Alzheimer's Research & Therapy最新文献

{"title":"Correction: Hypertension and diabetes on cognitive impairment: a case-control study in China.","authors":"Jing Wu, Xiangjun Yin, Weiqiang Ji, Yang Liu, Jing Tang, Han Zhang, Shige Qi, Jie Li, Li Lin, Xueqing Yang, Chengdong Xu, Qingfeng Du","doi":"10.1186/s13195-025-01824-5","DOIUrl":"10.1186/s13195-025-01824-5","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"181"},"PeriodicalIF":7.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783260","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":"Aducanumab binds high molecular weight soluble Aβ oligomers and restores intracellular calcium levels.","authors":"Lu Yu, Xueying Wang, Tri H Doan, Yutian Fan, Thierry Bussiere, Brian J Bacskai, Ksenia V Kastanenka","doi":"10.1186/s13195-025-01812-9","DOIUrl":"10.1186/s13195-025-01812-9","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) accumulation, leading to the formation of neurotoxic soluble oligomers (AβOs) that impair calcium homeostasis in neurons and astrocytes. Aducanumab, a fully human monoclonal antibody targeting aggregated Aβ, has been approved for AD treatment due to its ability to reduce amyloid plaque burden. However, its specificity toward different AβO species and its functional impact on calcium homeostasis remain unclear.</p><p><strong>Methods: </strong>We investigated aducanumab's ability to recognize and immunodeplete low-molecular-weight (LMW) and high-molecular-weight (HMW) AβOs using three Aβ preparations: (1) transgenic conditioned media (TgCM) from cultured Tg2576 neurons, (2) synthetic Aβ42-derived diffusible ligands (ADDLs), and (3) TBS-soluble fractions from aged Tg2576 mouse brain. Size exclusion chromatography and ELISA were used to characterize AβO species. Multiphoton calcium imaging of neuron-astrocyte co-cultures was performed to assess the impact of aducanumab on AβO-induced calcium overload.</p><p><strong>Results: </strong>Aducanumab preferentially bound and immunodepleted HMW AβOs in ADDLs and the TBS-soluble fraction of Tg2576 mouse brain extracts but did not recognize LMW AβOs in TgCM. In calcium imaging experiments, all three AβO preparations induced calcium overload in neuron-astrocyte co-cultures. Immunodepletion with aducanumab prevented calcium overload in cultures exposed to ADDLs and Tg2576 brain extracts but not in those treated with immunodepleted TgCM, indicating that aducanumab selectively neutralizes HMW AβOs.</p><p><strong>Conclusions: </strong>Our findings demonstrate that aducanumab specifically targets HMW AβOs, mitigating their neurotoxic effects by restoring intracellular calcium homeostasis. These results provide mechanistic insight into aducanumab's therapeutic action and support its potential role in modifying AD pathology by selectively neutralizing Aβ species.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"180"},"PeriodicalIF":7.6,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144783259","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 intersection between circulatory microRNAs and biomarkers of neurodegeneration.","authors":"Amber Yaqub, Rima Mustafa, M Arfan Ikram, Mohsen Ghanbari","doi":"10.1186/s13195-025-01831-6","DOIUrl":"10.1186/s13195-025-01831-6","url":null,"abstract":"<p><strong>Background: </strong>MicroRNAs (miRNAs) are small non-coding RNAs with a vast array of biological functions, including the regulation of gene expression. It remains to be determined whether circulatory miRNAs are associated with markers of neurodegeneration in plasma (neurofilament light chain (NfL), total tau (t-tau) and amyloid beta (Aβ)), before the clinical onset of dementia.</p><p><strong>Methods: </strong>We included 1959 dementia-free participants of the population-based Rotterdam Study (mean age 70.5 years, 56.8% women), who visited the research center for blood sampling between 2002 and 2005. Plasma levels of 591 well-expressed circulatory miRNAs were measured by the HTG EdgeSeq Whole Transcriptome Assay, while t-tau, NfL, Aβ-40 and Aβ-42 were analysed using the Simoa NF-light^® and N3PA assays. We used linear regression models to determine associations between circulatory miRNAs and markers of neurodegeneration, while adjusting for potential confounders. To account for the high-dimensional structure of miRNAs, we repeated the analysis using elastic net regularization models. Finally, we performed a post-hoc in-silico analysis to study the common miRNAs between all four biomarkers, their potential target genes and their link to dementia.</p><p><strong>Results: </strong>We found 58 miRNAs significantly associated with t-tau, 96 miRNAs with NfL, 158 miRNAs with Aβ-40, and 83 miRNAs with Aβ-42 (all with false discovery rate (FDR)-adjusted p-value ≤ 0.05). Notably, twelve miRNAs (miR-3141, miR-7107-5p, miR-146a-5p, miR-6887-5p, miR-221-3p, miR-4681, miR-6810-3p, miR-6821-5p, miR-654-5p, miR-4486, miR-4478, miR-326) were shared among all four neurodegeneration biomarkers. Subsequent in-silico analysis showed that many of these miRNAs are expressed across various brain regions, where they have important putative target genes (e.g., SORT1, TSPAN14, ADAM17, KLF16, WDR12). A pathway analysis highlighted the Notch signalling cascade, with possible implications for the amyloid precursor protein (APP).</p><p><strong>Conclusions: </strong>This population-based study revealed many circulatory miRNAs associated with biomarkers of neurodegeneration, including 12 miRNAs that were common to all, potentially offering valuable insights into regulatory pathways underlying dementia. These miRNAs could be valuable for monitoring dementia and developing effective diagnostic or therapeutic strategies.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"179"},"PeriodicalIF":7.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752085","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":"Integrated plasma and red blood cell membrane lipidomics analysis unveils novel biomarker panel for Alzheimer's disease.","authors":"Dandan He, Yaran Bao, Siyi Yuan, Yingji Wang, Jingbo Cai, Fangfang Xu, Tiantian Chang, Pei Zhang, Menglu Yue, Xiaodong Pan, Haiping Hao, Qiuling Zheng","doi":"10.1186/s13195-025-01830-7","DOIUrl":"10.1186/s13195-025-01830-7","url":null,"abstract":"<p><strong>Background: </strong>Discovering new biomarkers for Alzheimer's disease (AD) are significant for early diagnosis and monitoring disease's progression. Blood-based lipid biomarkers, particularly from red cell membranes, offer a non-invasive alternative, providing insights into AD progression and potential therapeutic targets.</p><p><strong>Methods: </strong>This study innovatively incorporates red cell membrane (RCM) lipids, which reflect chronic physiological alterations and are linked to AD pathogenesis. A comprehensive lipid detection platform was employed to analyze lipid profiles from 156 individuals, including normal subjects, those with amnestic mild cognitive impairment, and AD patients. Differential lipids were identified and validated to be AD-associated by correlation analysis and big data analysis. Multi-dimensional criteria were applied to select potential lipid biomarkers.</p><p><strong>Results: </strong>PLS-DA revealed distinct lipidomic profiles between groups, with RCM samples showing superior separation. 138 differentially expressed lipids were identified and enriched in AD-related pathways, many uniquely associated with the RCM. Six lipids were selected as a potential biomarker panel for AD based on multi-dimensional criteria.</p><p><strong>Conclusions: </strong>RCM shows broader lipidomic relevance and stronger biomarker potential compared to plasma. Integrating RCM lipids with plasma analysis enhances AD diagnostics and highlights the potential of RCM as an underexplored biomarker resource.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"178"},"PeriodicalIF":7.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752084","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":"Reductions in brainstem volume as a key macrostructural indicator in at-risk populations for Alzheimer's disease.","authors":"Thomas M Lancaster, Kevin Murphy, Hannah Chandler","doi":"10.1186/s13195-025-01829-0","DOIUrl":"10.1186/s13195-025-01829-0","url":null,"abstract":"<p><strong>Background: </strong>Alterations to brain macrostructure, assessed via T1-weighted magnetic resonance imaging are observed in preclinical models of Alzheimer's disease (AD), reflecting susceptibility, prodromal stages of AD or correlates of early AD pathophysiology. While changes in cingulate and medial temporal lobe structures may be functionally implicated in cognitive decline, little is known about the viability of brain-based biomarkers that support autonomic functions implicated in preclinical AD risk such as the brainstem.</p><p><strong>Methods: </strong>In a series of multiple linear regressions, we assess the volume of the brainstem in two asymptomatic at-AD-risk samples, assessed via the presence of either mild cognitive impairment (MCI, N = 148), or extremely high polygenic risk (N = 13) with matched demographics (mean age = 67 [range 58-76], in both cases). We further determine the strength of the association, compared to 150 other structural MRI features.</p><p><strong>Results: </strong>We observed brainstem volume reductions (MCI: b = -0.29, P = 0.018; Genetic risk: b = -1.29, P = 0.002) in both samples. The magnitude of each preclinical AD marker (MCI / AD-polygenic risk)- brainstem association was empirically larger (Z > 2.3, P < 0.05, in both cases) than 150 frequently segmented MRI features. We further replicate the negative AD-polygenic risk score- brainstem association in UK Biobank (N = 31968; b = -0.002, P = 0.03), with weaker evidence that the association was larger than all other MRI features (Z = 1.622; P = 0.052).</p><p><strong>Conclusions: </strong>These observations suggest that AD risk, assessed via the presence of MCI or extremely high AD-polygenic risk score is linked to reduced brainstem volume before most typically observed morphological brain alterations. This conforms with evidence implicating the brainstem as one of the earliest sites of morphological neurodegeneration and provides a plausible biological mechanism linking prodromal autonomic symptoms to AD risk in later life. These observations warrant future investigation into the molecular correlates of AD-linked brainstem dysfunction, assessment as a candidate biomarker, and the exploration of brainstem mediated treatment strategies in AD prevention.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"177"},"PeriodicalIF":7.6,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12296611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A human neuron alzheimer's disease model reveals barriers to senolytic translatability.","authors":"Chaska C Walton, Ellen Wang, Suckwon Lee, Cynthia J Siebrand, Nicholas J Bergo, Zachary Mayeri, Julie K Andersen","doi":"10.1186/s13195-025-01822-7","DOIUrl":"10.1186/s13195-025-01822-7","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"176"},"PeriodicalIF":7.6,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12297865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717265","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 biomarkers identify brain ATN abnormalities in a dementia-free population-based cohort.","authors":"Menayit Tamrat Dresse, Pamela C L Ferreira, Akshay Prasadan, Jihui L Diaz, Xuemei Zeng, Bruna Bellaver, Guilherme Povala, Victor L Villemagne, M Ilyas Kamboh, Ann D Cohen, Tharick A Pascoal, Mary Ganguli, Beth E Snitz, C Elizabeth Shaaban, Thomas K Karikari","doi":"10.1186/s13195-025-01803-w","DOIUrl":"10.1186/s13195-025-01803-w","url":null,"abstract":"<p><strong>Introduction: </strong>Using the ATN framework, we evaluated the potential of plasma biomarkers to identify abnormal brain amyloid-beta (Aβ) positron emission tomography (PET), tau-PET and neurodegeneration in a socioeconomically disadvantaged population-based cohort.</p><p><strong>Methods: </strong>Community-dwelling dementia-free (n = 113, including 102 (91%) cognitively normal) participants underwent ATN neuroimaging and plasma biomarker assessments.</p><p><strong>Results: </strong>Plasma Aβ42/Aβ40, p-tau181, and p-tau217 showed significant associations with Aβ-PET status, (adjusted odds ratio [AOR] of 1.74*10^-24, 1.47, and 3.43*10³, respectively (p-values < 0.05), with p-tau217 demonstrating the highest classification accuracy for Aβ-PET status (AUC = 0.94). Plasma p-tau181 and p-tau217 showed significant associations with tau-PET status (AOR: 1.50 and 22.24, respectively (p-values < 0.05), with comparable classification accuracies for tau-PET status (AUC = 0.74 and 0.70, respectively). Only plasma NfL showed significant association with neurodegeneration based on cortical thickness (AOR = 1.09, p-value < 0.05).</p><p><strong>Conclusion: </strong>Our findings highlight the potential of plasma p-tau217 as a biomarker for brain Aβ and tau pathophysiology, p-tau181 for tau abnormalities, and NfL for neurodegeneration in the community.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"173"},"PeriodicalIF":7.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717269","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":"Hypometabolic subtypes of AD are linked to comorbid hippocampal sclerosis and Lewy body pathology.","authors":"Fedor Levin, Martin Dyrba, Stefan J Teipel, Michel J Grothe","doi":"10.1186/s13195-025-01796-6","DOIUrl":"10.1186/s13195-025-01796-6","url":null,"abstract":"<p><strong>Background: </strong>Neuroimaging studies have identified distinct 'typical/neocortical' and 'limbic-predominant' hypometabolic subtypes of AD with different clinical and biomarker characteristics. We investigated associations of these subtypes with postmortem neuropathological measures in an observational study.</p><p><strong>Methods: </strong>Antemortem FDG-PET scans of 74 participants from the ADNI autopsy cohort were classified into previously described typical/neocortical and limbic-predominant subtype patterns. We used Bayesian regression and ANCOVA to test associations between the subtypes and neuropathological features.</p><p><strong>Results: </strong>Results were inconclusive for Thal phases, Braak stages, CERAD neuritic plaque scores, hippocampal tangle density, and TDP-43 pathology (BF₁₀ between 0.447 and 1.146). However, the limbic-predominant subtype was associated with hippocampal sclerosis (BF₁₀ = 3.842, moderate level of evidence), whereas the typical/neocortical subtype was associated with Lewy body pathology (BF₁₀ = 10.093, strong level of evidence).</p><p><strong>Conclusions: </strong>These findings highlight the influence of AD and non-AD-specific pathologies on neurodegeneration patterns and may provide directions for research into hypometabolic pattern analysis as an indirect marker of comorbid pathology.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"172"},"PeriodicalIF":7.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717268","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":"Alcohol consumption and cerebrospinal fluid biomarkers for preclinical alzheimer's disease in a population-based sample of 70-year-olds.","authors":"Silke Kern, Tobias Skillbäck, Henrik Zetterberg, Anna Dittrich, Felicia Ahlner, Anna Zettergren, Margda Waern, Nazib M Seidu, Ulf Andreasson, Kaj Blennow, Ingmar Skoog","doi":"10.1186/s13195-025-01819-2","DOIUrl":"10.1186/s13195-025-01819-2","url":null,"abstract":"<p><strong>Background: </strong>It is largely unknown how alcohol use affects the risk of Alzheimer`s disease (AD). Therefore, studies on the influence of alcohol use on cerebrospinal fluid (CSF) biomarkers for the earliest preclinical phase of AD are needed.</p><p><strong>Methods: </strong>This was a cross-sectional cohort study. The sample (n = 301) was derived from the 2014-2016 examinations of the Gothenburg H70 Birth Cohort Studies. The study cohort consisted of 301 70-year-old women and men, where of 246 cognitively unimpaired and 55 with mild cognitive deficits. Information on alcohol consumption (g/week and type of alcohol) was collected and CSF amyloid-β_1-42 (Aβ42), total-tau (T-tau), tau phosphorylated at threonine 181 (P-tau181), neurofilament light protein (NfL) and neurogranin (Ng) were measured. We tested the association between the CSF biomarkers and alcohol consumption types using correlation and linear regression, adjusting for possible confounders when necessary according to the performed sensitivity analysis.</p><p><strong>Results: </strong>There were no correlations between weekly alcohol consumption and any of the CSF markers studied in the total sample of cognitively unimpaired participants (n = 246). After adjustments for multiplicity with FDR, there was an association between white wine and Ng in women with CDR = 0 (β:0.254, CI: ( 0.069: 0.439), p = 0.0076, FDR = 0.0455). Interaction analysis between female sex and red wine intake was a significant predictor of high Ng levels (β:0.410, CI: ( 0.099: 0.721), p = 0.0100, FDR = 0.0500). There were no correlations between consumption of specific types of alcohol (spirits, white wine, red wine, fortified wine, and beer) and any of the biomarkers studied in the total sample of cognitively unimpaired participants.</p><p><strong>Conclusions: </strong>Our findings indicate that higher alcohol use in older cognitively unimpaired women correlates with a biomarker of synaptic dysfunction in AD, which is an important observation in a time when alcohol use is increasing among women.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"175"},"PeriodicalIF":7.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717266","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 AL101 (GSK4527226), a progranulin-elevating monoclonal antibody, as a potential treatment for Alzheimer's disease.","authors":"Balasubrahmanyam Budda, Ananya Mitra, Lovingly Park, Hua Long, Michael Kurnellas, Nga Bien-Ly, William Estacio, Brady Burgess, Grace Chao, Tina Schwabe, Robert Paul, Sara Kenkare-Mitra, Arnon Rosenthal","doi":"10.1186/s13195-025-01817-4","DOIUrl":"10.1186/s13195-025-01817-4","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is characterized by amyloid plaques, tau tangles, and neuronal loss. Progranulin (PGRN) is a secreted immune regulator, lysosomal chaperone, and neuronal survival factor. Genetic polymorphisms that reduce PGRN levels are associated with an increased risk for AD and other neurodegenerative disorders. The receptor sortilin binds and targets PGRN for lysosomal degradation, resulting in a reduction of extracellular PGRN. AL101 (GSK4527226) is a monoclonal antibody that binds to the sortilin receptor and is being developed as a potential PGRN-elevating therapy for AD.</p><p><strong>Methods: </strong>Cell-based in vitro studies examined the interaction of AL101 with sortilin and its effect on PGRN levels. In vivo studies evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of AL101 in rats and nonhuman primates. A phase 1 study in healthy volunteers assessed PK, safety, tolerability, and PD biomarkers after intravenous or subcutaneous dosing of AL101.</p><p><strong>Results: </strong>Cell-based assays showed that AL101 increased PGRN levels by decreasing cell surface sortilin levels and partially blocking the sortilin-PGRN interaction. Preclinical studies in rats and monkeys demonstrated that AL101 decreased cell surface sortilin levels on white blood cells and increased PGRN levels by up to 2-fold in cerebrospinal fluid (CSF) and up to 4-fold in blood. In the phase 1 study in healthy volunteers, both single and multiple doses of AL101 led to significant increases in plasma and CSF PGRN levels, providing additional support for its potential as a PGRN-elevating therapy.</p><p><strong>Limitations: </strong>The first-in-human dose-finding study was aimed at investigating the safety and tolerability of AL101 and was not sufficiently powered to detect changes in exploratory outcomes, such as neurodegeneration biomarkers. Clinical studies are needed to evaluate AL101 in AD patients.</p><p><strong>Conclusions: </strong>AL101 was shown to bind sortilin and decrease cell surface sortilin levels, leading to consistent elevations of PGRN across in vitro, preclinical, and human studies. These results support continued development of AL101 and its investigation as a potential treatment for AD and other neurodegenerative conditions where PGRN could play a role.</p><p><strong>Trial registration: </strong>Clinicaltrials.gov, NCT04111666. Registered on October 1, 2019. https://clinicaltrials.gov/ct2/show/NCT04111666 .</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"174"},"PeriodicalIF":7.6,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717267","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}