Comorbid Alzheimer's Disease and Type 2 Diabetes Microbiota Shape Age-Associated Gut-Brain Axis Profiles.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share metabolic and inflammatory mechanisms, potentially mediated by the gut microbiota, yet the neurobiological impact of comorbid AD+T2DM microbiota from elderly donors remains unexplored. Fecal microbiota from healthy, AD, T2DM, and AD+T2DM postmenopausal female donors (aged 56-89 years) was transplanted into antibiotic-treated male mice. Behavioral testing, blood profiling, hippocampal neurotrophic gene expression, and 16S rRNA sequencing with taxonomic, functional, and metabolic analyses were performed. Human AD+T2DM microbiota displayed the greatest dysbiosis, characterized by enrichment of pro-inflammatory taxa, depletion of butyrate-producing genera, and loss of neuroprotective metabolic pathways. FMT induced robust engraftment, with AD+T2DM recipients diverging most from controls (PERMANOVA R2 = 0.209, p = 0.001) and healthy recipients (PERMANOVA R2 = 0.111, p = 0.002). Donor age contributed significantly to recipient microbiota variation (R2 = 0.028, p = 0.006), suggesting transmission of aging-associated microbial signatures. Hippocampal neurotrophic gene expression was most suppressed in AD+T2DM recipients (adjusted p value < 0.05) and negatively correlated with disease- and aging-associated taxa and microbial functions (|r| > 0.4, FDR p < 0.05). AD recipients showed reduced olfactory discrimination and increased daytime locomotor activity. Metabolic network analysis revealed depletion of flavonoid, isoflavonoid, and lignan biosynthesis pathways in disease recipients. These findings suggest that microbiota from elderly donors with comorbid AD+T2DM may induce gut-brain axis alterations, linking aging, metabolic dysfunction, and neurodegeneration through convergent taxonomic, functional, and neurotrophic changes. We underscore the potential role of age-associated gut microbial signatures in modulating neurobiological outcomes.