Serum <i>N</i>-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 <i>N</i>-glycan alterations, in the pathogenesis of AD. This study utilizes advanced LC-MS/MS techniques to profile <i>N</i>-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 <i>N</i>-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 <i>N</i>-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 <i>N</i>-glycans as biomarkers for early detection of AD and its precursors, offering new avenues for therapeutic intervention. The differential expression of specific <i>N</i>-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.