Natural polysaccharides as multi-target therapeutic candidates for Alzheimer's disease: Mechanisms,...

Alzheimer's disease (AD) is increasingly recognized as a systems-level disorder involving amyloid-β (Aβ) deposition, tau pathology, oxidative stress, mitochondrial dysfunction, neuroinflammation, synaptic impairment, and microbiota-gut-brain axis dysregulation. Although previous reviews have summarized the anti-AD effects of natural polysaccharides according to individual pathological pathways, an integrated framework linking polysaccharide structure, gut microbial metabolism, peripheral immune regulation, and central AD pathology remains insufficiently developed.

This review aims to provide an updated and integrative synthesis of natural polysaccharides as multi-target therapeutic candidates for AD, with particular emphasis on their mechanistic networks, structure-activity relationships, and translational potential.

A systematic PubMed search was performed for studies published from January 1, 2016, to June 7, 2026. Eligible studies investigated natural polysaccharides as primary therapeutic interventions in in vivo AD models. Reviews, editorials, purely in vitro studies, studies using polysaccharides solely as drug-delivery carriers, synthetic derivatives, and inseparable compound formulations were excluded. Seventy-four original studies were included for mechanistic and structure-activity analyses.

Natural polysaccharides were found to regulate multiple interconnected AD-related processes, including Aβ production, aggregation, and clearance, tau phosphorylation, redox homeostasis, glial activation, inflammasome signaling, synaptic plasticity, cholinergic function, intestinal barrier integrity, gut microbiota composition, and short-chain fatty acid production. Unlike earlier pathway-based summaries, this review proposes a structure-microbiota-metabolite-barrier-inflammation-redox-brain pathology framework to explain how polysaccharide structural features may determine microbial utilization, metabolite generation, immune modulation, and downstream neuroprotective effects.

Natural polysaccharides represent promising multi-target candidates for AD prevention and treatment. Future studies should prioritize structurally defined polysaccharide fractions, causal microbiota validation, pharmacokinetic/pharmacodynamic profiling, biomarker-guided assessment, and rigorously designed clinical trials.