3rd Edition of Dementia World Conference 2026

Abstract

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, amyloid-β (Aβ) deposition, tau hyperphosphorylation, and persistent neuroinflammation, yet effective mechanism-based interventions remain limited. The gut–brain axis has recently emerged as a therapeutically actionable route for modulating neuroimmune dysfunction in AD. Polydatin (PLD), a natural stilbene glucoside and resveratrol precursor, has shown neuroprotective potential; however, whether its efficacy depends on gut microbiota remodeling and microbial metabolites remains insufficiently defined. In this study, APP/PS1 transgenic mice were treated with PLD and subjected to an integrated multi-omics analysis, including 16S rRNA sequencing, hippocampal RNA sequencing, targeted fecal short-chain fatty acid profiling, and PICRUSt2-based functional prediction. Antibiotic-mediated microbiota depletion and fecal microbiota transplantation (FMT) were further used to evaluate microbiota dependence and transmissibility of the therapeutic phenotype. PLD markedly reshaped the intestinal microbial ecosystem, with selective enrichment of butyrate-producing taxa, including Roseburia and members of Lachnospiraceae, accompanied by a pronounced increase in fecal butyrate compared with untreated AD model mice. At the central level, PLD treatment suppressed hippocampal TLR4/NF-κB/NLRP3 inflammatory signaling, reversed disease-associated microglial transcriptional features, and reduced Aβ deposition and tau phosphorylation. Functionally, PLD improved learning and memory performance in APP/PS1 mice. Importantly, antibiotic depletion largely abolished the neuroprotective and anti-inflammatory effects of PLD, whereas FMT from PLD-treated donors transferred cognitive and pathological benefits to recipient mice. These findings identify a gut microbiota–butyrate–neuroinflammation axis as a key mechanistic pathway linking PLD treatment to AD improvement. This work provides causal multi-omics evidence supporting microbiota-activatable polyphenols as promising candidates for gut–brain axis-based intervention in Alzheimer’s disease.