Alzheimer's Research & Therapy最新文献

{"title":"Combinatorial targeting of NMDARs and 5-HT₄Rs exerts beneficial effects in a mouse model of Alzheimer's disease.","authors":"Briana K Chen, Holly C Hunsberger, Alicia Whye, Louise C Matthews, Alyson Yook, Moshe J Willner, Ryan W Logan, Stefanie Johns, Eric Weisblum, Christine A Denny","doi":"10.1186/s13195-025-01804-9","DOIUrl":"10.1186/s13195-025-01804-9","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the leading cause of dementia. There are limited approved medications that delay cognitive decline or lessen neuropsychiatric symptoms. Numerous clinical trials for AD using a single drug administration have failed to meet therapeutic endpoints, which is most likely due to the complexity of AD. A multimodal therapeutic intervention is more likely to improve symptoms by targeting multiple targets implicated in AD. Here, we investigated if targeting both N-Methyl-D-aspartic acid receptors (NMDARs) and serotonin type 4 receptors (5-HT₄R) may have beneficial effects in a mouse model of AD, as they have separately been shown to improve cognition and/or mood.</p><p><strong>Methods: </strong>Male and female control (Ctrl) or APP/PS1 mice were administered single, intermittent, or chronic administration of 1) saline; 2) (R,S)-ketamine, an NMDAR antagonist; 3) prucalopride, a 5-HT₄R agonist; or 4) (R,S)-ketamine + prucalopride to simultaneously target co-morbid neuropsychiatric and cognitive deficits. Behavioral assays were then administered to measure cognition, perseverative behavior, hyponeophagia, and/or sleep. Brains were processed for glial fibrillary acidic protein (GFAP) immunohistochemistry.</p><p><strong>Results: </strong>Single and chronic administration of (R,S)-ketamine + prucalopride administration improved cognitive decline by increasing memory retrieval in a contextual fear conditioning (CFC) paradigm in APP/PS1 mice. Drug efficacy was less effective in females than in males and was age dependent. Hippocampal GFAP immunoreactivity was decreased by chronic (R,S)-ketamine + prucalopride treatment in females.</p><p><strong>Conclusions: </strong>Our results indicate that combined administration of (R,S)-ketamine + prucalopride is a novel multimodal therapeutic strategy to treat cognitive decline in AD. Future work will further characterize these interactions with the goal of clinical development.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"160"},"PeriodicalIF":7.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641551","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":"Dual risk of anticholinergic burden and CSF alzheimer's biomarkers in older patients: a mortality follow-up study from daily medical practice.","authors":"Théodore Decaix, Julien Dumurgier, Emmanuel Cognat, Karl Götze, François Mouton-Liger, Jacques Hugon, Elodie Bouaziz-Amar, Matthieu Lilamand, Claire Paquet","doi":"10.1186/s13195-025-01814-7","DOIUrl":"10.1186/s13195-025-01814-7","url":null,"abstract":"<p><strong>Background: </strong>Anticholinergic medications are widely prescribed to older adults and are linked to increased mortality and cognitive decline. Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD)-amyloid and tau-are strong prognostic indicators in neurocognitive disorders (NCD). However, it remains unclear whether anticholinergic burden amplifies mortality risk depending on CSF biomarker profiles in cognitively impaired individuals.</p><p><strong>Methods: </strong>We conducted a retrospective monocentric study of 927 patients aged ≥ 65 years with mild or major NCD from a tertiary memory clinic in Paris, France. Participants underwent CSF biomarker assessment for amyloid (A), phosphorylated tau (T), and total tau (N), and were classified into ATN profiles. Anticholinergic burden was evaluated at baseline using the Anticholinergic Cognitive Burden (ACB) scale: none (ACB = 0), low-moderate (ACB = 1-2), or high (ACB ≥ 3). The primary outcome was all-cause mortality. Proportional hazards regression assessed associations between ACB, ATN profiles, and mortality, adjusting for demographic, clinical, and genetic covariates.</p><p><strong>Results: </strong>High ACB was associated with increased mortality in model 1 (HR = 1.30, 95% CI: 1.03-1.64, p = 0.02), but not after full adjustment (HR = 1.26, 95% CI: 0.96-1.66, p = 0.09). ATN profiles remained strong independent predictors of mortality, with highest risks for A-T-N + and A + T + Nx profiles. Combined high ACB and abnormal biomarkers conferred greater risk than either alone (e.g., HR = 2.24 for A + T + Nx and high ACB).</p><p><strong>Conclusion: </strong>Anticholinergic burden may increase vulnerability to mortality in older adults with an AD biomarker profile. These results support integrating pharmacological and biological risk factors into personalized dementia care.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"162"},"PeriodicalIF":7.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641552","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 role of structural and functional parameters in designing pathology-specific tDCS protocols for primary progressive aphasia.","authors":"Sagarika Bhattacharjee, P T Sivakumar, Ganesan Venkatasubramanian, Kenichi Oishi, Kyrana Tsapkini, S H Annabel Chen, Brenda Rapp, John E Desmond, T N Sathyaprabha, Kaviraja Udupa, Rajan Kashyap","doi":"10.1186/s13195-025-01737-3","DOIUrl":"10.1186/s13195-025-01737-3","url":null,"abstract":"<p><strong>Background: </strong>The two subtypes of primary progressive aphasia (PPA) associated with Frontotemporal Lobar Degeneration (FTLD)-non-fluent (nfvPPA) and semantic (svPPA)-have distinct structural and functional abnormalities. Transcranial direct current stimulation (tDCS) targets the language network to address deficits, yet a single, arbitrary montage is often applied despite pathophysiological differences. Since tDCS current distribution depends on brain structure and function, variant-specific montages are essential. This study presents a pathology-specific approach for tDCS montage selection, identifying the optimal montage for each PPA variant.</p><p><strong>Method: </strong>T1-weighted and resting-state fMRI data from 38 healthy, 31 nfvPPA and 32 svPPA subjects were obtained. Grey matter volume and functional entropy were analysed across 116 brain regions. Patients and controls were compared to identify significant differences in atrophy and entropy. Electric-field modelling of three widely used dorsal, ventral, and frontal tDCS montages provided current intensity estimates in the language network. Canonical Correlation Analysis examined the relationship between current intensity, atrophy, and entropy.</p><p><strong>Results: </strong>Structural and functional changes differed between the two PPA variants: nfvPPA showed left frontal atrophy and reduced entropy in the left parietal/cerebellar areas, while svPPA exhibited left temporal atrophy and reduced entropy in the left frontal and right temporal regions. Atrophy distribution primarily influenced tDCS current spread, determining montage suitability. In nfvPPA, the frontal montage showed a strong association between delivered current and grey mettwr volume of atrophied areas, whereas in svPPA, a similar pattern was observed for the ventral montage.</p><p><strong>Conclusion: </strong>The study identifies the frontal montage as the most suitable for nfvPPA and the ventral montage for svPPA. This study highlights the importance of pathology-specific tDCS montage selection, emphasizing the need for variant-based modulation of the language network in PPA.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"156"},"PeriodicalIF":7.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635973","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":"Combined effects of physical activity, cognitive activity, and dietary patterns on cognitive impairment in older adults with consideration of APOE genotype: a cohort study.","authors":"Wen-Fang Zhong, Xiao-Meng Wang, Huan Chen, Wei-Qi Song, Jian Gao, Pei-Liang Chen, Qiao-Qiao Shen, Fang-Fei You, Chuan Li, Yue-Bin Lv, Zhi-Hao Li, Xiao-Ming Shi, Chen Mao","doi":"10.1186/s13195-025-01806-7","DOIUrl":"10.1186/s13195-025-01806-7","url":null,"abstract":"<p><strong>Background: </strong>This study aims to evaluate the combination effects of physical activity (PA), cognitive activity (CA), and dietary patterns impacts cognitive impairment among older adults, and whether these associations differ by apolipoprotein E (APOE) genotype.</p><p><strong>Methods: </strong>A total of 18,909 adults aged 65 years or older at baseline were enrolled from 1998 to 2014 years. PA and CA was assessed using scores that reflected participation in various activities, and a total activity (TA) score was calculated as the sum of PA and CA scores. Diet quality was assessed with the SHE-index. Participants were categorized into lifestyle groups based on combinations of activity levels and SHE-index. The APOE genotype was categorized as APOEε4 carriers versus non-carriers. Cognitive function was evaluated using the Mini-Mental State Examination at baseline and follow-up. Adjusted Cox proportional hazards models was used to estimate the association and interaction between lifestyle and APOE genotype on the risk of cognitive impairment.</p><p><strong>Results: </strong>During a mean follow-up time of 5.27 ± 3.67 years, 5713 participants developed cognitive impairment. Participants with higher levels of TA, PA, or CA, combined with a healthy diet, consistently exhibited the lowest risk of cognitive impairment, with hazard ratios (HR) of 0.65 [95% confidence intervals (CIs): 0.60-0.71] for TA, 0.72 (95% CI: 0.66-0.78) for PA, and 0.73 (95% CI: 0.67-0.79) for CA. This protective effect remained consistent across APOEε4 genotype groups, with HRs ranging from 0.54 to 0.67 in carriers and 0.63 to 0.69 in non-carriers for higher TA, PA, or CA combined with a healthy diet. In addition, participants engaging in high PA, high CA, and a healthy diet simultaneously showed the greatest protection against cognitive impairment, with HRs of 0.46 (95% CI: 0.28-0.76) in APOEε4 carriers and 0.47 (95% CI: 0.37-0.58) in non-carriers.</p><p><strong>Conclusions: </strong>The greatest decrease in cognitive impairment was observed among older Chinese adults adhering to both high activity levels and healthy diet, The protective effect was even stronger when high physical activity, high cognitive activity, and a healthy diet were maintained simultaneously, and this trend was consistent regardless of APOEε4 status.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"158"},"PeriodicalIF":7.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635971","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 efficacy and pharmacological mechanism of Guilingji to prevent Alzheimer's disease.","authors":"Fengrui Hu, Yaling Lei, Rui Han, Bo Yang, Yanlin Liang, Jing Luan, Bei Zhang, Shan Wang, Xingchun Gou","doi":"10.1186/s13195-025-01790-y","DOIUrl":"10.1186/s13195-025-01790-y","url":null,"abstract":"<p><strong>Background: </strong>Effective treatments for Alzheimer's disease (AD) are limited, so preventing or delaying its onset is crucial. Previous clinical trials have shown the safety and potential efficacy of the Chinese herbal formula Guilingji (GLJ), but its preventive effect on AD and mechanism are still unclear.</p><p><strong>Methods: </strong>In this study, a network pharmacology approach was employed to elucidate the mechanism of GLJ in AD. Behavioral assessments and biochemical experiments were conducted on APPswe/PS1ΔE9 transgenic (APP/PS1) mice. The pivotal pathways and biological processes were validated in vitro AD model using HT22 and BV-2 cells stimulated by Aβ1-42. Additionally, molecular docking was utilized to illustrate the binding affinity of GLJ's active components to key genes implicated in AD prevention.</p><p><strong>Results: </strong>Network pharmacology analysis identified 482 common targets associated with the active components of GLJ. KEGG enrichment analysis highlighted the PI3K-AKT and retrograde endocannabinoid signaling pathways as the key mechanisms. GLJ significantly postponed cognitive decline, suppressed Aβ plaque accumulation, mitigated neuronal damage, and reduced inflammatory responses in glial cells in AD mice. GLJ and its compounds quercetin and carvone assist in neuron survival by regulating the PI3K/AKT pathway and the apoptotic proteins Bcl-2 and Bax. Additionally, GLJ, kaempferol and stigmasterol enhance microglial clearance of Aβ through the CB2 receptor. Moreover, molecular docking suggested that quercetin and carvone interacted effectively with PI3K, while kaempferol and stigmasterol combined well with CB2.</p><p><strong>Conclusions: </strong>GLJ effectively delays AD progression by modulating critical pathological pathways such as neuronal survival, neuroinflammation, and Aβ clearance through a synergistic multi-target approach, offering a promising avenue for AD prevention.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"157"},"PeriodicalIF":7.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635972","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":"Cerebral small vessel disease in memory center patients with dementia with lewy bodies and Alzheimer's disease.","authors":"Giulia Bommarito, Alessandra Griffa, Patrik Michel, Caroline Hall, Chiabotti Paolo Salvioni, Silvia Pistocchi, Yasser Alemán-Gómez, Daniel Damian, Mario Jreige, John O Prior, Vincent Dunet, Olivier Rouaud, Patric Hagmann, Gilles Allali","doi":"10.1186/s13195-025-01805-8","DOIUrl":"10.1186/s13195-025-01805-8","url":null,"abstract":"<p><strong>Introduction: </strong>Cerebral small vessel disease (CSVD) is a common co-pathology in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). A comprehensive characterization of CSVD load in DLB and AD patients referred to a memory center is lacking.</p><p><strong>Methods: </strong>In this retrospective study, we collected data from patients with a clinical DLB diagnosis or clinico-biological AD diagnosis, evaluated at our memory center. They were assessed for CSVD MRI features, including enlarged perivascular spaces (PVS), presence of cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HTNA). Differences in CSVD features between AD and DLB and across clinical stages were investigated. Regression models were used to evaluate the association between (i) cerebrovascular risk factors (CVRF) and HTNA, and (ii) CSVD features and cognition as expressed by Montreal Cognitive Assessment (MoCA).</p><p><strong>Results: </strong>We included 71 DLB (76.8 ± 7.4 years old, 25 females) and 71 age- and sex-matched AD patients (and 75.2 ± 5.3 years old, 27 females). Probable CAA, according to current Boston 2.0 criteria, was observed in 22.5% of DLB and 35.2% of AD patients, while any (probable + possible) CAA rate was higher in the two groups (71.8% and 91.5%, respectively). A moderate/severe HTNA was present in 45% of DLB and 28.2% of AD patients. When comparing the two groups, DLB presented with higher HTNA score (p =.012), while AD patients had higher prevalence of any CAA (p =.002). Patients with DLB had a greater PVS burden in the basal ganglia (p =.011) and centrum semiovale (p =.004) and higher number of deep microbleeds (p =.004). Certain HTNA-related features were more pronounced at dementia stage, with respect to mild cognitive impairment. No association was observed between CVRF and HTNA. Regarding the association between CSVD and cognition, only deep microbleeds count was related to MoCA in DLB patients.</p><p><strong>Discussion: </strong>DLB or AD patients present with high CSVD burden and differ in terms of features and subtype. Patients with DLB present with increased HTNA, PVS load and deep microbleeds, while patients with AD present with a higher any CAA prevalence. CSVD might impact global cognition.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"154"},"PeriodicalIF":7.6,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12254957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615814","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":"An improved immunoassay detects Aβ oligomers in human biofluids: their CSF levels rise with tau and phosphotau levels.","authors":"Ting Yang, Yi Ran Xu, Shanxue Jin, Nagendran Ramalingam, Jean-Pierre Bellier, Alexandra M Lish, Beth L Ostaszewski, Tracy Young-Pearse, Lei Liu, Hyun-Sik Yang, Jasmeer P Chhatwal, Trebor L Lawton, Dennis J Selkoe","doi":"10.1186/s13195-025-01802-x","DOIUrl":"10.1186/s13195-025-01802-x","url":null,"abstract":"<p><strong>Background: </strong>Diffusible Aβ oligomers (oAβ) confer cytotoxicity in Alzheimer's disease. The dynamic complexity of this hydrophobic analyte means few immunoassays exist to quantify oAβ in CSF and plasma.</p><p><strong>Methods: </strong>We characterized antibody 71A1 to a cyclized dimer of Aβ9-18 for oAβ preference over monomers by surface plasmon resonance. We improved an earlier bead-based immunoassay by using 71A1 streptavidin plates for capture and N-terminal antibody 3D6 for detection. Numerous controls systematically validated accuracy.</p><p><strong>Results: </strong>71A1 showed highly selective binding kinetics to Aβ oligomers over monomers. It enriched bioactive oligomers from AD brain that altered neuronal excitatory currents and calcium transients. 71A1/3D6 immunoassay exhibited specificity and reproducibility in human biofluids. CSF oAβ levels correlated positively with CSF tau and phosphorylated-tau-181. APP and PS1 FAD mutations increased oAβ levels in human neuronal media.</p><p><strong>Conclusions: </strong>CSF oAβ levels rise in concert with rising tau levels. A new plate-based ELISA offers improved consistency, less sample volume, and lower cost, thus better suited to quantify this challenging analyte.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"153"},"PeriodicalIF":7.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615813","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":"Comorbidities predict institutionalization and mortality in biomarker-confirmed alzheimer's disease.","authors":"Xin Xia, Alice Clark, Niels Juul Brogaard, Alex Mourer, Anna Areovimata, Maria Eriksdotter, Henrik Zetterberg, Silke Kern, Tobias Skillbäck, Linus Jönsson","doi":"10.1186/s13195-025-01807-6","DOIUrl":"10.1186/s13195-025-01807-6","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"155"},"PeriodicalIF":7.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615815","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":"Prognostic value of light reflex pupillometry in Alzheimer's disease - a longitudinal cohort study.","authors":"Mathias Holsey Gramkow, Frederikke Kragh Clemmensen, Ulrich Lindberg, Ian Law, Otto Mølby Henriksen, Gunhild Waldemar, Steen Gregers Hasselbalch, Kristian Steen Frederiksen","doi":"10.1186/s13195-025-01794-8","DOIUrl":"10.1186/s13195-025-01794-8","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"152"},"PeriodicalIF":7.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12247382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615816","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 cerebrospinal fluid and plasma apoE glycosylation is associated with reduced levels of Alzheimer's disease biomarkers.","authors":"Dobrin Nedelkov, Zoe E Tsokolas, Matheus Scarpatto Rodrigues, Isabel Sible, S Duke Han, Bilal E Kerman, Michael Renteln, Wendy J Mack, Tharick A Pascoal, Hussein N Yassine","doi":"10.1186/s13195-025-01795-7","DOIUrl":"10.1186/s13195-025-01795-7","url":null,"abstract":"<p><p>The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE is glycosylated with an O-linked Core-1 sialylated glycan at several sites; however, the impact and function of this glycosylation on AD biomarkers remain unclear. We examined apoE glycosylation (total and secondary) in a cohort of cerebrospinal fluid (CSF, n = 181) and plasma (n = 178) samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) stratified into 4 groups: cognitively normal (CN), Mild Cognitive Impairment (MCI), progressors, and non-progressors based on delayed word recall performance over 4 years. We observed decreasing glycosylation (reduced % of apoE being glycosylated) from apoE2 > apoE3 > apoE4 in the CSF and in plasma (apoE3 > apoE4), with stronger effect sizes for secondary glycosylation in CSF (total glycosylation in CSF: E2 > E3 (4.6%), E3 > E4 (5.1%), E2 > E4 (9.4%); secondary glycosylation in CSF: E2 > E4 (33.1%), E3 > E4 (25.4%); total glycosylation in plasma: E3 > E4 (24.2%). Secondary ApoE glycosylation was reduced (8%, p = 0.009) in the MCI group compared with the CN group and in the progressor group compared with the non-progressor group (7%, p = 0.01). In CSF, higher apoE glycosylation was cross-sectionally associated with lower total tau (t-tau) and p-tau181. In CSF, greater apoE4 glycosylation was associated with lower t-tau and p-tau181 levels. These results indicate strong associations between apoE glycosylation and biomarkers of AD pathology independent of apoE genotype, warranting a deeper understanding of the functional role of apoE glycosylation in AD tau pathology.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"151"},"PeriodicalIF":7.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599095","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}