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Basic Science and Pathogenesis.

Tianyi Zhang1, Guoping Peng2

  • 1The first Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 23, 2025
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Summary
This summary is machine-generated.

Gut microbiome alterations and bile acids (BAs) impact Alzheimer's disease (AD) cognitive decline. The basal forebrain cholinergic system (BFCS) mediates this relationship, influenced by tau pathology, revealing brain-gut axis mechanisms in AD.

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Area of Science:

  • Neuroscience
  • Gastroenterology
  • Microbiome Research

Background:

  • Emerging research links the gut microbiome to Alzheimer's disease (AD) progression.
  • Altered serum bile acid (BA) profiles in AD patients suggest a connection to gut microbial activity.
  • The precise mechanisms linking gut metabolites to cognitive decline in AD remain unclear.

Purpose of the Study:

  • To investigate the relationship between gut microbiome-derived metabolites (BAs) and cognitive function in AD.
  • To explore the role of the basal forebrain cholinergic system (BFCS) in mediating the effects of BAs on cognition.
  • To examine the influence of AD pathology, specifically tau, on the BA-BFCS-cognition axis.

Main Methods:

  • Analysis of data from 1,414 participants (controls, MCI, AD) in the Alzheimer's Disease Neuroimaging Initiative (ADNI).
  • Examination of 15 BA metabolites and 8 BA ratios for correlations with BFCS volumes and cognitive performance.
  • Mediation analyses to assess the roles of BFCS and AD pathology in the observed relationships.

Main Results:

  • Significant associations were found between serum BA profiles, BFCS volumes, and cognitive performance.
  • The basal forebrain cholinergic system (BFCS) was identified as a mediator between gut microbiota metabolism-related BA ratios and cognitive function.
  • Secondary-to-primary BA ratios influenced BFCS, and this effect was modulated by tau pathology.

Conclusions:

  • The basal forebrain cholinergic system (BFCS) may modulate the impact of bile acids (BAs) on cognitive function in Alzheimer's disease (AD).
  • Tau pathology potentially mediates the influence of BAs on BFCS, highlighting the brain-gut axis in AD.
  • These findings deepen the understanding of the complex interplay between the gut microbiome, BAs, and cognitive function in AD pathogenesis.