Protein glycosylation and glycation in Alzheimer's disease: mechanisms, crosstalk, and therapeutic perspectives

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, pathologically characterized by extracellular senile plaques composed of amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau. Despite decades of research, the molecular mechanisms underlying AD pathogenesis remain incompletely understood, and effective disease-modifying therapies are still lacking. Protein glycosylation and glycation, two distinct post-translational modifications, have emerged as critical contributors to AD pathophysiology. Glycosylation, an enzymatically regulated process including N-linked glycosylation, O-GlcNAcylation, and O-GalNAc glycosylation, modulates the processing of amyloid precursor protein (APP), the aggregation propensity and hyperphosphorylation of tau, the function of apolipoprotein E (ApoE), and neuroinflammatory signaling. Aberrant glycosylation patterns have been consistently detected in the brain, cerebrospinal fluid (CSF), and plasma of AD patients, highlighting their potential as diagnostic biomarkers. In contrast, glycation is a non-enzymatic reaction between reducing sugars and proteins that generates advanced glycation end products (AGEs), which promote oxidative stress, neuroinflammation, blood-brain barrier (BBB) dysfunction, and Aβ and tau aggregation through interaction with the receptor for AGEs (RAGE). This review systematically summarizes recent advances in understanding the roles of glycosylation and glycation in AD pathogenesis, their crosstalk with classical hallmarks, and their translational value as biomarkers and therapeutic targets, providing novel perspectives for early diagnosis and multi-target intervention strategies for AD.