Gut Microbiota Diversity and Function in Adults With Type 2 Diabetes, Alzheimer's Disease, and Both Conditions.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is known to increase the risk of Alzheimer's disease (AD), but the role of the gut microbiota in this relationship is not fully understood. This study investigated the gut microbiota profiles of adults with T2DM, adults with AD, both conditions (AD-T2DM), and healthy controls to identify patterns associated with metabolic and neurodegenerative conditions. METHODS: A cross-sectional study was conducted with 148 participants divided into six groups: CTRL < 60 years, CTRL ≥ 60 years, T2DM < 60 years, T2DM ≥ 60 years, AD, and AD-T2DM. Clinical assessments and 16S rRNA gene sequencing of fecal samples were performed to analyze microbial diversity and composition. RESULTS: Compared with controls, older adults with T2DM, AD, and AD-T2DM presented reduced microbial diversity and distinct microbial compositions. Notably, SCFA-producing genera (Veillonella and Dialister) decreased in T2DM patients ≥ 60 years, whereas Roseburia and Blautia were more abundant in AD patients and those with AD-T2DM. GDP-mannose biosynthesis was downregulated in AD-T2DM patients. CONCLUSION: This study highlights changes in the microbiota in T2DM and AD-T2DM patients, suggesting that targeting these microbial alterations could offer new prevention strategies for metabolic-neurodegenerative comorbidities. SIGNIFICANCE STATEMENT: T2DM and AD share metabolic and inflammatory pathways, yet their combined impact on the gut microbiota remains unexplored. By profiling 148 adults, healthy individuals, those with T2DM, AD, and co-occurring AD-T2DM, using 16S rRNA gene V4 region sequencing, we identified specific dysbiosis in AD-T2DM. Rather than examining T2DM and AD as independent conditions, the present study conceptualizes their coexistence as a metabolic-neurodegenerative interaction state and assesses whether this comorbidity is associated with a distinct gut microbiota composition and predicted functional profile. Therefore, we examine the gut microbiota of adults with AD-T2DM using an age-stratified design in an underrepresented Mexican population, integrating clinical, metabolic, cognitive, taxonomic, and functional data to explore potential mechanisms underlying metabolic-neurodegenerative crosstalk. These findings identify microbial genera that may mediate the "diabeto-neuro" crosstalk, offering novel targets for early intervention and precision microbiota-based therapies to mitigate metabolic-neurodegenerative comorbidity.