Alzheimer's Research & Therapy最新文献

{"title":"The autocrine motility factor receptor delays the pathological progression of Alzheimer's disease via regulating the ubiquitination-mediated degradation of APP.","authors":"Jingjing Zhang, Congcong Liu, Jing Liu, Yuting Cui, Yuli Hou, Qiao Song, Xiaomin Zhang, Xiaoling Wang, Qian Zhang, Min Cao, Wenchao Wang, Peichang Wang, Yaqi Wang","doi":"10.1186/s13195-025-01741-7","DOIUrl":"https://doi.org/10.1186/s13195-025-01741-7","url":null,"abstract":"<p><strong>Background: </strong>The ubiquitin-proteasome system (UPS) is responsible for most protein degradation and its malfunction is normally observed in neurodegenerative diseases, including Alzheimer's disease (AD). The autocrine motility factor receptor (AMFR) is an E3 ubiquitin ligase that resides on the endoplasmic reticulum membrane and is involved in various essential biological processes. However, the role of AMFR in AD is still unidentified.</p><p><strong>Methods: </strong>Behavioral experiments, including open-field test (OFT), novel object recognition test (NORT) and morris water maze test (MWMT) were conducted after adeno-associated virus (AAV) microinjection into AD model mice. Western blot, co-immunoprecipitation (Co-IP), qPCR and ubiquitination assay were used to analyze AMFR mediated ubiquitination degradation of amyloid precursor protein (APP). ELISA was employed to evaluate changes in amyloidogenic cleavage products of APP following upregulation or downregulation of AMFR in neural cells and analyze AMFR levels in serum and cerebrospinal fluid (CSF) of AD patients.</p><p><strong>Results: </strong>The progressive decline in AMFR levels was found not only in the hippocampus of APPswe/PSEN1dE9 (APP/PS1) mice but also in the CSF and serum of patients with AD. Moreover, the interaction of AMFR and APP was observed both in hippocampal tissues and brain neurons. In addition, AMFR promoted the K11-linked polyubiquitination of APP to speed up its proteasomal degradation, resulting in decreased Aβ production. Importantly, AMFR overexpression largely rescued the cognitive and synaptic deficits in APP/PS1 mice.</p><p><strong>Conclusions: </strong>Taken together, our results demonstrated that AMFR reduced Aβ production and alleviated cognitive impairment by promoting the ubiquitination-mediated degradation of APP. This study indicated that AMFR could have the potential to be a therapeutic target of early-stage AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"95"},"PeriodicalIF":7.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955767","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":"Clinical phenotypes of Alzheimer's disease: investigating atrophy patterns and their pathological correlates.","authors":"Niels Reijner, I Frigerio, M M A Bouwman, B D C Boon, N Guizard, T Jubault, J J M Hoozemans, A J M Rozemuller, F H Bouwman, F Barkhof, E Gordon, W D J van de Berg, L E Jonkman","doi":"10.1186/s13195-025-01727-5","DOIUrl":"https://doi.org/10.1186/s13195-025-01727-5","url":null,"abstract":"<p><strong>Background: </strong>In Alzheimer's disease (AD), MRI atrophy patterns can distinguish between amnestic (typical) and non-amnestic (atypical) clinical phenotypes and are increasingly used for diagnosis and outcome measures in clinical trials. However, understanding how protein accumulation and other key features of neurodegeneration influence these imaging measurements, are lacking. The current study aimed to assess regional MRI patterns of cortical atrophy across clinical AD phenotypes, and their association with amyloid-beta (Aβ), phosphorylated tau (pTau), neuro-axonal degeneration and microvascular deterioration.</p><p><strong>Methods: </strong>Post-mortem in-situ 3DT1 3 T-MRI data was obtained from 33 AD (17 typical, 16 atypical) and 16 control brain donors. Additionally, ante-mortem 3DT1 3 T-MRI scans of brain donors were collected if available. Regional volumes were obtained from MRI scans using an atlas based parcellation software. Eight cortical brain regions were selected from formalin-fixed right hemispheres of brain donors and then immunostained for Aβ, pTau, neurofilament light, and collagen IV. Group comparisons and volume-pathology associations were analyzed using linear mixed models corrected for age, sex, post-mortem delay, and intracranial volume.</p><p><strong>Results: </strong>Compared to controls, both typical and atypical AD showed volume loss in the temporo-occipital cortex, while typical AD showed additional volume loss in the parietal cortex. Posterior cingulate volume was lower in typical AD compared to atypical AD (- 6.9%, p = 0.043). In AD, a global positive association between MRI cortical volume and Aβ load (βs = 0.21, p = 0.010), and a global negative association with NfL load (βs = - 0.18, p = 0.018) were observed. Regionally, higher superior parietal gyrus volume was associated with higher Aβ load in typical AD (βs = 0.47, p = 0.004), lower middle frontal gyrus volume associated with higher NfL load in atypical AD (βs = - 0.50, p < 0.001), and lower hippocampal volume associated with higher COLIV load in typical AD (βs = - 1.69, p < 0.001). Comparing post-mortem with ante-mortem scans showed minimal volume differences at scan-intervals within 2 years, highlighting the translational aspect of this study.</p><p><strong>Conclusion: </strong>For both clinical phenotypes, cortical volume is affected by Aβ and neuro-axonal damage, but in opposing directions. Differences in volume-pathology relationships between clinical phenotypes are region-specific. The findings of this study could improve the interpretation of MRI datasets in heterogenous AD cohorts, both in research and clinical settings.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"93"},"PeriodicalIF":7.9,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956352","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":"Response to Xing et al.: post-marketing safety concerns with Lecanemab: a pharmacovigilance study based on the FDA adverse event reporting system database.","authors":"Michael Irizarry, Ilona Surick, Ari Michael, Lynn D Kramer","doi":"10.1186/s13195-025-01735-5","DOIUrl":"10.1186/s13195-025-01735-5","url":null,"abstract":"<p><p>A recent paper published a lecanemab analysis with data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. While the authors mention the limitations of FAERS, such as \"voluntary (underreporting), the inability to establish causality, reporting bias, data quality issues, and the absence of a denominator, which precludes calculating incidence rates\", they proceed with generalizations, clinical conclusions, and even treatment recommendations based on the crude disproportionality analysis. Consideration of post-marketing safety reports, including those found in the FAERS database, is an essential component of pharmacovigilance. However, FDA guidance [2, 3] highlights that: (1) \"Rates of occurrence cannot be established with reports,\" (2) \"Documenting one or more of these outcomes in a report does not necessarily mean that the suspect product(s) named in the report was the cause of the outcomes,\" and (3) \"Importantly, the FAERS data by themselves are not an indicator of the safety profile of the drug.\" The FAERS database includes reports from many sources, including reports by companies, as well as from health care professionals and consumers. The reports in the FDA database have significant limitations, including submission of incomplete, inaccurate, untimely, duplicate, relatedness to drug uncertainty, and/or unverified information. Therefore, broader generalizations, clinical conclusions, and treatment recommendations should not be made based solely on FAERS databases analyses.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"92"},"PeriodicalIF":7.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952551","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":"Optimizing midlife metabolic syndrome thresholds for dementia: a prospective study of two UK population-based cohorts.","authors":"Sam Vidil, Archana Singh-Manoux, Benjamin Landré, Aurore Fayosse, Séverine Sabia, Marcos D Machado-Fragua","doi":"10.1186/s13195-025-01732-8","DOIUrl":"https://doi.org/10.1186/s13195-025-01732-8","url":null,"abstract":"<p><strong>Background: </strong>The concept of metabolic syndrome (MetS) was developed to identify individuals at higher risk of type 2 diabetes and cardiovascular disease, but its relevance for dementia remains unclear. We examined MetS in midlife for association with late-onset dementia, focusing on the thresholds of MetS components that carry risk for dementia.</p><p><strong>Methods: </strong>MetS components (waist circumference, blood pressure, triglycerides, HDL-C, and fasting glucose) were measured on 6,137 white participants < 60 years from the Whitehall II (WII) cohort study. A changepoint method in time-to-event analyses was used to identify optimal thresholds, and those exhibiting better performance for dementia were retained to develop a revised MetS definition. Results were validated on 171,886 participants in the UK Biobank (UKB) study.</p><p><strong>Results: </strong>Over a median follow-up of 22.6 years in WII and 13.8 years in UKB, 522 and 418 late-onset dementia cases were recorded, respectively. Optimized thresholds for triglycerides and fasting glucose performed better than original MetS thresholds in WII, and were used to develop a revised MetS definition. The MetS scale had a linear association with dementia, and 1-component increment (range 0 to 5) was associated with higher dementia risk using the revised MetS definition (HR, 95% CI: 1.11, 1.03-1.19) but not the original MetS definition (HR, 95% CI: 1.06, 0.98-1.14) in WII. In UKB, the revised MetS definition exhibited better performance for dementia risk than the original definition (p for HR comparison < 0.01).</p><p><strong>Conclusions: </strong>MetS in midlife is potentially an important target for dementia prevention. However, the thresholds for triglycerides and glucose that carry risk need to be tailored specifically for dementia.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"89"},"PeriodicalIF":7.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of choroid plexus volume with white matter hyperintensity volume and susceptibility and plasma amyloid markers in cerebral small vessel disease.","authors":"Pengcheng Liang, Meng Li, Yiwen Chen, Zhenyu Cheng, Na Wang, Yuanyuan Wang, Nan Zhang, Yena Che, Jing Li, Changhu Liang, Lingfei Guo","doi":"10.1186/s13195-025-01740-8","DOIUrl":"https://doi.org/10.1186/s13195-025-01740-8","url":null,"abstract":"<p><strong>Background: </strong>White matter hyperintensity (WMH) is a key feature of cerebral small vessel disease (CSVD). The impact of the choroid plexus (CP) volume on disease progression remains largely unexplored. This study evaluated the relationship between CP volume and CSVD severity via WMH volume and susceptibility values. Additionally, we explored whether Alzheimer's disease (AD)-related plasma proteins influence the volume of the CP.</p><p><strong>Methods and materials: </strong>Our study included 291 CSVD individuals, with 84 participants completing subsequent brain MRI at a mean follow-up of 20 months. To explore the potential CP-associated pathways, we assessed the relationships between AD-related plasma biomarkers and CP volume via multiple linear regression analysis. The longitudinal associations between CP volume and WMH characteristics (WMH volume and susceptibility) were analyzed via linear mixed-effects models. Finally, we employed random forest analysis with the Boruta algorithm to identify key predictors of CSVD severity.</p><p><strong>Results: </strong>Plasma Aβ1‒40 levels were positively correlated with CP volume (β = 0.115, P = 0.009), whereas Aβ42‒40 ratio were negatively associated with CP volume (β = -0.135, P = 0.03). Notably, increased CP volume was associated with both greater WMH burden (β = 0.191, P = 0.011) and decreased WMH susceptibility (β = -0.192, P = 0.012). Furthermore, random forest modeling identified CP volume and WMH susceptibility as the strongest predictors of CSVD severity.</p><p><strong>Conclusions: </strong>CP volume changes were significantly correlated with both WMH volume and WMH susceptibility in CSVD patients. These findings suggest that CP-mediated pathways may link amyloid metabolism to CSVD progression.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"90"},"PeriodicalIF":7.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959661","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":"Correction: Investigating the Aβ and tau pathology in autosomal dominant Alzheimer's disease: insights from hybrid PET/MRI and network mapping.","authors":"Zhi Zhou, Qigeng Wang, Linwen Liu, Qi Wang, Xiaojun Zhang, Can Li, Jiajin Liu, Yidan Wei, Jin Gao, Liping Fu, Ruimin Wang","doi":"10.1186/s13195-025-01730-w","DOIUrl":"https://doi.org/10.1186/s13195-025-01730-w","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"87"},"PeriodicalIF":7.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12013027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961845","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":"Relationships between blood pressure indicators and fluid biomarkers of brain aging in functionally intact older adults.","authors":"Anna M VandeBunte, Bailey L Ortiz, Emily W Paolillo, Rowan Saloner, Valentina Diaz, Shubir Dutt, Claire J Cadwallader, Coty Chen, Argentina Lario Lago, Julio C Rojas, Brandon Chan, Isabel Sible, Joel H Kramer, Kaitlin B Casaletto","doi":"10.1186/s13195-025-01731-9","DOIUrl":"https://doi.org/10.1186/s13195-025-01731-9","url":null,"abstract":"<p><strong>Background: </strong>Dementia risk is significantly shaped by cardiovascular health, with elevated blood pressure emerging as a key risk factor for adverse brain aging. Blood biomarkers such as pTau181, Aβ42/40, NfL, and GFAP have improved our understanding of dementia pathophysiology, however, few studies have explored how specific blood pressure metrics relate to biomarker levels, which could inform personalized dementia prevention strategies as these biomarkers move into clinic. We examined how different blood pressure metrics associated with molecular markers of astrocytic activation (GFAP), neuronal axon breakdown (NfL), and Alzheimer's disease pathobiology (pTau181, Aβ42/40) in plasma.</p><p><strong>Methods: </strong>109 functionally intact (Clinical Dementia Rating Scale = 0) older adults completed blood draws with plasma assayed for Aβ42/40, GFAP, NfL, and pTau181 (Quanterix Simoa) and in-lab blood pressure quantification. Blood pressure metrics included diastolic blood pressure, systolic blood pressure, and pulse pressure (systolic minus diastolic). Separate regression models evaluated plasma biomarkers as a function of each blood pressure metric, adjusting for age and biological sex. Interaction models tested whether relationships between blood pressure metrics and plasma biomarkers differed by sex, age, or APOE-ε4 status.</p><p><strong>Results: </strong>With the exception of Aβ42/40, higher pulse pressure related to higher levels of all plasma biomarkers examined (pTau181, NfL, GFAP). Additionally, higher systolic blood pressure related to higher pTau181, while diastolic blood pressure did not meaningfully associate with any biomarker. Interaction models revealed a significantly stronger relationship between elevated pulse pressure and higher GFAP concentrations in females compared to males, as well as a significantly stronger association between elevated pulse pressure and lower Aβ42/40 plasma concentrations in APOE-ε4 carriers compared to non-carriers.</p><p><strong>Conclusions: </strong>Our findings suggest that elevated pulse pressure, and to a lesser extent systolic blood pressure, are associated with increased Alzheimer's disease and neurodegenerative (axonal and astrocytic health) biology among typically aging adults. These associations underscore the importance of blood pressure management, particularly pulse pressure, for reducing dementia risk. Cardiovascular health may be incorporated with biomarkers to further personalize dementia prevention and management strategies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"85"},"PeriodicalIF":7.9,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952154","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":"Abdominal obesity and the risk of young-onset dementia in women: a nationwide cohort study.","authors":"Ye Seul Yang, Kyungdo Han, Dae Young Cheon, Minwoo Lee","doi":"10.1186/s13195-025-01738-2","DOIUrl":"10.1186/s13195-025-01738-2","url":null,"abstract":"<p><strong>Background and objectives: </strong>The association between obesity and young-onset dementia (YOD, defined as dementia diagnosed before age 65) is established, but the specific impact of abdominal obesity in women remains unclear. Abdominal obesity, driven by excess visceral fat, may increase dementia risk through metabolic and vascular pathways. We investigated the association between abdominal obesity and YOD risk in women using a large nationwide cohort.</p><p><strong>Methods: </strong>We analyzed 964,536 Korean women aged 40-60 years who underwent national health checkups in 2009. General obesity was defined by body mass index (BMI), and abdominal obesity was categorized by waist circumference (WC) into < 75 cm, 76-84 cm, 85-94 cm, and ≥ 95 cm. YOD was identified using ICD-10 codes and dementia medication prescriptions. Hazard ratios (HRs) for YOD were estimated using multivariable Cox proportional hazard models adjusted for lifestyle and clinical factors.</p><p><strong>Results: </strong>Over a median follow-up of 8.2 years, YOD incidence increased progressively with higher WC. Women with WC ≥ 95 cm had a 55% increased risk of YOD (HR 1.55; 95% CI 1.34-1.79) compared to those with WC < 75 cm. The association was particularly strong for vascular dementia (VD), with HR 1.83 (95% CI 1.30-2.57). By contrast, BMI showed a U-shaped relationship, with the lowest YOD risk observed in women with normal BMI (18.5-22.9 kg/m²), and significantly elevated risks in both underweight (BMI < 18.5 kg/m²; HR 1.39, 95% CI 1.13-1.71) and morbidly obese women (BMI ≥ 30 kg/m²; HR 1.26, 95% CI 1.10-1.45).</p><p><strong>Discussion: </strong>Abdominal obesity is a significant, independent risk factor for YOD in women, particularly for VD. These findings underscore the importance of addressing abdominal obesity in middle-aged women to reduce dementia risk.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"86"},"PeriodicalIF":7.9,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12010638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961615","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":"Enhanced associations between subjective cognitive concerns and blood-based AD biomarkers using a novel EMA approach.","authors":"Ángel García de la Garza, Caroline Nester, Cuiling Wang, Jacqueline Mogle, Nelson Roque, Mindy Katz, Carol A Derby, Richard B Lipton, Laura Rabin","doi":"10.1186/s13195-025-01720-y","DOIUrl":"https://doi.org/10.1186/s13195-025-01720-y","url":null,"abstract":"<p><strong>Background: </strong>Subjective cognitive concerns (SCC) have emerged as important early indicators of Alzheimer's disease (AD) risk. Traditional measures of SCC rely on recall-based assessments, which may be limited in capturing real-time fluctuations in cognitive concerns. Ecological Momentary Assessment (EMA) offers a promising alternative by providing real-time data. This study aimed to link SCC assessed via EMA and traditional measures with blood-based AD biomarkers in a diverse, dementia-free, community-based sample based in the Bronx, NY.</p><p><strong>Methods: </strong>Einstein Aging Study (EAS) participants underwent in-person, recall-based assessments of SCC during an in-clinic visit. Additionally, EMA SCC assessments were collected once per day over two weeks. Linear regressions were conducted to examine the relationships between SCC variables and plasma biomarkers adjusted for demographics and mild cognitive impairment (MCI) status.</p><p><strong>Results: </strong>In N = 254 participants, EMA-reported SCCs demonstrated significant associations with AD biomarkers, particularly p-tau181 (β = 0.21, p = 0.001). Further, significant associations remain across both cognitive (cognitively unimpaired vs. MCI) and racial groups. In contrast, traditional SCC measures exhibited limited associations with these biomarkers. The findings highlight the added value of EMA in capturing SCCs that could indicate early ADRD risk.</p><p><strong>Conclusions: </strong>EMA provides a more dynamic and potentially sensitive method for detecting early AD risk compared to traditional SCC assessments. These real-time measures could enhance early detection and clinical intervention, particularly in diverse and under-resourced populations. This study underscores the potential of EMA for broad applicability and inclusivity in monitoring AD progression and facilitating early therapeutic interventions.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"82"},"PeriodicalIF":7.9,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11998261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955658","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":"Novel CSF β-synuclein-specific assays signal early synaptic degeneration in Alzheimer's disease.","authors":"Sherif Bayoumy, Julie Goossens, Charlotte De Rocker, Senna Y Sie, Nolan J Barrett, Wiesje M van der Flier, Charlotte E Teunissen, Eugeen Vanmechelen, Inge M W Verberk","doi":"10.1186/s13195-025-01716-8","DOIUrl":"https://doi.org/10.1186/s13195-025-01716-8","url":null,"abstract":"<p><strong>Background: </strong>Beta-synuclein (β-syn), measured at N-terminal epitopes, is an emerging cerebrospinal fluid (CSF) biomarker for synaptic degeneration in Alzheimer's disease (AD). Targeting the mid-region or C-terminus of β-syn may enhance analytical specificity due to the distinct structures of these regions across the synuclein protein family, unlike targeting the N-terminus, which is conserved across the family. This study aimed to confirm that β-syn is a promising CSF biomarker in AD, using novel assays designed to target different regions of β-syn, to investigate whether these regions are differentially affected in AD.</p><p><strong>Methods: </strong>We developed two novel CSF β-syn-specific ELISAs targeting mid-region and C-terminus epitopes and assessed their analytical performance. Using these novel assays in combination with the established N-terminus ELISA, we analyzed a proof-of-concept cohort comprising biomarker-confirmed AD (n = 25) and non-AD subjects (n = 25) and a larger clinical cohort (n = 160) from the Amsterdam Dementia Cohort, wich included 41 individuals with subjective cognitive decline (SCD, controls; AD biomarker negative; 64.3 ± 3.3 years, 23 females), 39 with SCD (AD biomarker positive; 65.7 ± 3.1 years, 17 females), 40 with mild cognitive impairment due to AD (MCI-AD; 66.2 ± 2.9 years, 20 females), and 40 with AD dementia (AD-dem; 65.3 ± 3.4 years, 20 females).</p><p><strong>Results: </strong>Both the mid-region and C-terminus assays demonstrated reliable analytical performance. All assays consistently detected β-syn in all clinical samples above their limits of detection, with a good average intra-assay coefficient of variation (range of the three assays: 2.7-6.5%CV) in the proof-of-concept cohort and clinical cohort (range of the three assays: 3.9-7.5%CV). CSF β-syn levels, with all the assays, were significantly elevated in all the AD groups compared with the controls in both cohorts. The diagnostic performance of the assays for distinguishing AD patients from controls was comparable (Delong's p > 0.05, AUC 0.71-0.80). Notably, mid-region β-syn significantly differentiated SCD-AD patients from AD-dem patients (p = 0.035) and MCI-AD patients at a trend level. Only mid-region and C-terminal levels correlated with MMSE scores (mid-region rho = -0.22, p = 0.006; C-terminal rho = -0.19, p = 0.016; N-terminus rho = -0.14, p = 0.069).</p><p><strong>Conclusion: </strong>Our novel assays demonstrated good analytical and clinical performance. CSF β-syn reliably indicates early synaptic degeneration in AD. The mid-region assay uniquely differentiated SCD-AD from AD-dem, showing promise for early disease detection.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"81"},"PeriodicalIF":7.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11995646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959703","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}