Plant Polysaccharides in Alzheimer’s Disease: from Phytochemistry to Microbiota-Gut–Brain Axis Mechanisms—Resolving the Pharmacokinetic-Pharmacodynamic Paradox

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ deposition, tau hyperphosphorylation, and neuroinflammation. No effective drugs can slow disease progression. Polysaccharides from traditional Chinese medicine (TCM) exhibit neuroprotective activities (e.g., antioxidant, anti-inflammatory) with good safety. However, their clinical application is limited by low oral bioavailability, poor blood–brain barrier (BBB) permeability, and a pharmacokinetic–pharmacodynamic paradox. The emerging role of the microbiota–gut–brain axis in AD offers a strategy to overcome this paradox. This review summarizes the structural features and classification of TCM polysaccharides (from plants, fungi, and roots/rhizomes) and highlights their anti-AD mechanisms via the gut–brain axis. Acting as prebiotics, these polysaccharides escape upper digestion and are fermented by gut microbiota into short-chain fatty acids (SCFAs) and other metabolites, which enter circulation, cross the BBB, and alleviate AD pathology through metabolic, immune, and neuronal pathways. Outcomes include reduced Aβ deposition and tau phosphorylation, suppressed neuroinflammation, restored synaptic function, and improved cognition. This review provides a theoretical framework for TCM polysaccharide intervention in AD via the gut–brain axis and a pharmacological basis for developing natural product-based AD therapies.