Serum N‑Glycan Profiling Identifies Candidate Glycan Biomarkers for Early Detection and Prediction of Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder marked by progressive cognitive decline, affecting millions worldwide. Early diagnosis and intervention are crucial yet challenging, particularly in distinguishing between Mild Cognitive Impairment (MCI) subtypes, which often precede AD. Recent studies have highlighted the significant role of glycosylation, specifically N-glycan alterations, in the pathogenesis of AD. This study utilizes advanced LC–MS/MS techniques to profile N-glycan changes between serum samples from participants with normal cognition denoted as (CTRL), nonamnestic MCI (naMCI), amnestic MCI (aMCI), and AD. The analysis identified 99 unique N-glycans and revealed distinct glycan expression patterns among the groups. Notably, sialylation was significantly upregulated in AD, while fucosylation was downregulated, suggesting their involvement in AD pathology. Additionally, the study examined the role of isomeric N-glycans, identifying several isomers that differentiate naMCI from aMCI and those that can monitor progression from aMCI to AD dementia. These findings emphasize the potential of N-glycans as biomarkers for early detection of AD and its precursors, offering new avenues for therapeutic intervention. The differential expression of specific N-glycans and their isomers could serve as valuable biomarkers for distinguishing MCI subtypes and predicting progression to AD dementia, thereby aiding in the development of targeted therapies aimed at mitigating cognitive decline in affected individuals.阿尔茨海默病（Alzheimer’s disease, AD）是一类以进行性认知衰退为核心特征的神经退行性疾病，全球数百万人群受其影响。早期诊断与干预至关重要却极具挑战，尤其是在区分常先于AD发生的轻度认知障碍（Mild Cognitive Impairment, MCI）亚型这一环节。现有研究已证实，糖基化修饰（尤其是N-聚糖的异常改变）在AD发病机制中发挥着关键作用。本研究借助先进的液相色谱-串联质谱（LC–MS/MS）技术，对认知正常人群（记为CTRL）、非遗忘型轻度认知障碍（naMCI）、遗忘型轻度认知障碍（aMCI）以及AD患者的血清样本开展N-聚糖谱分析。本次分析共鉴定出99种独特的N-聚糖，并揭示了四组人群间截然不同的聚糖表达模式。值得关注的是，AD患者体内的唾液酸化水平显著上调，而岩藻糖化水平则呈下调趋势，提示这两种糖基化修饰参与了AD的病理进程。此外，本研究还探究了异构N-聚糖的生物学功能，成功鉴定出若干可区分naMCI与aMCI的异构体，以及能够监测aMCI向AD痴呆进展的特异性异构体。上述研究结果充分凸显了N-聚糖作为AD及其前驱阶段早期检测生物标志物的潜力，为靶向治疗干预开辟了全新路径。特定N-聚糖及其异构体的差异表达，可作为区分MCI亚型、预测向AD痴呆进展的可靠生物标志物，进而助力开发旨在减缓患者认知衰退的靶向治疗方案。