gt;FDR&lt;/sub&gt; = .001), executive functioning (η&lt;sup&gt;2&lt;/sup&gt; = 0.04, p&lt;sub&gt;FDR&lt;/sub&gt; = .046), and social cognition (η&lt;sup&gt;2&lt;/sup&gt; = 0.04, p&lt;sub&gt;FDR&lt;/sub&gt; = .040). No differences were found for visuospatial abilities (η&lt;sup&gt;2&lt;/sup&gt; = 0.01, p&lt;sub&gt;FDR&lt;/sub&gt; = .221) and, although borderline significant, attention and processing speed (η&lt;sup&gt;2&lt;/sup&gt; = 0.03, p&lt;sub&gt;FDR&lt;/sub&gt; = .074). Greater TES severity was associated with poorer performance on all cognitive domains. No significant associations were found between executive function or social cognition and behavioural disinhibition, as measured with the NPI and the FBI positive subscale (all p &gt; .05).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;RHI-exposed individuals showed poorer cognitive performance across several domains (episodic memory, executive functioning, social cognition and language and semantic memory). We found no association between cognitive function and behavioural disinhibition. Further longitudinal studies employing neuroimaging and biomarker data are needed to disentangle the underlying pathology in populations at risk ","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13711815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260688","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":"SuperAging is not the inverse of common-variant Alzheimer's risk: evidence across genetic ancestries.","authors":"Ignazio Stefano Piras, Ana Werneck Capuano, Amanda Cook Maher, Rhiana Schafer, Anna Bonfitto, Serena Song, Francis Taguinod, Felicia Goldstein, Angela Roberts, Ozioma Okonkwo, Adam Martersteck, Matt J Huentelman, Emily Rogalski","doi":"10.1186/s13195-026-02124-2","DOIUrl":"10.1186/s13195-026-02124-2","url":null,"abstract":"<p><strong>Background: </strong>As longevity increases and the population over age 65 expands, advancing age remains the most reliable predictor of cognitive decline, highlighting the need to identify biological mechanisms that support exceptional cognitive aging. We tested whether lower inherited risk of Alzheimer's disease (AD) dementia predicts SuperAger status (adults ≥ 80 years with episodic memory at least as good as middle-age adults) using prospectively enrolled SuperAgers and Cognitively Average Controls (Controls) from the multisite SuperAging Research Initiative.</p><p><strong>Methods: </strong>We studied 231 participants (SuperAgers n = 142; Controls n = 89). We confirmed that the genetic ancestry structure across groups was comparable. We evaluated whether APOE status (ε2, ε3, ε4) and three AD polygenic risk scores (PRS) derived from large contemporary Genome-Wide Association Studies (GWAS) (PRS_Lambert, PRS_Wightman, PRS_Bellenguez) predicted SuperAging status using logistic regression models adjusted for age, sex, and education, considering ancestry interactions.</p><p><strong>Results: </strong>APOE allele and genotype distributions did not differ between groups, and neither APOE nor any of the three PRS predicted SuperAger status. Results were unchanged when accounting for global non-European or African ancestry or principal components. In this well-characterized cohort, neither APOE nor contemporary PRS explained SuperAger status.</p><p><strong>Conclusions: </strong>These findings suggest that the exceptional late-life memory phenotype that is characteristic of SuperAging is not explained by common-variant AD genetic risk captured by APOE or contemporary AD PRS, motivating a deeper investigation of potential rare genetic variations and experiential factors contributing to exceptional cognitive aging.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"18 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13397696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576317","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":"Personalized non-invasive combined magnetic and electrical stimulation of the default mode network in mild AD patients (CMES-AD): a multicentric randomized sham-controlled trial protocol.","authors":"Sonia Bonnì, Romina Esposito, Lucia Mencarelli, Francesco Di Lorenzo, Francesco Ricci, Fulvia Di Iulio, Elena Savastano, Francesca Candeo, Francesca De Masi, Antonella Coletta, Andrea Carolina Vinci, Matteo Ferraresi, Marta Mancini, Elias Paolo Casula, Ilaria Borghi, Danny Adrian Spampinato, Michele Maiella, Alex Martino Cinnera, Martina Assogna, Matilde Bruno, Matteo Nocilli, Marica Ferrara, Marta Russo, Nevio Luigi Tagliamonte, Clarissa Ferrari, Salvatore Bertino, Rocco Salvatore Calabrò, Maria Grazia Maggio, Rosaria De Luca, Rachele Burrascano, Elvira Gjonaj, Alessio Mirabile, Paolo De Pasquale, Andrea d'Avella, Angelo Quartarone, Giacomo Koch","doi":"10.1186/s13195-026-02145-x","DOIUrl":"https://doi.org/10.1186/s13195-026-02145-x","url":null,"abstract":"<p><strong>Background: </strong>Patients with Alzheimer's disease (AD) exhibit early alterations in the Default Mode Network (DMN), a key brain network involved in episodic memory where the precuneus plays a central role. Precision-targeted, non-invasive brain stimulation represents a promising strategy to improve cognitive function in individuals with dementia. The DMN can be modulated through personalized non-invasive electromagnetic stimulation, a therapeutic approach that enhances neural plasticity and stabilizes network connectivity. This trial implements an innovative therapeutic protocol based on precision delivery of personalized electromagnetic stimulation targeting the precuneus, the main hub of the DMN.</p><p><strong>Methods: </strong>This phase 2 multicenter, randomized, double-blind, sham-controlled, three-arm trial evaluates the safety and efficacy of combined repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) targeting the precuneus in AD patients. rTMS will be applied using the intermittent theta burst stimulation (iTBS) protocol, while tACS will be delivered at gamma frequency (70 Hz). Personalization of iTBS-tACS treatment is established using neuronavigated TMS with electroencephalography (TMS-EEG). The 24-week intervention starts with a 2-week intensive course of daily combined treatment over the precuneus (5 sessions per week), followed by a 22-week maintenance phase with weekly stimulation. The primary outcome measure is the change in the integrated Alzheimer Disease Rating Scale (iADRS) between baseline and week 24. Secondary outcomes include score changes in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, Clinical Dementia Rating Scale-Sum of Boxes (CDR-SoB), the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog₁₃), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Frontal Assessment Battery (FAB), the Face-Name Association Task (FNAT), the Neuropsychiatric Inventory (NPI), and the Apathy Motivation Index (AMI). Exploratory outcomes will include changes in cortical activity and connectivity (assessed through TMS-EEG, MRI), in blood based biomarkers of neurodegeneration, synaptic activity and neural inflammation, and sensorimotor functions in virtual environments. Evaluation at week 12 and a follow-up assessment at week 32 will be conducted to assess short-term and follow-up treatment effects, respectively.</p><p><strong>Significance: </strong>This trial aims to provide evidence that personalized combined electrical and magnetic stimulation of the DMN may slow functional and cognitive decline in AD patients, contributing to the development of personalized interventions for AD treatment.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT07075770, registered 10 July 2025.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resting-state functional dynamics alterations relate to plasma amyloid markers and statistically explain memory impairments in the TgF344-AD model of Alzheimer's disease.","authors":"Alya Al-Awlaqi, Lori Berckmans, Sam De Waegenaere, Sarah Vanherle, Joseph Griffis, Ilse Dewachter, Marleen Verhoye, Mohit H Adhikari","doi":"10.1186/s13195-026-02146-w","DOIUrl":"10.1186/s13195-026-02146-w","url":null,"abstract":"<p><strong>Background: </strong>Resting-state functional MRI studies of Alzheimer's disease (AD) show lower functional connectivity (FC) of AD-relevant regions and resting-state networks in patients and transgenic rodent models at symptomatic stages. However, at early stages of the disease, both hyper and hypo connectivity has been reported. Traditional FC overlooks temporal fluctuations in connectivity and network dynamics at a short timescale captured by transient brain states such as co-activation patterns (CAPs). CAPs have been shown to be more sensitive than FC to detect early alterations in neurodegenerative diseases and therefore can shed light on hyper versus hypo connectivity observed at early stages. Moreover, how brain functional signatures of Alzheimer's disease are related to its behavioral and pathological markers and whether they have prognostic relevance remain scarcely investigated.</p><p><strong>Methods: </strong>We acquired high temporal resolution resting-state functional MRI data in the TgF344-AD model rats and age-matched wild-type animals at 4 and 10 months of age corresponding to the pre-plaque and plaque stages, respectively and delineated brain functional alterations using FC and CAPs in the model animals. We also assessed the levels of amyloid beta (Aβ) in blood and working and reference memory performance in the same animals at the plaque stage and investigated their statistical relationship with pre-plaque and plaque-stage changes in FC and CAPs.</p><p><strong>Results: </strong>TgF344-AD rats had significantly elevated blood Aβ levels, committed more working and reference memory errors and showed reduced hippocampal FC with the lateral cortical and default-mode-like network compared to wild-type animals at the plaque stage. FC at the pre-plaque stage did not differ between TgF344-AD and wild-type rats. TgF344-AD rats showed hyper- and hypo-activation in the default-mode-like-network and hippocampal regions at pre-plaque and plaque stages, respectively, in multiple CAPs. Blood Aβ levels were statistically explained more accurately by plaque-stage, than pre-plaque stage, FC values and CAP activations. CAP activations, especially at the pre-plaque stage, outperformed FC in accurate statistical explanation of memory impairments.</p><p><strong>Conclusion: </strong>Our findings demonstrate pre-plaque stage hyperconnectivity not in the traditional, static measure of functional connectivity but in transient, dynamic brain states and that these early brain functional signatures have prognostic relevance for memory deficits in a translational rat model of Alzheimer's disease.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468375","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":"Blood-based immunophenotyping of T cell profiles in patients with neurodegenerative disorders.","authors":"Frederika Malichova, Peter Swann, Stacey L Kigar, Natalia Savinykh Yarkoni, Julia Goddard, Kei Onn Lai, Leonidas Chouliaras, Ajenthan Surendranathan, Lorinda Turner, George Savulich, Richard Bevan-Jones, Nicholas J Ashton, Kaj Blennow, Henrik Zetterberg, Edward Needham, Joanne Jones, William A McEwan, James B Rowe, John T O'Brien, Maura Malpetti","doi":"10.1186/s13195-026-02144-y","DOIUrl":"10.1186/s13195-026-02144-y","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;There is increasing evidence for the role of central and peripheral inflammation across neurodegenerative disorders, with animal models and post-mortem studies identifying T-cell infiltration in the brain associated with pathology and neurodegeneration. Peripheral T-cell changes have been measured in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). This study examines a unique cohort of blood-based T-cell profiles across a range of neurodegenerative dementias including AD, DLB, FTD, corticobasal syndrome (CBS), PSP, and aged-matched healthy controls. Then it also explores their associations with dementia-relevant plasma biomarkers and clinical outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Freshly prepared peripheral blood mononuclear cells (PBMCs) from 174 participants (AD = 20, DLB = 24, FTD = 19, CBS = 18, PSP = 58, controls = 35) were studied using a flow-cytometry panel designed to analyse major T-cell subpopulations, including memory and T-helper subtypes. Neurodegeneration-relevant biomarkers (p-tau217, p-tau231, GFAP, NfL, and A-beta42/40) were measured in plasma samples. T-cell populations were compared between groups and in association with biomarkers, and principal components analysis (PCA) was used to identify T-cell profiles and their association with dementia-relevant biomarkers in diagnostic classification and survival prediction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;There was a significant reduction in the fraction of CD3+ cells in patients with DLB compared to other diagnostic groups, and an increase in relative Th1/17-like cell levels in patients with FTD compared to controls. This increase in Th1/17-like cells correlated with NfL and GFAP plasma levels in patients with FTD. PCA identified five components primarily representing CD4+ memory cell population subsets. After sex and age adjustments, component 4 marked by effector memory types including Th2-like, Th-like1 and Th1/17-like cells was a significant predictor of FTD, however was not as accurate as plasma NfL. Higher scores in specific T-cell components (1 and 3) were associated with reduced mortality across all diseases, with component 3 remaining a significant predictor even when controlling for traditional neurodegenerative biomarkers like NfL and p-tau217.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study provides evidence that T-cell dysregulation is not unified in patients with neurodegenerative diseases. We observe different involvement across different dementia types establishing adaptive immunity as a key contributor to disease heterogeneity. However, although plasma biomarkers such as NfL and p-tau217 exhibit superior diagnostic accuracy for clinical classification, peripheral T-cell signature were associated with survival outcomes across diagnostic groups, highlighting their promise for prognostic applications and disease monitoring. The characterisation of T-cell","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468381","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":"Disruption of temporo-parietal network in Alzheimer's disease and its association with memory impairment.","authors":"Yanin Suksangkharn, Björn Hendrik Schott, Peter Zeidman, Niklas Vockert, René Lattmann, Hartmut Schütze, Renat Yakupov, Oliver Peters, Julian Hellmann-Regen, Lukas Preis, Ersin Ersözlü, Josef Priller, Eike Jakob Spruth, Janna Beckmann, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Claudia Bartels, Ayda Rostamzadeh, Wenzel Glanz, Enise I Incesoy, Stefan Teipel, Ingo Kilimann, Doreen Goerss, Christoph Laske, Annika Spottke, Marie Kronmüller, Frederic Brosseron, Falk Lüsebrink, Matthias Schmid, Luca Kleineidam, Melina Stark, Stefan Hetzer, Peter Dechent, Frank Jessen, Anne Maass, Emrah Düzel, Gabriel Ziegler","doi":"10.1186/s13195-026-02138-w","DOIUrl":"10.1186/s13195-026-02138-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterised by the accumulation of β-amyloid (Aβ) and tau proteins, resulting in neurodegeneration and cognitive decline. Although Aβ and tau disrupt synaptic function, the association linking these molecular pathologies to network-level dysfunction and memory impairment remains poorly understood. Here, we investigated the effects of Aβ and tau pathology (CSF Aβ42/40 ratio and tau phosphorylated at position 181, p-tau-181, respectively) on effective connectivity related to memory encoding, which may provide a link between synaptic pathology and cognitive outcomes. Functional magnetic resonance imaging (fMRI) during visual memory encoding was acquired from 205 participants in the multicentric DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) across the AD spectrum. Effective connectivity was assessed using Dynamic Causal Modelling (DCM) of task-fMRI data, focusing on the parahippocampal place area (PPA), hippocampus (HC), and precuneus (PCU)-regions central to memory encoding. Disruptions in connectivity between temporal and parietal lobes were associated with both memory impairment and indices of AD pathology. Specifically, reduced positive effective connectivity from the PCU to the PPA and from the HC to the PCU were linked to higher p-tau-181 levels, with an amplification effect observed in the presence of amyloid accumulation for the latter connectivity. The disruption from the PCU to the PPA was found to be associated with decreased memory performance. Together, these findings indicate that temporo-parietal connectivity is associated with both AD molecular pathology and, for a subset of connections, with memory performance.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443922","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":"Steroid hormones in Alzheimer's disease: a molecular analysis of blood and cerebrospinal fluid.","authors":"Tik Muk, Asger Wretlind, Kourosh Hooshmand, Marc Clos-Garcia, Yue Liu, Anja Hviid Simonsen, Laura M Winchester, Tarunveer S Ahluwalia, Petroula Proitsi, Riccardo E Marioni, Thomas Kümler, Steen Gregers Hasselbalch, Cristina Legido-Quigley","doi":"10.1186/s13195-026-02117-1","DOIUrl":"10.1186/s13195-026-02117-1","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) disproportionately affects women, yet existing studies have been limited to single biofluids, individual hormones, or single dementia subtypes, leaving sex-stratified profiles across the cognitive impairment spectrum poorly defined. Here we address this gap by simultaneously quantifying nine steroid hormones spanning glucocorticoid (cortisol, 11-deoxycortisol), mineralocorticoid (aldosterone), progestogen (progesterone, 17-hydroxyprogesterone), androgen (testosterone, dihydrotestosterone), and estrogen (estradiol, estrone) pathways in paired CSF and plasma across five cognitive categories: no cognitive impairment, mild cognitive impairment (MCI) with AD pathology, MCI without AD pathology, AD dementia, and vascular dementia.</p><p><strong>Methods: </strong>Steroid hormones were quantified by liquid chromatography-tandem mass spectrometry in paired cerebrospinal fluid (CSF) and plasma samples drawn from the same individuals from a cross-sectional study including 204 participants across five cognitive categories at the Danish Dementia Research Centre. Gender-stratified generalized linear models adjusted for age were applied. Cortisol findings were validated externally using the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (n = 426).</p><p><strong>Results: </strong>Female participants with AD exhibited elevated CSF cortisol (fold change [FC] = 1.13; P = .04) and CSF 11-deoxycortisol (FC = 1.01; P = .03), alongside reduced plasma progesterone (FC = 0.90; P = .04). Male participants with AD showed elevated plasma aldosterone (FC = 1.19; P = 2.81e-03; q = 0.02). CSF cortisol correlated with amyloid-β42 and phosphorylated tau in female participants. ADNI validation confirmed elevated plasma cortisol in AD, with a larger effect in female participants.</p><p><strong>Conclusions: </strong>Gender-dependent steroid hormone dysregulation in dementia highlights cortisol and aldosterone as potentially modifiable targets warranting further investigation.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454292","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":"Three-order interactions in the alpha band of default mode network EEGs based on O-information rate: insights from aging and Alzheimer's disease.","authors":"Hamed Azami, Yuri Antonacci, Daniel M Blumberger, Heather Brooks, Luca Faes, Corinne E Fischer, Alastair Flint, Nathan Herrmann, Sanjeev Kumar, Damien Gallagher, Linda Mah, Benoit H Mulsant, Nicole Schoer, Bruce G Pollock, Tarek K Rajji","doi":"10.1186/s13195-026-02131-3","DOIUrl":"10.1186/s13195-026-02131-3","url":null,"abstract":"<p><strong>Background: </strong>Alpha-band default mode network (DMN) connectivity declines with aging and Alzheimer's disease (AD), yet most electroencephalography (EEG) connectivity studies used pairwise (two-order) measures, such as mutual information rate (MIR). We leveraged O-information rate (OIR) to quantify three-order interactions and to separate redundant from synergistic information processing across frontal, temporal, and parietal DMN regions. We hypothesized that, extending established findings of reduced pairwise connectivity, (i) OIR (and its components) would be reduced in older versus younger adults and in AD versus healthy controls (HC); (ii) combining MIR with OIR would improve classification compared with MIR alone; and (iii) OIR measures would correlate positively with global cognition (as assessed by the Montreal Cognitive Assessment (MoCA)).</p><p><strong>Methods: </strong>Resting-state EEG from two samples-healthy adult lifespan aging (95 younger; 93 older) and AD spectrum (44 HC; 84 amnestic mild cognitive impairment [aMCI]; 41 AD)-was source-localized using eLORETA to DMN regions. Alpha band (8-13 Hz) MIR and OIR were computed through multivariate spectral analysis. Group differences were tested using t-tests or analysis of covariance (ANCOVA) with multiple comparison correction. Classification (OIR, MIR, demographic, and combined feature sets) used cross-validated logistic-regression, linear-SVM, and random-forest models, with bootstrap 95% confidence intervals and DeLong tests for AUC comparisons.</p><p><strong>Results: </strong>OIR and its redundancy component were significantly reduced in older versus younger adults and in AD versus HC/aMCI, with no HC-aMCI differences. The synergy component showed no group differences. MIR decreased broadly with aging and fronto-parietally in AD. Regarding classification (AD spectrum dataset, cross-validated AUC), OIR-based metrics outperformed MIR (AD vs. HC: 0.93 vs. 0.73; AD vs. aMCI: 0.93 vs. 0.71; aMCI vs. HC: 0.48 vs. 0.46). Combining demographics with all information-theoretic features improved AD vs. HC (0.98; DeLong p = 0.023) but not AD vs. aMCI (0.93), where OIR alone was already at ceiling; no feature set exceeded chance for aMCI vs. HC. After correction, OIR and its redundancy component correlated positively with MoCA scores; MIR and the synergy component did not.</p><p><strong>Conclusions: </strong>Alpha-band three-order DMN interactions-particularly redundant information processing-decline with aging and AD and provide additional information beyond two-order connectivity for diagnostic classification. OIR offers complementary measures to traditional metrics, and future studies should examine its value when combined with more established AD biomarkers.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443902","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}