Investigating the Causal Relationships Between Brain Imaging Phenotypes and Dementia and Its Subtypes: Comprehensive...

Area of Science:

• Neuroimaging
• Genetics
• Neurodegenerative Diseases

Background:

• Observational studies suggest links between brain imaging phenotypes (IDPs) and resting-state functional networks (rs-fMRI) with dementia.
• The causal nature of these associations remains unclear.

Purpose of the Study:

• To investigate the causal relationships between IDPs and rs-fMRI phenotypes with dementia and its subtypes using Mendelian randomization.
• To identify potential imaging-based predictors and therapeutic targets for dementia.

Main Methods:

• Applied bidirectional two-sample Mendelian randomization analysis.
• Utilized genetic variants (SNPs) as instrumental variables.
• Analyzed 587 IDPs and 191 rs-fMRI networks against dementia, Alzheimer's disease (AD), progressive supranuclear palsy (PDD), frontotemporal dementia (FTD), and Lewy body dementia (DLB).

Main Results:

• Forward MR identified 14 IDPs causally associated with dementia risk, including FTD and DLB.
• Reverse MR revealed associations between 153 IDPs and risk of FTD/DLB, and 73 rs-fMRI phenotypes with dementia/AD.
• Specific findings include decreased frontal cortex thickness linked to increased dementia risk and reduced thalamic radiation FA linked to DLB risk.

Conclusions:

• Identified 14 IDPs causally linked to dementia or its subtypes.
• Revealed potential causal effects of FTD/DLB on IDPs and dementia/AD on rs-fMRI phenotypes.
• Findings offer insights into dementia etiology, highlighting structural and functional brain changes, and suggest potential imaging biomarkers.