The “Glyco-Remodeling” Hypothesis in Alzheimer’s Disease: Linking Protein N-Glycosylation to Pathogenesis and Translation

Abstract

Alzheimer’s disease (AD), an age-associated neurodegenerative disorder characterized by cognitive decline and accumulation of amyloid-β (Aβ) plaques and tau tangles, has long been studied through the lens of protein aggregation and phosphorylation. However, emerging evidence suggests that aberrant protein N-glycosylation, a key post-translational modification governing protein folding, trafficking, and signaling, plays an equally pivotal role in AD pathogenesis. This review consolidates current knowledge on N-glycosylation, and very briefly about the prominent O-Glycosylation dynamics in the healthy and diseased brain, with a focus on six key proteins amyloid precursor protein, immunoglobulin G (IgG), triggering receptor expressed on myeloid cells-2 (TREM2), tau (τ), apolipoprotein E, and transferrin whose altered glycosylation patterns perturb amyloidogenic processing, tau aggregation, microglial activity, lipid transport, and systemic immune balance. We introduce the glyco-remodeling hypothesis, proposing that stage-specific glycosylation changes act as molecular “remodeling” driving the progression from normal aging, to mild cognitive impairment, and ultimately AD. Framing AD through this lens positions glycans as both markers and modulators of disease progression, with direct implications for biomarker discovery, therapeutic targeting, and systems-level integration across aging and neurodegeneration.