Natural Bioactive Compound Combinations in Alzheimer's Disease: Gut-brain Axis and Quantitative Interaction Assessment

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which singletarget therapies have repeatedly shown limited clinical efficacy. Natural bioactive compounds offer multi-target neuroprotective potential, yet contemporary research has predominantly focused on individual compounds rather than rationally defined combinations. This review examines natural bioactive compound combinations in AD through the gut-brain axis, with particular attention to distinguishing mechanistic complementarity from quantitatively demonstrated pharmacological synergy. The major pathways connecting gut microbiota dysbiosis to AD pathology were first summarized, and then discussed how compound combinations may produce enhanced effects through complementary microbiota modulation, metabolic regulation, and coordinated actions at intestinal and central nervous system targets. As an illustrative case, the combination of Icariin (ICA) and Panax Notoginseng Saponins (PNS), derived from the deconstruction of a traditional Chinese medicine formula, is critically evaluated. Available studies suggest combination-associated changes in gut microbiota, hippocampal protein expression, and AD-related outcomes, while evidence from the individual components supports biologically plausible complementary mechanisms. However, current evidence remains largely qualitative and does not establish that ICA-PNS produces supraadditive effects or that microbiota changes causally mediate its benefits. Improved combination efficacy should therefore not be equated with synergy. Future studies should use informative doseresponse matrices and pre-specified interaction models, including the Chou-Talalay combination index with complementary Loewe or Bliss analyses, together with multi-omics and microbiotacausality experiments, to enable more rigorous and reproducible evaluation and support mechanistic validation and future translational development of natural compound combinations.