# Diet, gut microbiome, and cognition in neurodegeneration: a review and methodological framework

## TL;DR

This review explores how the gut microbiome affects brain health and cognition, especially in neurodegenerative diseases, and proposes a framework for studying diet-microbiome-cognition relationships.

## Contribution

The paper introduces a methodological framework for investigating causal links between diet, the gut microbiome, and cognitive outcomes.

## Key findings

- Microbiome diversity is linked to healthy aging and survival, while dysbiosis is associated with neurodegenerative diseases.
- Fecal transplants in mice show that microbiome changes can cause cognitive and neuropathological effects.
- Genetic and environmental factors influence both microbiome composition and neurodegeneration risk.

## Abstract

The gut microbiome influences brain function through the gut-brain axis via synthesis of neurotransmitters, production of metabolites affecting epithelial barrier integrity and immune modulation and signaling through the vagus nerve. In humans, microbiome diversity reflects healthy aging and predicts survival, while dysbiosis is increasingly implicated in neurodegenerative conditions including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and ALS. Fecal transplant studies in germ-free mice demonstrate that microbiome alterations are sufficient to induce cognitive and neuropathological phenotypes, supporting causality in preclinical models. Genetic risk factors and environmental exposures affect both neurodegeneration risk and microbiome composition. In this review, we synthesize evidence from human cohorts and preclinical models on the gut-brain axis in cognitive health and disease. We then present a methodological framework for diet-microbiome-cognition research, addressing causal inference through mediation analysis, supervised approaches for deriving diet scores, validation strategies, and individual heterogeneity. This framework can guide development of microbiome-targeted dietary interventions to improve cognitive outcomes.