Alzheimer's Research & Therapy最新文献

{"title":"Cerebrospinal fluid β2-microglobulin promotes the tau pathology through microglia-astrocyte communication in Alzheimer's disease.","authors":"Zehu Sheng, Lanyang Wang, Ming Chen, Fuxin Zhong, Shijing Wu, Shuyu Liang, Jiaqi Song, Lihua Chen, Yingxi Chen, Shiyu Chen, Weihua Yu, Yang Lü","doi":"10.1186/s13195-024-01665-8","DOIUrl":"10.1186/s13195-024-01665-8","url":null,"abstract":"<p><strong>Background: </strong>Cerebrospinal fluid (CSF) β2-microglobulin (β2M) has been demonstrated as an important factor in β-amyloid (Aβ) neurotoxicity and a potential target for Alzheimer's disease (AD). However, more investigation is required to ascertain the relationship between β2M and glial activities in AD pathogenesis.</p><p><strong>Methods: </strong>In this study, 211 participants from the Alzheimer's disease Neuroimaging Initiative (ADNI) with CSF and Plasma β2M, CSF glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), Aβ₄₂, phosphorylated-tau (P-tau) and total tau (T-tau) were divided into four groups, stage 0, 1, 2, and suspected non-AD pathology (SNAP) based on the National Institute on Aging- Alzheimer's Association (NIA-AA) criteria. Multiple linear regression, linear mixed effects models, and causal mediation analyses bootstrapped 10,000 iterations were used to investigate the underlying associations among β2M and CSF biomarkers at baseline and during a longitudinal visit.</p><p><strong>Results: </strong>CSF β2M concentration decreased with amyloid in stage 1 compared with stage 0 and increased with tau pathology and neurodegeneration in stage 2 and SNAP compared with stage 1. Moreover, CSF β2M level was positively correlated with the Aβ₄₂ (β = 0.230), P-tau (β = 0.564), T-tau (β = 0.603), GFAP (β = 0.552), and sTREM2 (β = 0.641) (all P < 0.001). CSF β2M was only longitudinally correlated with T-tau change. The correlation of CSF β2M with P-tau (proportion = 25.4%, P < 0.001) and T-tau (proportion = 26.7%, P < 0.001) was partially mediated by GFAP in total participants, reproduced in late-life individuals. Furthermore, the astrocyte cascade also partially mediated the pathological relationship between CSF β2M and tau pathology (β2M → GFAP → YKL-40 → P-tau/T-tau, IE: 0.424-0.435, all P < 0.001). Nevertheless, the mediation effects of sTREM2 were not significant. Additionally, there was no association between plasma β2M and CSF biomarkers.</p><p><strong>Conclusions: </strong>CSF β2M is dynamic in AD pathology and associated with neuroinflammation. CSF GFAP might mediate the association between β2M and tau pathology, complementing the existing research on the effect of β2M in AD pathology and providing a new perspective on treatment.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"2"},"PeriodicalIF":7.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920336","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":"Plasma phospho-tau217 as a predictive biomarker for Alzheimer's disease in a large south American cohort.","authors":"Neetesh Pandey, Zikun Yang, Basilio Cieza, Dolly Reyes-Dumeyer, Min Suk Kang, Rosa Montesinos, Marcio Soto-Añari, Nilton Custodio, Lawrence S Honig, Giuseppe Tosto","doi":"10.1186/s13195-024-01655-w","DOIUrl":"10.1186/s13195-024-01655-w","url":null,"abstract":"<p><strong>Background: </strong>Blood-based Alzheimer's disease (AD) biomarkers have been increasingly employed for diagnostic, prognostic, and therapeutic monitoring purposes, due to accuracy in distinguishing AD pathophysiologic process. Compared to other p-tau isoforms, plasma p-tau217 exhibits stronger associations with AD hallmarks in CSF and brain. However, most studies have been conducted in non-Hispanic Whites, limiting our understanding of the performances and utility of these biomarkers across ethnicities.</p><p><strong>Methods: </strong>We examined a cohort of Peruvians from the GAPP study, a recently established cohort of Peruvian mestizos from Lima and indigenous groups from Southern Peru (Aymaras and Quechuas). We tested plasma levels of p-tau using the Quanterix Simoa ALZpathp-tau217 assay in 525 samples and tested the association between p-tau217 and clinical diagnosis (healthy controls n = 234 vs. AD n = 113) using generalized mixed regression models, adjusting for sex, age, education, APOE-e4 allele (fixed effects) and study site (random effect). We also tested biomarker levels in MCI (n = 178) vs. other groups. The receiver operating characteristics area under the curve (ROC-AUC) was used to evaluate the biomarker's classification performances.</p><p><strong>Result: </strong>Participants showed on average 80% Native American ancestry. p-tau217 was significantly associated with AD (β = 2.61, 95%CI = 0.61-4.29) and its levels were inversely correlated with cognitive performances; p-tau217 levels did not differ between controls and MCI (p-value > 0.05). p-tau217 levels were higher in participants carrying at least one APOE-e4 allele (OR = 2.31, 95%CI = 1.85-2.90). The ROC-AUC for p-tau217 was estimated at 82.82% in the fully adjusted model.</p><p><strong>Conclusion: </strong>To our knowledge, this is the largest study conducted in a South American cohort phenotyped for AD with available p-tau217. Most investigations have previously focused on highly selected cohorts with established AD-endophenotypes (CSF biomarkers, autopsy report, PET etc.), while data on cohorts with clinical assessment are currently lacking, especially in non-European populations.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"1"},"PeriodicalIF":7.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex differences in the relationships between 24-h rest-activity patterns and plasma markers of Alzheimer's disease pathology.","authors":"Maxime Van Egroo, Elise Beckers, Nicholas J Ashton, Kaj Blennow, Henrik Zetterberg, Heidi I L Jacobs","doi":"10.1186/s13195-024-01653-y","DOIUrl":"10.1186/s13195-024-01653-y","url":null,"abstract":"<p><strong>Background: </strong>Although separate lines of research indicated a moderating role of sex in both sleep-wake disruption and in the interindividual vulnerability to Alzheimer's disease (AD)-related processes, the quantification of sex differences in the interplay between sleep-wake dysregulation and AD pathology remains critically overlooked. Here, we examined sex-specific associations between circadian rest-activity patterns and AD-related pathophysiological processes across the adult lifespan.</p><p><strong>Methods: </strong>Ninety-two cognitively unimpaired adults (mean age = 59.85 ± 13.77 years, range = 30-85, 47 females) underwent 10 days of actigraphic recordings, and blood drawing. Standard non-parametric indices of 24-h rest-activity rhythm fragmentation (intradaily variability, IV) and stability (interdaily stability, IS) were extracted from actigraphy data using the GGIR package. Plasma concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), amyloid-β_42/40 (Aβ_42/40), total tau, and tau phosphorylated at threonine 181 (p-tau₁₈₁) or threonine 231 (p-tau₂₃₁) were measured using Single molecule array technology. Multiple linear regression models were adjusted for age, sex, education, body mass index, and actigraphic recording duration.</p><p><strong>Results: </strong>Higher IV, indicating worse 24-h rest-activity rhythm fragmentation, was associated with elevated levels of plasma NfL (t(85) = 4.26, P < 0.0001), GFAP (t(85) = 2.49, P = 0.01), and at trend level with lower Aβ_42/40 ratio values (t(85) = -1.95, P = 0.054). Lower IS, reflecting less day-to-day stability in the 24-h rest-activity rhythm, was linked to elevated levels of plasma NfL (t(85) = -2.24, P = 0.03), but not with the other plasma biomarkers. Importantly, interaction models demonstrated that male participants were driving the observed relationships between IV and plasma NfL (t(84) = 4.05, P < 0.001) or GFAP (t(84) = 3.60, P < 0.001), but also revealed a male vulnerability in models testing interactions with p-tau₁₈₁ (IV: t(76) = 3.71, P < 0.001; IS: t(76) = -3.30, P = 0.001) and p-tau₂₃₁ (IV: t(82) = 3.28, P = 0.002). Sensitivity analyses further showed that accounting for potential confounding factors such as APOE genotype, depression, and self-reported symptoms of possible sleep apnea did not modify the observed relationships.</p><p><strong>Conclusions: </strong>These findings suggest that the association between disrupted circadian rest-activity patterns and AD pathophysiological processes may be more evident in cognitively unimpaired males. Our results contribute to the precision medicine approach, and they have clinical implications for improved early detection and selection of at-risk individuals to be enrolled in preventive interventions.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"277"},"PeriodicalIF":7.9,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906292","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 of an individualized dementia risk prediction model using deep learning survival analysis incorporating genetic and environmental factors.","authors":"Shiqi Yuan, Qing Liu, Xiaxuan Huang, Shanyuan Tan, Zihong Bai, Juan Yu, Fazhen Lei, Huan Le, Qingqing Ye, Xiaoxue Peng, Juying Yang, Yitong Ling, Jun Lyu","doi":"10.1186/s13195-024-01663-w","DOIUrl":"10.1186/s13195-024-01663-w","url":null,"abstract":"<p><strong>Background: </strong>Dementia is a major public health challenge in modern society. Early detection of high-risk dementia patients and timely intervention or treatment are of significant clinical importance. Neural network survival analysis represents the most advanced technology for survival analysis to date. However, there is a lack of deep learning-based survival analysis models that integrate both genetic and clinical factors to develop and validate individualized dynamic dementia risk prediction models.</p><p><strong>Methods and results: </strong>This study is based on a large prospective cohort from the UK Biobank, which includes a total of 41,484 participants with an average follow-up period of 12.6 years. Initially, 364 candidate features (predictor variables) were screened. The top 30 key features were then identified by ranking the importance of each predictor variable using the Gradient Boosting Machine (GBM) model. A multi-model comparison strategy was employed to evaluate the predictive performance of four survival analysis models: DeepSurv, DeepHit, Kaplan-Meier estimation, and the Cox proportional hazards model (CoxPH). The results showed that the average Harrell's C-index for the DeepSurv model was 0.743, for the DeepHit model it was 0.633, for the CoxPH model it was 0.749, and for the Kaplan-Meier estimator model it was 0.500. In addition, the average D-Calibration Survival Measure was 6.014, 4408.086, 32274.743, and 1.508, respectively. The Brier score (BS) was used to assess the importance of features for the DeepSurv dementia prediction model, and the relationship between features and dementia was visualized using a partial dependence plot (PDP). To facilitate further research, the team deployed the DeepSurv dementia prediction model on AliCloud servers and designated it as the UKB-DementiaPre Tool.</p><p><strong>Conclusion: </strong>This study successfully developed and validated the DeepSurv dementia prediction model for individuals aged 60 years and above, integrating both genetic and clinical data. The model was then deployed on AliCloud servers to promote its clinical translation. It is anticipated that this prediction model will provide more accurate decision support for clinical treatment and will serve as a valuable tool for the primary prevention of dementia.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"278"},"PeriodicalIF":7.9,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood-based biomarkers and plasma Aβ assays in the differential diagnosis of Alzheimer's disease and behavioral-variant frontotemporal dementia.","authors":"Pablo Mohaupt, Jana Kindermans, Jérôme Vialaret, Sarah Anderl-Straub, Leonie Werner, Sylvain Lehmann, Christophe Hirtz, Markus Otto, Patrick Oeckl","doi":"10.1186/s13195-024-01647-w","DOIUrl":"10.1186/s13195-024-01647-w","url":null,"abstract":"<p><strong>Introduction: </strong>The differentiation between Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD) can be complicated in the initial phase by shared symptoms and pathophysiological traits. Nevertheless, advancements in understanding AD's diverse pathobiology suggest the potential for establishing blood-based methods for differential diagnosis.</p><p><strong>Methods: </strong>We devised a novel assay combining immunoprecipitation and mass spectrometry (IP-MS) to quantify Amyloid-beta (Aβ) peptides in plasma. We then assessed its performance against existing assays (Shimadzu and Simoa) and evaluated a range of other blood-based biomarkers, including GFAP, NfL, and pTau-181, for differentiating between AD and bvFTD.</p><p><strong>Results: </strong>The novel IP-MS assay measuring the Aβ42/40 ratio demonstrated an AUC of 0.82 for differentiating AD from control subjects. While it did not significantly outperform the composite biomarker score from the Shimadzu assay (AUC = 0.79, P = 0.67), it significantly outperformed the Shimadzu Aβ42/40 ratio (AUC = 0.65, P = 0.037) and the Simoa Aβ42/40 assay (AUC = 0.57, P = 0.023). Aβ biomarkers provided limited utility in distinguishing AD from bvFTD. In contrast, pTau181 and GFAP exhibited strong discriminatory power for differentiating AD from bvFTD, with AUCs of 0.90 and 0.87, respectively. Combining pTau181 and GFAP enhanced diagnostic accuracy, achieving an AUC of 0.94.</p><p><strong>Conclusion: </strong>We introduced a novel IP-MS assay that demonstrated comparable precision to the Shimadzu composite score in differentiating AD from non-neurodegenerative control groups. However, Aβ levels did not enhance the discrimination between AD and bvFTD. Furthermore, our findings support the utility of combining pTau181 and GFAP as a robust strategy for the blood-based differentiation of AD and bvFTD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"279"},"PeriodicalIF":7.9,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11687143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906288","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: Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a mendelian randomization analysis.","authors":"Amand F Schmidt, Michael H Davidson, Marc Ditmarsch, John J Kastelein, Chris Finan","doi":"10.1186/s13195-024-01639-w","DOIUrl":"10.1186/s13195-024-01639-w","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"276"},"PeriodicalIF":7.9,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11674080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891360","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":"Therapeutic implications of necroptosis activation in Alzheimer´s disease.","authors":"Elizabeth Carrazana, Natalia Salvadores","doi":"10.1186/s13195-024-01649-8","DOIUrl":"10.1186/s13195-024-01649-8","url":null,"abstract":"<p><p>In recent years, a growing body of research has unveiled the involvement of the necroptosis pathway in the pathogenesis of Alzheimer's disease (AD). This evidence has shed light on the mechanisms underlying neuronal death in AD, positioning necroptosis at the forefront as a potential target for therapeutic intervention. This review provides an update on the current knowledge on this emerging, yet rapidly advancing topic, encompassing all published studies that present supporting proof of the role of the necroptosis pathway in the neurodegenerative processes of AD. The implication of misfolded tau and amyloid-β (Aβ) aggregates is highlighted, with evidence suggesting their direct or indirect involvement in necroptosis activation. In summary, the review underscores the significance of understanding the complex interplay between necroptosis, protein aggregates, and neurodegeneration in AD. The findings advocate for a comprehensive approach, combining therapeutic and early diagnostic strategies, to intervene in the disease process before irreversible damage occurs.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"275"},"PeriodicalIF":7.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891361","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":"Retinal thickness predicts the risk of cognitive decline over five years.","authors":"Leila Sara Eppenberger, Chi Li, Damon Wong, Bingyao Tan, Gerhard Garhöfer, Saima Hilal, Eddie Chong, An Qi Toh, Narayanaswamy Venketasubramanian, Christopher Li-Hsian Chen, Leopold Schmetterer, Jacqueline Chua","doi":"10.1186/s13195-024-01627-0","DOIUrl":"10.1186/s13195-024-01627-0","url":null,"abstract":"<p><strong>Background: </strong>Dementia poses a significant burden on healthcare systems. Early identification of individuals at risk for cognitive decline is crucial. The retina, an extension of the central nervous system, reflects neurodegenerative changes. Optical coherence tomography (OCT) is a non-invasive tool for assessing retinal health and has shown promise in predicting cognitive decline. However, prior studies produced mixed results.</p><p><strong>Methods: </strong>This study investigated a large cohort (n = 490) of Asian individuals attending memory clinics. Participants underwent comprehensive neuropsychological testing annually for five years. Retinal thickness was measured by OCT at baseline. We assessed the association between baseline retinal thickness and subsequent cognitive decline.</p><p><strong>Results: </strong>Participants with a significantly thinner macular ganglion cell-inner plexiform layer (GCIPL) at baseline (≤ 79 μm) had a 38% greater risk of cognitive decline compared to those who did not (≥ 88 μm; p = 0.037). In a multivariable model accounting for age, education, cerebrovascular disease status, hypertension, hyperlipidemia, diabetes and smoking, thinner GCIPL was associated with an increased risk of cognitive decline (hazard ratio = 1.14, 95% CI = 1.01-1.30, p = 0.035). Retinal nerve fiber layer (RNFL) thickness was not associated with cognitive decline.</p><p><strong>Conclusions: </strong>This study suggests that OCT-derived macular GCIPL thickness may be a valuable biomarker for identifying individuals at risk of cognitive decline. Our findings highlight GCIPL as a potentially more sensitive marker compared to RNFL thickness for detecting early neurodegenerative changes.</p><p><strong>Trial registration number and name of the trial registry: </strong>National Healthcare Group Domain-Specific Review Board (NHG DSRB) reference numbers DSRB Ref: 2018/01368. Name of the trial: Harmonisation project.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"273"},"PeriodicalIF":7.9,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880900","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":"Anti-diabetic agents and the risks of dementia in patients with type 2 diabetes: a systematic review and network meta-analysis of observational studies and randomized controlled trials.","authors":"Zonglin Li, Chu Lin, Xiaoling Cai, Fang Lv, Wenjia Yang, Linong Ji","doi":"10.1186/s13195-024-01645-y","DOIUrl":"10.1186/s13195-024-01645-y","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate the association between anti-diabetic agents and the risks of dementia in patients with type 2 diabetes (T2D).</p><p><strong>Methods: </strong>Literature retrieval was conducted in PubMed, Embase, the Cochrane Central Register of Controlled Trials and Clinicaltrial.gov between January 1995 and October 2024. Observational studies and randomized controlled trials (RCTs) in patients with T2D, which intercompared anti-diabetic agents or compared them with placebo, and reported the incidence of dementia were included. Conventional and network meta-analyses of these studies were implemented. Results were exhibited as the odds ratio (OR) or risk ratio (RR) with 95% confidence interval (CI).</p><p><strong>Results: </strong>A total of 41 observational studies (3,307,483 participants) and 23 RCTs (155,443 participants) were included. In the network meta-analysis of observational studies, compared with non-users, sodium glucose cotransporter-2 inhibitor (SGLT-2i) (OR = 0.56, 95%CI, 0.45 to 0.69), glucagon-like peptide-1 receptor agonist (GLP-1RA) (OR = 0.58, 95%CI, 0.46 to 0.73), thiazolidinedione (TZD) (OR = 0.68, 95%CI, 0.57 to 0.81) and metformin (OR = 0.89, 95%CI, 0.80 to 0.99) treatments were all associated with reduced risk of dementia in patients with T2D. The surface under the cumulative ranking curve (SUCRA) evaluation conferred a rank order as SGLT-2i > GLP-1RA > TZD > dipeptidyl peptidase-4 inhibitor (DPP-4i) > metformin > α-glucosidase inhibitor (AGI) > glucokinase activator (GKA) > sulfonylureas > glinides > insulin in terms of the cognitive benefits. Meanwhile, compared with non-users, SGLT-2i (OR = 0.43, 95%CI, 0.30 to 0.62), GLP-1RA (OR = 0.54, 95%CI, 0.30 to 0.96) and DPP-4i (OR = 0.73, 95%CI, 0.57 to 0.93) were associated with a reduced risk of Alzheimer's disease while a lower risk of vascular dementia was observed in patients receiving SGLT-2i (OR = 0.42, 95%CI, 0.22 to 0.80) and TZD (OR = 0.52, 95%CI, 0.36 to 0.75) treatment. In the network meta-analysis of RCTs, the risks of dementia were comparable among anti-diabetic agents and placebo.</p><p><strong>Conclusion: </strong>Compared with non-users, SGLT-2i, GLP-1RA, TZD and metformin were associated with the reduced risk of dementia in patients with T2D. SGLT-2i, and GLP-1RA may serve as the optimal choice to improve the cognitive prognosis in patients with T2D.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"272"},"PeriodicalIF":7.9,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880874","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":"Data-driven CSF biomarker profiling: imaging and clinical outcomes in a cohort at risk of Alzheimer's disease.","authors":"Georgette Argiris, Muge Akinci, Cleofé Peña-Gómez, Eleni Palpatzis, Marina Garcia-Prat, Mahnaz Shekari, Kaj Blennow, Henrik Zetterberg, Gwendlyn Kollmorgen, Clara Quijano-Rubio, Nicholas J Ashton, Thomas K Karikari, Ann Brinkmalm-Westman, Juan Lantero-Rodriguez, Karine Fauria, Gonzalo Sánchez-Benavides, Oriol Grau-Rivera, Marc Suárez-Calvet, Eider M Arenaza-Urquijo, For The Alfa Study","doi":"10.1186/s13195-024-01629-y","DOIUrl":"10.1186/s13195-024-01629-y","url":null,"abstract":"<p><strong>Background: </strong>Cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction, neuroinflammation, and glial response, complementing Alzheimer's disease (AD) core biomarkers, have improved the pathophysiological characterization of the disease. Here, we tested the hypothesis that the co-expression of multiple CSF biomarkers will help the identification of AD-like phenotypes when biomarker positivity thresholds are not met yet.</p><p><strong>Methods: </strong>Two hundred and seventy cognitively unimpaired adults with family history (FH) of sporadic AD (mean age = 60.6 ± 4.85 years, 64.8% women) underwent lumbar puncture, magnetic resonance imaging (n = 266) and positron emission tomography imaging (n = 239) protocols, and clinical evaluations. CSF Aβ₄₂, Aβ₄₀, p-tau₁₈₁, p-tau_217, p-tau_231, NfL, neurogranin, sTREM2, YKL40, GFAP, S100, α-Synuclein, SYT1, and SNAP25 were measured. Participants were clustered based on CSF biomarker co-expression with an agglomerative algorithm. The predictive value of the classification against brain and cognitive outcomes was evaluated.</p><p><strong>Results: </strong>Three clusters (C) were identified. Higher Aβ burden and CSF p-tau was the hallmark of C1. The other two clusters showed lower Aβ burden but higher expression of glial (C2) or synaptic markers (C3). Participants in C1 showed an AD-like clinical phenotype, comprising participants with the overall highest percentage of two parent FH and APOE-ε4 carriers, in addition to comprising more females compared to C2. C3 displayed better vascular health compared to C1. C2 were older and comprised a lower percentage of females compared to C3. C1 showed an AD-like gray matter reduction in medial temporal (notably hippocampus) and frontal regions that were not observed in Aβ_42/40 + compared with Aβ_42/40 - . Furthermore, Aβ_42/40 - participants in C1 showed GM reduction in inferior temporal areas compared with Aβ_42/40 + participants overall. C1 membership also predicted cognitive decline in executive function, but not memory, beyond Aβ + status, overall suggesting a better prognosis in Aβ_42/40 + participants without C1 membership. Additionally, C1 displayed a higher rate of conversion to Aβ + (25%) over time.</p><p><strong>Conclusions: </strong>Our results suggest that examining multiple CSF biomarkers reflecting diverse pathological pathways may complement and/or outperform AD core biomarkers and thresholding approaches to identify individuals showing a clinical and cognitive AD-like phenotype, including higher conversion to Aβ + , GM reductions and cognitive decline. The clinical utility of this approach warrants further investigation and replication in other cohorts.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"274"},"PeriodicalIF":7.9,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880839","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}