Exploring causal links between brain functional networks and neurodegenerative disease risk using Mendelian...

Area of Science:

• Neuroimaging and Genetics
• Brain functional networks
• Neurodegenerative diseases

Background:

• Resting-state functional MRI (rsfMRI) maps brain network changes in neurodegenerative diseases.
• Causal links between network dysfunction and disease pathogenesis are not fully understood.

Purpose of the Study:

• To investigate bidirectional causal relationships between rsfMRI phenotypes and six neurodegenerative diseases.
• Utilizing data from 34,691 individuals and disease-specific GWAS.

Main Methods:

• Bidirectional two-sample Mendelian randomization (MR) analysis.
• rsfMRI phenotypes and GWAS summary statistics for Alzheimer's disease (AD), ALS, FTD, MS, DLB, and PD.
• Sensitivity analyses including MR-PRESSO and Cochran's Q for robustness.

Main Results:

• Forward MR identified 26 rsfMRI phenotypes linked to neurodegenerative diseases.
• AD risk associated with reduced cerebellum-subcortical connectivity; heightened cerebellar activity linked to DLB risk.
• Reverse MR showed AD altering default mode network connectivity and PD disrupting salience-central executive network interactions.

Conclusions:

• Established robust bidirectional causal pathways between brain functional networks and neurodegenerative diseases.
• Alzheimer's disease exhibits unique vulnerability in cerebellar-subcortical and default mode networks.
• Findings suggest network-specific therapeutic targets for AD and related disorders.