Emerging neuroprotective mechanisms and therapeutic potential of natural polysaccharides in Alzheimer's disease
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, affecting millions worldwide. Despite extensive research, effective treatments remain limited. Polysaccharides, abundant biological macromolecules derived from natural resources have emerged as promising therapeutic candidates due to their antioxidant, anti-inflammatory, and neuroprotective properties. This narrative review summarizes recent preclinical and limited clinical evidence on natural polysaccharides and their structure–activity relationships (SAR) in AD. We focus on their ability to mitigate amyloid-beta (Aβ) aggregation, reduce tau hyperphosphorylation, modulate neuroinflammation, and enhance cognitive function. We emphasize novel mechanistic insights and highlight how fungal, algal, plant, and bacterial polysaccharides exert broad multi-targeted effects. Importantly, this is the first review to integrate SAR with challenges of bioavailability and blood–brain barrier (BBB) penetration, offering a framework for optimizing therapeutic design. Novel insights into the molecular mechanisms, such as activation of Nrf2 and autophagy pathways, are discussed. We also underscore the translational value of polysaccharides, noting that strategies such as structural modification, nanoparticle conjugation, and pharmacokinetic profiling could accelerate their progression toward clinical application. However, most evidence is limited to in vitro and animal models, with critical challenges including poor bioavailability, limited blood-brain barrier penetration, and a lack of standardized clinical data. We conclude that natural polysaccharides are promising, low-toxicity therapeutic agents for AD management. But for complete validation of their therapeutic potential, standardized pharmacokinetic profiling, rigorous safety assessment, and well-designed clinical trials are urgently required.