Phytosterols as modulators of gut-brain axis and neuroinflammation in Alzheimer's disease: A novel therapeutic avenue in aging research.

Alzheimer's disease (AD) is characterized by amyloid-β deposition and neuroinflammation. Emerging evidence implicates gut microbiota dysbiosis and gut-brain axis dysfunction in AD pathogenesis, while phytosterols-plant sterols similar to cholesterol-modulate microbiota composition, lipid metabolism, and inflammatory pathways. To review evidence of phytosterols as modulators of the gut-brain axis and neuroinflammation in AD, outlining mechanisms, therapeutic potential, and delivery approaches. A literature search of PubMed, Scopus, and Web of Science identified studies on phytosterols, gut microbiota modulation, neuroinflammation, and AD. Mechanistic data on sterol structure-activity relationships, microbiota-derived metabolites, and in vivo AD outcomes were extracted and synthesized. Phytosterols lower systemic cholesterol, cross the blood-brain barrier, and accumulate in neural tissue. They enrich short-chain fatty acid-producing gut microbes, suppress pathogens, and increase secondary bile acids that activate FXR and TGR5 signaling, attenuating neuroinflammation. Preclinical AD models show reduced amyloid-β, decreased microglial activation, and improved cognition. Nanoencapsulation and esterification strategies enhance CNS bioavailability. Phytosterols modulate cholesterol, gut microbiota, and neuroinflammatory pathways through FXR- and TGR5-mediated signaling. Advanced delivery systems and microbiome-informed dosing strategies may enhance their therapeutic precision and uptake. Future studies should focus on stratified human trials to validate efficacy and enable personalized interventions in Alzheimer's disease.