Gut-Brain Nexus: Mapping Multi-Modal Links to Neurodegeneration at Biobank Scale

Area of Science:

• Neuroscience
• Genetics
• Metabolomics
• Gastroenterology

Background:

• Alzheimer's disease (AD) and Parkinson's disease (PD) are complex neurodegenerative disorders influenced by genetic and environmental factors.
• The gut-brain axis, involving interactions between the digestive system and the central nervous system, is increasingly recognized for its role in neurodegenerative disease pathogenesis.
• Understanding the interplay between metabolic/digestive conditions and AD/PD risk is crucial for developing preventative strategies.

Purpose of the Study:

• To investigate the association between 155 endocrine, nutritional, metabolic, and digestive disorders and the risk of AD and PD prior to diagnosis.
• To assess the specificity of plasma biomarkers for AD or PD in individuals with these comorbid conditions.
• To develop and evaluate a multi-modal classification model integrating genetic, proteomic, and clinical data for AD and PD prediction.

Main Methods:

• Population-scale study utilizing data from UK Biobank, SAIL Biobank, and FinnGen.
• Analysis of associations between various disorders and subsequent AD/PD diagnosis, considering genetic predisposition using polygenic risk scores.
• Proteomic profiling and development of multi-modal prediction models incorporating clinical, genetic, proteomic, and demographic data.

Main Results:

• Several disorders, including diabetes mellitus, gastroenteritis, colitis, functional intestinal disorders, and bacterial intestinal infections, were associated with increased pre-diagnostic risk for AD and PD.
• Polygenic risk scores indicated a lower genetic predisposition to AD and PD in individuals with these co-occurring disorders.
• Multi-modal prediction models integrating diverse data types demonstrated superior performance in disease classification compared to single-modality approaches.

Conclusions:

• Comorbid endocrine, nutritional, metabolic, and digestive conditions significantly influence AD and PD risk and progression.
• Modulating the gut-brain axis presents a potential therapeutic target for preventing or delaying neurodegenerative diseases.
• Integrated multi-modal approaches offer a more comprehensive and accurate framework for AD and PD classification and prediction.