Alzheimer's Research & Therapy最新文献

{"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}

{"title":"Sequential associations of myelin dysfunction with Aβ and Tau pathology in Alzheimer's disease: a dynamic myelin perturbation.","authors":"Jingxiang Wen, Guoyu Lan, Yuan Fu, Weiru Jiang, Bin Xu, Jing Zhang","doi":"10.1186/s13195-026-02139-9","DOIUrl":"10.1186/s13195-026-02139-9","url":null,"abstract":"<p><strong>Background: </strong>Myelin dysfunction has emerged as a potentially pivotal factor in Alzheimer's disease (AD); however, its temporal dynamics and relationship with hallmark pathological processes remain incompletely understood. This study aimed to investigate dynamic demyelination and its association with the progression of Aβ and Tau pathology in AD.</p><p><strong>Methods: </strong>A total of 1,237 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 18F-florbetapir (FBP) PET imaging were included. White matter SUVR (WM SUVR), defined as the adjusted FBP signal in white matter, was used as a proxy measure of myelin integrity. Cross-sectional and longitudinal analyses were conducted to examine associations between WM SUVR and AD progression, as well as AD-related biomarkers. Using cortical Aβ accumulation as a temporal reference, we further evaluated two-year changes in cortical Aβ and cumulative Tau PET signals in individuals with and without reduced myelin integrity (WM - vs. WM + uptake).</p><p><strong>Results: </strong>WM SUVR demonstrated a gradual decline with advancing AD severity. Lower WM SUVR was associated with changes in Aβ_42/40 and pTau₁₈₁ levels in both cerebrospinal fluid (CSF) and plasma. In early-stage AD, the WM - group exhibited a higher two-year rate of cortical Aβ accumulation compared with the WM + uptake group. At comparable levels of cortical amyloid, the WM - group showed significantly higher Tau PET signals in temporal meta-regions of interest and more extensive cortical spread in later stages.</p><p><strong>Conclusions: </strong>Progressive myelin dysfunction is observed across the course of AD as a notable perturbation within neurodegenerative processes. Early alterations in myelin integrity are associated with subsequent Aβ accumulation, whereas later changes coincide with increased Tau aggregation. These findings support a conceptual framework in which myelin degeneration shows temporally structured associations with AD pathology and may serve as a sensitive marker of vulnerability, particularly in early disease stages.</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/PMC13656713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454224","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":"Real-world safety and implementation challenges of lecanemab therapy for Alzheimer's disease in South Korea: a single-center experience.","authors":"Hyemin Jang, Jae Woo Kim, Jung Won Hwang, Da Woon Jeong, Jeongeun Ka, Da Min Kang, Chong Hyun Suh, Yangsean Choi, Minyoung Oh, Jae Seung Kim, Jae-Sung Lim, Jae-Hong Lee","doi":"10.1186/s13195-026-02141-1","DOIUrl":"10.1186/s13195-026-02141-1","url":null,"abstract":"<p><strong>Background: </strong>Lecanemab, an amyloid-targeting monoclonal antibody, was recently approved for early symptomatic Alzheimer's disease in South Korea. Asians were underrepresented in prior trials, and real-world data from Korea remain scarce, particularly regarding treatment settings, adverse events, and barriers to scalability. We assessed the feasibility and safety of lecanemab among Korean patients in a real-world tertiary hospital.</p><p><strong>Methods: </strong>A total of 112 patients initiated lecanemab treatment between December 2024 and October 2025 at Asan Medical Center. Prevalence of infusion-related reactions (IRRs), Amyloid-Related Imaging Abnormalities (ARIA), treatment discontinuation, and factors limiting implementation were evaluated.</p><p><strong>Results: </strong>Among 112 patients (mean age 71 years; 59% female), IRRs occurred in 41 (37%) and were generally mild or moderate under active surveillance. Among 105 at-risk patients who received at least four infusions and had at least one monitoring MRI, ARIA developed in 20 (19%): ARIA-E/H in 6 (5.7%) and isolated ARIA-H in 14 (13.3%). Only 1 patient with isolated ARIA-H presented with transient confusion. Patients with ARIA-E/H were younger, whereas those with ARIA-H were older and more likely to have baseline microhemorrhages. Eleven out of 105 were APOE ε4/ε4 homozygotes, of whom 5 developed ARIA. The rapid increase in treatment demand exceeded outpatient infusion capacity, resulting in progressively longer waiting times-up to 20 weeks 9 months after program initiation.</p><p><strong>Conclusion: </strong>This single-center experience from a tertiary referral hospital in Korea demonstrates that lecanemab treatment was feasible and generally well-tolerated, with manageable adverse events including ARIA and IRRs; however, limited infusion capacity, lack of reimbursement, and patient concentration in tertiary centers highlight the need for referral networks and system-level strategies to improve nationwide accessibility.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443925","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":"Thresholds for meaningful change in Mini-Mental State Examination scores in rare dementias.","authors":"Tamar Abzhandadze, Minh Tuan Hoang, Xinqi Bao, Madeleine Åkerman, Jakob Norgren, Belén García Pascual, Minjia Mo, Maria Eriksdotter, Hong Xu, Sara Garcia-Ptacek","doi":"10.1186/s13195-026-02136-y","DOIUrl":"10.1186/s13195-026-02136-y","url":null,"abstract":"<p><strong>Background: </strong>We conceptualize the Real-World Reassessment Threshold (RWRT) as representing the smallest change that exceeds expected measurement variability while accounting for clinically expected cognitive decline over the assessment interval, whereas the minimum clinically important difference (MCID) indicates the smallest change likely to be clinically meaningful. To date, no study has empirically defined the RWRT or MCID for Mini-Mental State Examination (MMSE) scores in Lewy body dementia (LBD) or frontotemporal dementia (FTD), limiting the interpretation of longitudinal changes and clinical trial designs. We therefore aimed to estimate 12-month, diagnosis-specific MMSE thresholds for RWRT and MCID among individuals with LBD and FTD, and to evaluate the generalizability of these thresholds in an independent validation cohort.</p><p><strong>Methods: </strong>This registry-based cohort study included individuals diagnosed with LBD or FTD from the Swedish Registry for Cognitive/Dementia Disorders (SveDem, 2007-2022) with a 91-400-day MMSE follow-up, and an independent validation cohort from the U.S. National Alzheimer's Coordinating Center (NACC). The RWRT was estimated using distribution-based methods based on intraclass correlation coefficients (ICCs). MCID was estimated using both anchor-based and distribution-based (0.5 standard deviation) approaches.</p><p><strong>Results: </strong>We included 1,158 individuals from SveDem (873 LBD, 285 FTD) and 1,060 individuals from NACC (469 LBD, 591 FTD). Over the 91-400-day follow-up interval, MMSE scores demonstrated moderate to high reliability (ICC 0.70-0.90), corresponding to RWRT estimates ranged from 5 to 7 MMSE points. Anchor-based MCIDs differed by diagnosis, with a mean threshold of 0.7 points in LBD and 3.8 points in FTD in SveDem; similar diagnosis- and baseline severity-dependent patterns were observed in NACC. In contrast, distribution-based MCIDs were consistent across diagnoses, clustering around 2-3 MMSE points.</p><p><strong>Conclusions: </strong>MMSE changes of less than five points over one year may reflect expected test variability combined with expected individual decline. However, average changes of 2-3 points may still be meaningful when combined with a clinical anchor of change, depending on diagnosis and disease stage. These results emphasize the importance of using both RWRT and MCID when evaluating MMSE change and selecting clinical trial endpoints.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417966","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 probabilistic framework for clinicopathological Alzheimer's disease using tau-PET.","authors":"Bastiaan G J van Tol, Colin Groot, Marie R Vermeiren, Elsmarieke van de Giessen, Yolande A L Pijnenburg, Emma M Coomans, Rik Ossenkoppele","doi":"10.1186/s13195-026-02133-1","DOIUrl":"10.1186/s13195-026-02133-1","url":null,"abstract":"<p><strong>Background: </strong>[¹⁸F]flortaucipir tau-PET detects neurofibrillary tangle (NFT) pathology in Alzheimer's disease (AD), one of the core pathological hallmarks of the disease. In clinical settings, tau-PET is usually interpreted qualitatively, and therefore quantitative estimates of how scan results alter the probability that AD explains a patient's symptoms are lacking. Here, we evaluate the probability of clinicopathological AD given a positive or negative tau-PET scan and examine how patient age and amyloid-PET status modulate this probability.</p><p><strong>Methods: </strong>We computed positive and negative predictive values (PPV/NPV) of tau-PET for clinicopathological AD, defined as mild cognitive impairment or dementia with AD as the primary etiology. To account for potential pathological and clinicopathological mismatches, PPV and NPV were modeled using literature-derived sensitivity and specificity estimates of [¹⁸F]flortaucipir PET for postmortem Braak V/VI NFT pathology, together with literature-derived age-dependent tau-PET positivity rates in cognitively unimpaired individuals. We also considered hypothetical clinician-estimated pre-PET AD probabilities. PPV and NPV were calculated for tau-PET and for sequential amyloid- and tau-PET scenarios.</p><p><strong>Results: </strong>Tau-PET PPV for clinicopathological AD was generally high, particularly in individuals with higher clinician-estimated pre-PET AD probabilities, and showed minor age-related declines (e.g., 84% at ages 50-55 vs. 75% at ages 85-90, at 50% pre-PET probability). Tau-PET NPV was consistently higher than PPV and showed negligible age-related decline (e.g., 92% at ages 50-55 vs. 90% at ages 85-90, at 50% pre-PET probability). A positive tau-PET following positive amyloid-PET substantially increased PPV, particularly in older individuals (e.g., PPV increased from 56% to 83% at ages 75-80 and 30% pre-PET probability), whereas the corresponding gain in NPV after tau-PET following amyloid-PET was smaller.</p><p><strong>Conclusions: </strong>Tau-PET demonstrates high PPV and NPV for clinicopathological AD. A positive tau-PET following positive amyloid-PET further increases the probability of clinicopathological AD, particularly in older adults. This underscores tau-PET's clinical utility and highlights the effect of age and pre-PET certainty on post-PET AD probabilities.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417994","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":"Analytical and clinical validation of a novel proximity extension assay-based plasma biomarker panel in a cohort of prevalent neurodegenerative dementias.","authors":"Giuseppe Mario Bentivenga, Angela Mammana, Simone Baiardi, Erica Vittoriosi, Andrea Mastrangelo, Edoardo Ruggeri, Claudia Marina Vargiu, Barbara Polischi, Michelangelo Stanzani-Maserati, Giovanni Rizzo, Roberta Pantieri, Alberto Raggi, Sabina Capellari, Piero Parchi","doi":"10.1186/s13195-026-02142-0","DOIUrl":"10.1186/s13195-026-02142-0","url":null,"abstract":"<p><strong>Background: </strong>Blood-based biomarkers are increasingly recognized as promising tools for the diagnosis and monitoring of neurodegenerative diseases, offering a minimally invasive alternative to cerebrospinal fluid (CSF) testing. We evaluated the analytical performance and clinical utility of the Olink Target 48 Neurodegeneration panel, a novel multiplex proteomic platform based on the proximity extension assay (PEA) technology, in a large, clinically diverse dementia cohort.</p><p><strong>Methods: </strong>We retrospectively analyzed plasma samples from 238 patients with Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal dementia, progressive supranuclear palsy, and corticobasal degeneration, along with 65 healthy controls, quantifying 41 proteins in each sample. We assessed analytical performance using intra- and inter-assay coefficients of variation, evaluated diagnostic accuracy through receiver operating characteristic curve analysis, and investigated associations between biomarker levels, clinical severity measures, and pathology-specific CSF biomarkers for AD and Lewy body pathology (LBP) using general linear models.</p><p><strong>Results: </strong>The platform quantified 32 proteins with variable analytical performance; nine were excluded due to poor detectability. Strong correlations were observed between PEA-based measurements and established immunoassays for plasma pTau217, NEFL, and GFAP (all p < 0.001). Plasma pTau217 demonstrated superior diagnostic accuracy for AD, achieving an area under the curve (AUC) exceeding 0.91 against all comparison groups. Novel ratios combining NEFL with markers of immune function or synaptic integrity (NEFL/ITGB2, NEFL/ITGAM, NEFL/SCG2) achieved AUCs exceeding 0.93 for discriminating patients from controls, significantly outperforming NEFL alone (all p < 0.001). Thirteen proteins, spanning markers of neuroaxonal damage, myelin-associated processes, and immune function (i.e., Abeta40, Abeta42, BMP7, CLSTN3, ENO2, KLK8, MMP10, NEFL, NPTXR, OMG, RTN4R, SCG2, SDC4, all p < 0.01) showed significant independent associations with disease stage as measured by the Clinical Dementia Rating scale. Four proteins (i.e., pTau217, GFAP, SYT1, and SDC4) were significantly associated with AD pathology, while three (ENO2, ITGAM, and ITGB2) showed significant associations with LBP (all p < 0.05).</p><p><strong>Conclusions: </strong>This multiplex platform provides multiplex biomarker measurements with potential utility for AD diagnosis and disease staging across neurodegenerative disorders. These findings support further validation studies for its implementation in clinical and research settings.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417985","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":"In vivo evidence for soluble Aβ oligomer-driven neuronal metabolic dysfunction in 5xFAD mice.","authors":"Chaynita Dashora, Anant Bahadur Patel","doi":"10.1186/s13195-026-02130-4","DOIUrl":"https://doi.org/10.1186/s13195-026-02130-4","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is characterized by the extracellular accumulation of amyloid-β (Aβ). Brain glucose hypometabolism, an early feature of AD, reflects neuronal metabolic dysfunction before the onset of clinical symptoms. While Aβ plaques are central to AD pathogenesis, the mechanisms by which different Aβ species, such as plaques and soluble oligomers, drive cell-type-specific neurometabolic dysfunction during disease progression remain poorly understood. This study evaluated the roles of different Aβ species in the neurometabolic trajectory across the presymptomatic, symptomatic, and advanced stages of AD.</p><p><strong>Methods: </strong>5xFAD and wild-type (WT) mice were investigated for cognitive performance, quantitative Aβ levels, and glial activation markers at 3, 6, and 12 months of age. Neuronal and astroglial metabolic activities were evaluated ex vivo using state-of-the-art ¹H-[¹³C]-NMR spectroscopy in conjunction with administration of [1,6-¹³C₂]glucose and [2-¹³C]acetate, respectively.</p><p><strong>Results: </strong>The 5xFAD mice exhibited cognitive decline from 6 months that further deteriorated by 12 months. There was a marked increase in Aβ-plaque burden and soluble oligomers from 3 to 12 months of age. These mice showed a significant reduction in hippocampal glutamatergic (0.145 ± 0.031 vs. 0.172 ± 0.016 µmol/g/min, p = 0.035) and GABAergic neuronal metabolic activity (0.027 ± 0.006 vs 0.033 ± 0.003 µmol/g/min, p = 0.028) as early as 3 months of age, with similar reductions observed in the cerebral cortex. The neurometabolic impairments further aggravated with age. Astrocytic metabolic activity was not significantly changed till 6 months but was increased at 12 months in 5xFAD mice in both the cerebral cortex (0.101 ± 0.014 vs. 0.084 ± 0.006 µmol/g/min, p = 0.011) and hippocampus (0.103 ± 0.006 vs. 0.089 ± 0.012 µmol/g/min, p = 0.011). The increase in astrocytic metabolic activity paralleled reactive gliosis, suggesting a shift from early neuronal metabolic impairment to heightened astroglial metabolic activity and inflammatory glial responses during the advanced AD stage. Notably, Aβ₄₀ oligomers exhibited a greater sensitivity to impairment in neuronal glucose oxidation and cognitive function than Aβ₄₂ oligomers or fibrillar plaques.</p><p><strong>Conclusions: </strong>These findings delineate a sequential neurometabolic cascade during AD progression, characterized by early neuronal glucose hypometabolism, subsequent cognitive decline linked to soluble Aβ₄₀ oligomers, and late-stage astroglial metabolic activation. Collectively, these results suggest that soluble Aβ₄₀ oligomers exhibit the greatest sensitivity to neurometabolic and cognitive impairment during AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417964","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":"Activity profiles and their associations with transitions between fall and dementia: findings from a multistate time-to-event analysis.","authors":"Benjamin Kröger, Maria M Ekblom, Hui-Xin Wang, Charlotta Thunborg, Miia Kivipelto, Rui Wang","doi":"10.1186/s13195-026-02140-2","DOIUrl":"10.1186/s13195-026-02140-2","url":null,"abstract":"<p><strong>Background: </strong>The potential link between data-driven classifications of individuals' activity profiles and the occurrence of fall and dementia, including within-person transitions from dementia- or fall-only states to their co-occurrence over time, remains unclear.</p><p><strong>Method: </strong>To examine whether distinct activity profiles were associated with the risk of fall, dementia, and their transitions over time in middle-aged and older adults, this prospective longitudinal study included 288,287 adults (53.6% women) aged 40-69 years at baseline (2006-2010) from the UK Biobank. Latent class analysis was used to classify participants into distinct activity profiles based on self-reported physical activity, transportation, work, social, and sleep behaviours. Incident fall and dementia were identified through linkage to health records and the death registry up to December 2022. Multistate time-to-event analysis was conducted to examine the associations between activity profiles and the risks of fall, dementia, and their transitions over time.</p><p><strong>Results: </strong>Based on various activity levels and work status, participants were categorized into four groups: active-non-working (29.2%), inactive-non-working (14.4%), active-working (26.7%), and inactive-working (29.7%). Of them, 19,753 (6.85%) experienced a fall injury, and 4,407 (1.53%) developed dementia over an average follow-up of 13.4 years. The inactive-non-working group showed the highest risk of both fall and dementia (HR_range: 1.45-2.38) over 13.4 years. In the non-working groups, where fall and dementia occurred most often, the inactive profile was linked to a higher risk of both fall and dementia, and to an increased likelihood of transitioning between the two. Transitions from dementia to subsequent fall were associated with insufficient physical activity, whereas transitions from fall to subsequent dementia were linked to social isolation, particularly living alone and frequent loneliness. In the working groups, no differences in fall or dementia risk were observed between active and inactive profiles.</p><p><strong>Conclusions: </strong>This study highlights the important role of social and physical activity in simultaneously preventing fall, dementia, and their transitions, particularly among non-working individuals, including those on sick leave or retired.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":" ","pages":""},"PeriodicalIF":7.6,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417992","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}