Compositional and functional gut microbiota alterations in mild cognitive impairment: links to Alzheimer's disease pathology

Abstract

Background: Emerging evidence highlights the bidirectional communication between the gut microbiota and the brain, suggesting a potential role for gut dysbiosis in Alzheimer's disease (AD) pathology and cognitive decline. Existing literature on gut microbiota lacks species-level insights. This study investigates gut microbiota alterations in mild cognitive impairment (MCI), focusing on their association with comprehensive AD biomarkers, including amyloid burden, tau pathology, neurodegeneration, and cognitive performance.

Methods: We analyzed fecal samples from 119 individuals with MCI and 320 cognitively normal controls enrolled in the Taiwan Precision Medicine Initiative on Cognitive Impairment and Dementia cohort. Shotgun metagenomic sequencing was conducted with taxonomic profiling using MetaPhlAn4. Amyloid burden and plasma pTau181 were quantified via PET imaging and Simoa assays, respectively, while APOE genotyping was performed using TaqMan assays. Microbial diversity, differential abundance analysis, and correlation mapping with neuropsychological and neuroimaging measures were conducted to identify gut microbiota species signatures associated with MCI and AD biomarkers.

Results: We identified 59 key microbial species linked to MCI and AD biomarkers. Notably, species within the same genera, such as Bacteroides and Ruminococcus, showed opposing effects, while Akkermansia muciniphila correlated with reduced amyloid burden, suggesting a protective role. Functional profiling revealed microbial pathways contributing to energy metabolism and neuroinflammation, mediating the relationship between gut microbes and brain health. Co-occurrence network analyses demonstrated complex microbial interactions, indicating that the collective influence of gut microbiota on neurodegeneration.

Conclusions: Our findings challenge genus-level microbiome analyses, revealing species-specific modulators of AD pathology. This study highlights gut microbial activity as a potential therapeutic target to mitigate cognitive decline and neurodegeneration.

Keywords: APOE; Alzheimer’s disease pathology; Amyloid PET; Gut microbiome; Gut-brain axis; Mild cognitive impairment; Plasma pTau181; Shotgun metagenomics.

Fig. 1

Correlation Heatmaps of Key Microbes and Cognitive Functions/Brain Structure in (A) Whole Dataset and (B) AT subgroup. Partial correlations between key microbial species and neuropsychological test scores were adjusted for age, gender, and years of education. For consistency in interpretation, the outcomes of Color Trails Test 1 and 2 were assigned a negative sign so that the correlation colors would reflect the same direction across measures. Partial correlations between key microbial species and brain volume indicators, as well as fractional anisotropy (FA) from DTI analysis, were adjusted for age, gender, and estimated intracranial volume (eTIV). Correlations between key microbial species and the AD-CTS, a cortical thickness indicator, were adjusted only for age and gender. The cross sign indicates a significant correlation with p < 0.05. Key microbes that show correlations with a greater number of cognitive functions and brain structures are considered more robust in their relationship with cognitive impairment

Fig. 2

Co-occurrence Network Analysis of Key Microbes with SPIEC-EASI. The color of the nodes represents the clusters of each key microbial species, with blue edges indicating positive associations between species and red edges indicating negative associations. The intensity of the edge color corresponds to the strength of the association. Larger nodes indicate a higher degree of connectivity, and Enterocloster bolteae was identified as the central hub in this co-occurrence network.