Alzheimer's Research & Therapy最新文献

{"title":"Revealing heterogeneity in mild cognitive impairment based on individualized structural covariance network.","authors":"Xiaotong Wei, Ronglong Xiong, Ping Xu, Tingting Zhang, Junjun Zhang, Zhenlan Jin, Ling Li","doi":"10.1186/s13195-025-01752-4","DOIUrl":"10.1186/s13195-025-01752-4","url":null,"abstract":"<p><strong>Background: </strong>Mild cognitive impairment (MCI) is a heterogeneous disorder with significant individual variabilities in clinical and biological features. Abnormal inter-regional structural covariance suggests disruption of the brain structural network in MCI. Most studies have examined group-level structural covariance alterations while ignoring individual-level differences. Hence, we aimed to investigate the heterogeneity of MCI using individual differential structural covariance network (IDSCN) analysis.</p><p><strong>Methods: </strong>T1-weighted images of 596 MCI patients and 309 cognitively normal (CN) were collected from the ADNI database as discovery dataset, and 122 MCI and 117 CN from the OASIS-3 dataset as validation cohort. We constructed each patient's IDSCN using regional gray matter volume and applied K-means clustering analysis to identify MCI subtypes based on significantly altered covariance edges. Then, clinical features, brain structure, and gene expression profiles were evaluated for each subtype.</p><p><strong>Results: </strong>In the ADNI dataset, MCI patients exhibited significant alterations in structural covariance edges, mainly involving the hippocampus, parahippocampal gyrus, and amygdala. Two robust MCI subtypes were identified. Subtype 1 showed faster disease progression relative to subtype 2, which was validated in the independent OASIS-3 dataset. Significant differences between two subtypes were found in clinical cognition and biomarkers, cerebral atrophy patterns, and enriched genes for metal ion transport and neuron projection development. Finally, correlation analysis and functional annotation further revealed that the affected edges were related to cognitive performance and implicated in memory and emotion terms.</p><p><strong>Conclusions: </strong>In summary, these findings offer new perspectives into understanding the heterogeneity of MCI and facilitate strategies for future precision medicine.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"106"},"PeriodicalIF":7.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep normative modelling reveals insights into early-stage Alzheimer's disease using multi-modal neuroimaging data.","authors":"Ana Lawry Aguila, Luigi Lorenzini, Mohammed Janahi, Frederik Barkhof, Andre Altmann","doi":"10.1186/s13195-025-01753-3","DOIUrl":"10.1186/s13195-025-01753-3","url":null,"abstract":"<p><strong>Background: </strong>Exploring the early stages of Alzheimer's disease (AD) is crucial for timely intervention to help manage symptoms and set expectations for affected individuals and their families. However, the study of the early stages of AD involves analysing heterogeneous disease cohorts which may present challenges for some modelling techniques. This heterogeneity stems from the diverse nature of AD itself, as well as the inclusion of undiagnosed or 'at-risk' AD individuals or the presence of comorbidities which differentially affect AD biomarkers within the cohort. Normative modelling is an emerging technique for studying heterogeneous disorders that can quantify how brain imaging-based measures of individuals deviate from a healthy population. The normative model provides a statistical description of the 'normal' range that can be used at subject level to detect deviations, which may relate to pathological effects.</p><p><strong>Methods: </strong>In this work, we applied a deep learning-based normative model, pre-trained on MRI scans in the UK Biobank, to investigate ageing and identify abnormal age-related decline. We calculated deviations, relative to the healthy population, in multi-modal MRI data of non-demented individuals in the external EPAD (ep-ad.org) cohort and explored these deviations with the aim of determining whether normative modelling could detect AD-relevant subtle differences between individuals.</p><p><strong>Results: </strong>We found that aggregate measures of deviation based on the entire brain correlated with measures of cognitive ability and biological phenotypes, indicating the effectiveness of a general deviation metric in identifying AD-related differences among individuals. We then explored deviations in individual imaging features, stratified by cognitive performance and genetic risk, across different brain regions and found that the brain regions showing deviations corresponded to those affected by AD such as the hippocampus. Finally, we found that 'at-risk' individuals in the EPAD cohort exhibited increasing deviation over time, with an approximately 6.4 times greater t-statistic in a pairwise t-test compared to a 'super-healthy' cohort.</p><p><strong>Conclusion: </strong>This study highlights the capability of deep normative modelling approaches to detect subtle differences in brain morphology among individuals at risk of developing AD in a non-demented population. Our findings allude to the potential utility of normative deviation metrics in monitoring disease progression.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"107"},"PeriodicalIF":7.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075369","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":"Increased excitability of dentate gyrus mossy cells occurs early in life in the Tg2576 model of Alzheimer's disease.","authors":"David Alcantara-Gonzalez, Meghan Kennedy, Chiara Criscuolo, Justin Botterill, Helen E Scharfman","doi":"10.1186/s13195-025-01747-1","DOIUrl":"10.1186/s13195-025-01747-1","url":null,"abstract":"<p><strong>Background: </strong>Hyperexcitability in Alzheimer's disease (AD) is proposed to emerge early and contribute to disease progression. The dentate gyrus (DG) and its primary cell type, granule cells (GCs) are implicated in hyperexcitability in AD. Hence, we hypothesized that mossy cells (MCs), important regulators of GC excitability, contribute to early hyperexcitability in AD. Indeed, MCs and GCs are linked to hyperexcitability in epilepsy.</p><p><strong>Methods: </strong>Using the Tg2576 model of AD and WT mice (~ 1 month-old), we compared MCs and GCs electrophysiologically and morphologically, assessed the activity marker c-Fos, Aβ expression and a hippocampal- and MC-dependent memory task that is impaired at 3-4 months of age in Tg2576 mice.</p><p><strong>Results: </strong>Tg2576 MCs had increased spontaneous excitatory events (sEPSP/Cs) and decreased spontaneous inhibitory currents (sIPSCs), increasing the excitation/inhibition ratio. Additionally, Tg2576 MC intrinsic excitability was enhanced. Consistent with in vitro results, Tg2576 MCs showed enhanced c-Fos protein expression. Tg2576 MCs had increased intracellular Aβ expression, suggesting a reason for increased excitability. GCs showed increased excitatory and inhibitory input without changes in intrinsic properties, consistent with effects of increased MC activity. In support, increased GC activity was normalized by an antagonist of MC input to GCs. Also in support, Tg2576 MC axons showed sprouting to the area of GC dendrites. These effects occurred before an impairment in the memory task, suggesting they are extremely early alterations.</p><p><strong>Conclusions: </strong>Alterations in Tg2576 MCs and GCs early in life suggest an early role for MCs in increased GC excitability. MCs may be a novel target to intervene in AD pathophysiology at early stages.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"105"},"PeriodicalIF":7.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075007","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":"tRF^Ala-AGC-3-M8 attenuates neuroinflammation and neuronal damage in Alzheimer's disease via the EphA7-ERK_1/2-p70S6K signaling pathway.","authors":"Zihao Deng, Yudi Li, Wenjun Chi, Wanzhou Zhang, Fangming Li, Li Ling","doi":"10.1186/s13195-025-01734-6","DOIUrl":"10.1186/s13195-025-01734-6","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disorder clinically characterized by memory decline, cognitive dysfunction, language impairment, deterioration of visuospatial skills, and personality changes. Pathologically, AD is marked by the deposition of β-amyloid (Aβ) plaques in the brain, the formation of neurofibrillary tangles, and progressive neuronal loss. Recent research has highlighted transfer RNA (tRNA)-derived small RNAs (tsRNAs) as crucial regulators in various biological processes; however, their roles in the pathophysiology of AD remain largely unexplored. The erythropoietin-producing hepatocellular (Eph) receptor family has recently drawn attention in the study of neurodegenerative diseases due to their role in regulating critical processes, including cell migration, neural development, angiogenesis, and tumor formation. This study aimed to investigate specific tsRNAs associated with AD by performing RNA sequencing on the cortex of APP/PS1 transgenic mice and to explore the relationship between tsRNAs and their target genes within the Eph receptor family, thereby elucidating insights into the specific regulatory functions of these molecules.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Eight-month-old male C57BL/6 and APP/PS1 transgenic mice were used in the study. BV-2 and HT22 cells were cultured and treated with Aβ&lt;sub&gt;25-35&lt;/sub&gt; at concentrations ranging from 0 µM to 40 µM. RNA was extracted from cortical tissues, and tRNA-derived fragments were analyzed after pre-treatment to remove RNA modifications. Differential expression of tRFs and tiRNAs was identified through sequencing, followed by bioinformatics analysis of target genes using TargetScan and miRanda. Transfection of BV-2 and HT22 cells with EphA7-siRNA and tRF&lt;sup&gt;Ala-AGC-3-M8&lt;/sup&gt;-mimic was conducted, and their interaction was validated using dual-luciferase reporter assays. Protein expression levels were assessed by western blotting and immunofluorescence. Statistical analyses were performed using R and GraphPad Prism, with significance set at p &lt; 0.05.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;We identified for the first time that EphA7 expression is upregulated in aggregated microglia and neuronal cells in the dentate gyrus region of the hippocampus, with increased phosphorylation of ERK&lt;sub&gt;1/2&lt;/sub&gt; and p70S6K in AD. This upregulation occurred following the downregulation of tRF&lt;sup&gt;Ala-AGC-3-M8&lt;/sup&gt; due to Aβ stimulation and was confirmed via in vitro experiments. By inhibiting EphA7 expression and increasing tRF&lt;sup&gt;Ala-AGC-3-M8&lt;/sup&gt; expression, we suppressed the ERK&lt;sub&gt;1/2&lt;/sub&gt;-p70S6K signaling pathway in BV-2 and HT22 cells. This intervention alleviated neuronal damage and tau hyperphosphorylation in HT22 cells and reduced the M1-type polarization state of BV-2 cells induced by Aβ&lt;sub&gt;25-35&lt;/sub&gt; (see Graphical Abstract).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study clarifies the specific role of tRF&lt;sup&gt;Ala-AGC-3-M8&lt;/","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"104"},"PeriodicalIF":7.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075373","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":"The cost effectiveness of a multidomain intervention on physical, cognitive, vascular, dietary and psychosocial outcomes among community dwelling older adults with cognitive frailty in Malaysia: The AGELESS Trial.","authors":"Pavapriya Ponvel, Suzana Shahar, Devinder Kaur Ajit Singh, Arimi Fitri Mat Ludin, Ponnusamy Subramaniam, Norhayati Ibrahim, Hasnah Haron, Aniza Ismail, Chin Ai-Vyrn, Mazlyfarina Mohamad, Hidayah Fadzil, Norhayati Mustafa Khalid, A'isyah Mohammad Safien, Jamilah Mohammad Hanipah, Azyana Ibrahim, Jenni Lehtisalo, Miia Kivipelto, Francesca Mangialasche","doi":"10.1186/s13195-025-01722-w","DOIUrl":"10.1186/s13195-025-01722-w","url":null,"abstract":"<p><strong>Background: </strong>Cognitive frailty (CF) in older adults is a potentially reversible syndrome that may benefit from lifestyle-based multidomain interventions. This study assessed the AGELESS intervention's impact on cognitive, physical, vascular, dietary, and psychosocial outcomes, along with its cost-effectiveness, in a Low-Middle-Income Country (LMIC).</p><p><strong>Methods: </strong>The AGELESS randomized controlled trial recruited 106 older adults (above 60 years) from Klang Valley, Malaysia, with (pre)-CF (≥ 1 Fried's criteria and Clinical Dementia Rating scale = 0.5). Participants were randomly assigned to a 24-month multidomain intervention (physical activity, cognitive training, nutritional and psychological counselling, cardiovascular care) or control group (educational module). Primary outcomes, assessed at baseline, 12 and 24 months, included the modified Neuropsychological Tests Battery (mNTB) and physical performance measures. Intervention costs were calculated to determine Incremental Cost-Effectiveness Ratios (ICERs). An intention-to-treat analysis was conducted to account for attrition.</p><p><strong>Results: </strong>The trial occurred during the COVID-19 pandemic. Despite a 50% dropout rate, adherence among remaining participants was over 50% for all intervention components (range 53%-91%). The intervention led to significant improvements in selected parameters of cognitive function, physical performance, anthropometry, and dietary patterns (for all parameters, p < 0.05 for interaction time*group in repeat-measures ANOVA). The cost per participant was RM 1592.74 (≈USD 355.05) in the multidomain arm, and RM 488.21 (≈USD 108.83) in the control arm. The ICER computation indicated the 2-min step test as the most cost-effective measure (ICER RM 149.19 ≈USD33.26).</p><p><strong>Conclusion: </strong>The AGELESS trial demonstrates that a multidomain, lifestyle-based intervention can improve cognitive and physical function in older adults with (pre)-CF. This cost-effective approach highlights CF as a modifiable health condition and supports its potential inclusion in health policy to promote healthy aging and reduce health risks in LMICs, where there is a larger prevention potential due to prevalent lifestyle-related risk factors.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"101"},"PeriodicalIF":7.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959704","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":"Linking oxysterols and different stages of mild cognitive impairment: insights from gut metabolites and N6-methyladenosine.","authors":"Wenjing Feng, Mengwei Ju, Tao Wang, Shanshan Cui, Kexin Yang, Zhiting Guo, Miao Liu, Jiaxuan Tao, Huiyan Yu, Rong Xiao","doi":"10.1186/s13195-025-01743-5","DOIUrl":"10.1186/s13195-025-01743-5","url":null,"abstract":"<p><strong>Background: </strong>Oxysterols, gut metabolites, and N6-methyladenosine (m6A) are extensively implicated in the pathogenesis of cognitive dysfunction, while their alterations in different stages of mild cognitive impairment (MCI) have not been elucidated. Therefore, this study was conducted to explore the associations of oxysterols, gut metabolites, and m6A methylation profiles in early MCI (EMCI) and late MCI (LMCI) individuals.</p><p><strong>Methods: </strong>Liquid chromatography-mass spectrometry, untargeted metabolomic analysis, and m6A mRNA Epitranscriptomic Microarray were used to detect the characteristics of serum oxysterols (n = 35/group), fecal gut metabolites (n = 30/group), and m6A in whole blood (n = 4/group) respectively. The concentration of serum β-amyloid (Aβ) was detected with ELISA (n = 25/group). The gene expression of amyloid precursor protein (APP) and its key enzyme β-secretase (BACE1) in whole blood were measured by quantitative real-time PCR (n = 25/group).</p><p><strong>Results: </strong>EMCIs and LMCIs, especially LMCIs, exhibited poorer performance in almost all global and multidimensional cognitive tests. Serum 27-hydroxycholesterol (27-OHC) and 24S-hydroxycholesterol (24S-OHC) were elevated in EMCI and LMCI groups. Changes in gut metabolites occurred mainly in the EMCI group, in which several gut metabolites, including Procyanidin dimer B7 and Phorbol myristate, were significantly decreased. The m6A methylation landscape of EMCIs and LMCIs obviously differed from Controls. Hypomethylated mRNAs accounted for the majority and were mainly accompanied by downregulated mRNAs, which was consistent with the downregulated expression of the m6A writer methyltransferase-like 4 (METTL4). 27-OHC and 24S-OHC combined with various gut metabolites significantly distinguished between MCI subgroups from healthy controls (EMCI/Control: AUC = 0.877; LMCI/Control: AUC = 0.952). Heatmap revealed the correlation between Phorbol myristate and differentially m6A-methylated mRNAs. Differentially expressed gut metabolites and methylated mRNAs were commonly enriched in 34 KEGG metabolic pathways, including cholesterol metabolism and neurodegenerative disease-related pathways.</p><p><strong>Conclusions: </strong>Our study explored the altered oxysterols, gut metabolites, and m6A methylation and their associations in different stages of MCI. The potential function of aberrant gut metabolites in oxysterols and m6A methylation driving MCI progression warrants further mechanistic investigation.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"102"},"PeriodicalIF":7.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961890","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":"Development and validation of a novel predictive model for dementia risk in middle-aged and elderly depression individuals: a large and longitudinal machine learning cohort study.","authors":"Xuan Xiao, Yihui Li, Qiaoboyang Wu, Xinting Liu, Xu Cao, Maiping Li, Jianjing Liu, Lianggeng Gong, Xi-Jian Dai","doi":"10.1186/s13195-025-01750-6","DOIUrl":"10.1186/s13195-025-01750-6","url":null,"abstract":"<p><strong>Background: </strong>Depression serves as a prodromal symptom of dementia, and individuals with depression exhibit a significantly higher risk of developing dementia. The aim of this study is to develop and validate a novel dementia risk prediction tool among middle-aged and elderly individuals with depression based on machine learning algorithms.</p><p><strong>Methods: </strong>This study included 31,587 middle-aged and elderly individuals with depression who did not have a diagnosis of dementia at baseline from a large UK population-based prospective cohort. A rigorous variable selection strategy was employed to identify risk and protective factors of dementia from an initial pool of 190 candidate variables, ultimately retaining 27 variables. Eight distinct data analysis strategies were utilized to develop and validate the dementia risk prediction model. The DeLong's test was applied to compare the statistical differences between different models.</p><p><strong>Results: </strong>During a median follow-up of 7.98 years, 896 incident dementia cases were identified among study participants. In model development employing an 8:2 data split (fivefold cross-validation for training), the Adaboost classifier achieved the optimal performance (AUC 0.861 ± 0.003), followed by XGBoost (AUC 0.839 ± 0.005) and CatBoost (AUC 0.828 ± 0.007) classifiers. To facilitate community generalization and clinical applicability, we develop a simplified model through a forward feature subset selection algorithm, retaining 12 variables. The simplified model maintained robust performance, with AdaBoost achieving the highest discriminative ability (AUC 0.859 ± 0.002), followed by XGBoost (AUC 0.835 ± 0.001) and CatBoost (AUC 0.821 ± 0.005). The DeLong's test revealed no statistically significant difference in AUC values between models using 12 and 27 variables (p = 0.278). For practical implementation, we deployed the optimal model to a web application for visualization and dementia risk assessment, named DRP-Depression.</p><p><strong>Conclusions: </strong>We developed a practical and easy-to-promote risk prediction model based on machine learning algorithms, and deployed it to a web application to provide a new and convenient tool for dementia risk prediction in the middle-aged and elderly individuals with depression.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"103"},"PeriodicalIF":7.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963947","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":"Soluble SorLA in CSF, a novel biomarker to explore disrupted trafficking of SorLA protein in Alzheimer disease.","authors":"Romain Castelot, Aline Zarea, David Wallon, Anne Rovelet-Lecrux, Catherine Schramm, Muriel Quillard-Muraine, Anne Beaume, Frédéric Blanc, Olivier Bousiges, Julien Dumurgier, Maïté Formaglio, Gwenael Leguyader, Sylvain Lehmann, Cecilia Marelli, Matthieu Martinet, Leonor Nogueira, Jérémie Pariente, Isabelle Quadrio, Adeline Rollin-Sillaire, Susanna Schraen, Gaël Nicolas, Magalie Lecourtois","doi":"10.1186/s13195-025-01748-0","DOIUrl":"https://doi.org/10.1186/s13195-025-01748-0","url":null,"abstract":"<p><strong>Background: </strong>The SorLA protein, encoded by the Sortilin-related receptor 1 (SORL1) gene, is a major player in Alzheimer's disease (AD) pathophysiology. Functional studies demonstrated that SorLA deficiency results in increased production of Aβ peptide, and thus a higher risk of AD. SorLA can be subject to proteolytic shedding at the cell surface, leading to the release of the soluble ectodomain of the protein (sSorLA) in the extracellular space. Recently, we demonstrated that a large proportion (~25%) of rare SORL1 missense variants found in AD patients alter SorLA trafficking along the constitutive secretory pathway, resulting in reduced delivery of SorLA to the plasma membrane and thus a loss of function. Here, we aimed to determine if CSF levels of sSORLA in AD patients carrying SORL1 rare variants that impact or not the trafficking of the protein can be used as a novel biomarker to explore disrupted trafficking of SorLA protein in AD.</p><p><strong>Methods: </strong>A total of 151 participants were categorized into 5 study groups: controls without any neurodegenerative disease (n=30), patients suffering from Fronto-Temporal Lobar Degeneration (FTLD, n=34), AD patients not carrying a SORL1 rare variant (AD ^{SORL1 WT}, n=40), AD patients carrying SORL1 trafficking-defective variants or a protein-truncating variant (PTV) (AD^{SORL1 TD}, n=16), and AD patients carrying a SORL1 variant with no evidence of trafficking defect (AD ^{SORL1 nTD,} n=31). Thirty-three unique rare variants of SORL1 were included for this study: 3 PTVs, 13 missense variants that impact SorLA protein trafficking in in vitro cellular assays, and 17 variants with no detectable effect on SorLA protein trafficking. We measured amounts of cleaved sSorLA by western blot in CSF samples.</p><p><strong>Results: </strong>We found significantly decreased levels of sSorLA in AD^{SORL1 TD}, compared to all other groups. According to ROC curve analysis, levels of sSorLA showed good performances to distinguish AD^{SORL1 TD} patients from other AD patients (AUC=0.89 [95%CI: 0.81-0.97]).</p><p><strong>Conclusions: </strong>Our results suggest that differential levels of sSorLA in CSF could be used as a novel marker to explore disrupted trafficking of SorLA protein in Alzheimer disease. This could help solve some proportion of variants of uncertain significance in SORL1.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"100"},"PeriodicalIF":7.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959898","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":"\"It seems enormously valuable to me.\" Perspectives of Dutch (potential) carriers of genetic FTD on onset-predictive biomarker testing.","authors":"Charlotte H Graafland, Harro Seelaar, Jessica L Panman, Lize C Jiskoot, Tjitske Kleefstra, Jackie M Poos, Edo Richard, Maartje H N Schermer, John C van Swieten, Laura Donker Kaat, Eline M Bunnik","doi":"10.1186/s13195-025-01749-z","DOIUrl":"https://doi.org/10.1186/s13195-025-01749-z","url":null,"abstract":"<p><strong>Background: </strong>Onset-predictive biomarker tests (OPBT) in genetic frontotemporal dementia (FTD) may be used to recruit mutation carriers into preventive clinical trials before symptoms manifest. This would require disclosure of OPBT results to potential participants. This study investigates the perspectives of Dutch presymptomatic mutation carriers and individuals at 50% risk of genetic FTD on disclosure of OPBT results. It focuses on their willingness to receive OPBT results, what impacts they foresee from disclosure, and their preferences for the process of disclosure.</p><p><strong>Methods: </strong>Semi-structured interviews were conducted with presymptomatic mutation carriers and individuals at 50% risk of developing genetic FTD (n = 25), who had received genetic counselling or participate in a longitudinal cohort study. The interview transcripts were analysed using thematic inductive analysis.</p><p><strong>Results: </strong>Main themes were: willingness to undergo biomarker testing, foreseen impact of test results, preferences regarding biomarker test features, and understanding of biomarker testing. Most participants would be willing to receive OPBT results in the context of clinical trial recruitment. Participants would also be willing to receive OPBT results without access to clinical trial participation, as they perceived utility from these results. They would use positive OPBT results to prepare for the future, e.g. by planning for care, drawing up advance care directives, retiring early, and spending final healthy years well. At the same time, they thought positive OPBT results might also have negative psychological impacts on self-image or social dynamics with others. Implications of positive OPBT results for self-image as healthy or ill differed between participants. Negative OPBT results would provide relief and not lead to life changes.</p><p><strong>Conclusions: </strong>Dutch presymptomatic mutation carriers and individuals at 50% risk of developing genetic FTD tend to be willing to receive OPBT results. The results would allow for participation in a clinical trial and preparation for onset through personal life planning. At the same time, disclosure of OPBT results might have negative psychological consequences. This study provides valuable input for developing ethical guidance and an appropriate counselling process to ensure responsible disclosure of OPBT results with clinical trial recruitment.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"99"},"PeriodicalIF":7.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957062","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":"Assessment of the relationship between synaptic density and metabotropic glutamate receptors in early Alzheimer's disease: a multi-tracer PET study.","authors":"Elaheh Salardini, Ryan S O'Dell, Em Tchorz, Nabeel B Nabulsi, Yiyun Huang, Richard E Carson, Christopher H van Dyck, Adam P Mecca","doi":"10.1186/s13195-025-01739-1","DOIUrl":"https://doi.org/10.1186/s13195-025-01739-1","url":null,"abstract":"<p><strong>Background: </strong>The pathological effects of amyloid β oligomers (Aβo) may be mediated through the metabotropic glutamate receptor subtype 5 (mGluR5), leading to synaptic loss in Alzheimer's disease (AD). Positron emission tomography (PET) studies of mGluR5 using [¹⁸F]FPEB indicate a reduction of receptor binding that is focused in the medial temporal lobe in AD. Synaptic loss due to AD measured through synaptic vesicle glycoprotein 2A (SV2A) quantification with [¹¹C]UCB-J PET is also focused in the medial temporal lobe, but with clear widespread reductions is commonly AD-affected neocortical regions. In this study, we used [¹⁸F]FPEB and [¹¹C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD.</p><p><strong>Methods: </strong>Fifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [¹⁸F]FPEB to measure mGluR5 and [¹¹C]UCB-J to measure synaptic density. Parametric distribution volume ratio (DVR) images using equilibrium methods were generated from dynamic images. For [¹⁸F]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [¹¹C]UCB-J PET, DVR was calculated with a simplified reference tissue model - 2 and a whole cerebellum reference region.</p><p><strong>Results: </strong>A strong positive correlation between mGluR5 and synaptic density was present in the hippocampus for participants with AD (r = 0.81, p < 0.001) and in the CN group (r = 0.74, p = 0.005). In the entorhinal cortex, there was a strong positive correlation between mGluR5 and synaptic density in the AD group (r = 0.85, p < 0.001), but a weaker non-significant correlation in the CN group (r = 0.36, p = 0.245). Exploratory analyses indicated more widespread significant positive correlations between synaptic density and mGluR5 within regions, as well as significant positive correlations between synaptic density in the temporal lobe and mGluR5 across a broader set of regions commonly affected by AD.</p><p><strong>Conclusions: </strong>Our findings suggest that mGluR5 reduction in AD is closely linked to synaptic loss. Longitudinal studies are needed to clarify causality, deepen understanding of AD pathogenesis, and aid in developing novel biomarkers and treatments.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"98"},"PeriodicalIF":7.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955163","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}