Parsing the relationships among gut microbiome, neurotransmitter metabolome, glymphatic function, and cognition across healthy elderly, mild cognitive impairment, and probable Alzheimer's disease.

BACKGROUND: Evidence has suggested brain glymphatic dysfunction and gut microbial metabolic disturbance in Alzheimer's disease (AD), yet the relationships among gut microbiota, neurotransmitter metabolites, glymphatic function, and cognition across clinically defined groups of healthy elderly, mild cognitive impairment (MCI), and probable AD remain unclear.

METHODS: Using metagenomic sequencing, targeted metabolomics, and multi-modal magnetic resonance imaging, we measured the gut microbiome, neurotransmitter metabolome, and a variety of glymphatic markers in 30 patients with clinically diagnosed probable AD, 75 individuals with MCI, and 59 healthy controls (HC).

RESULTS: Although global microbial diversity showed no group difference, MCI and AD showed shared and unique species-level microbial alterations relative to HC. Despite the absence of overall metabolomic divergence, AD exhibited reduced levels of multiple neurotransmitter metabolites compared with MCI and HC. Prominent alterations in multiple glymphatic markers were present in AD rather than in MCI. Further integrated analyses revealed a wide range of associations among these multi-omics changes and established potential serial mediation pathways, manifesting as a pattern of gut microbiota → neurotransmitter metabolites → glymphatic function → cognition.

CONCLUSIONS: These findings could enrich our understanding of the biological mechanisms involved in cognitive impairment and clinically diagnosed probable AD, but also may inform future preventive and therapeutic interventions by targeting the established pathways.