From brain imaging phenotypes to vascular dementia subtypes: A comprehensive mendelian randomization study

Area of Science:

• Neuroimaging Genetics
• Neurodegenerative Diseases
• Causal Inference

Background:

• Vascular dementia (VaD) is heterogeneous with distinct subtypes and unknown neuropathological drivers.
• Previous neuroimaging studies identified some structural alterations but lacked causal evidence for VaD subtypes.

Purpose of the Study:

• To establish causal relationships between brain imaging-derived phenotypes (IDPs) and specific VaD subtypes using genetic methods.
• To identify subtype-specific neuroimaging signatures for potential diagnostic biomarkers.

Main Methods:

• Two-sample Mendelian Randomization (MR) analyses utilized 3,935 brain IDPs from UK Biobank and four VaD subtypes from FinnGen.
• Inverse variance weighted analysis was primary, with Bayesian Weighted MR (BWMR) and MR-RAPS for validation and pleiotropy mitigation.
• Sensitivity and reverse MR analyses confirmed robustness and directionality of findings.

Main Results:

• Significant causal associations were found between numerous brain IDPs and all four VaD subtypes.
• 22-21 robustly causal IDPs were identified per subtype, including gray matter changes and axonal/myelin damage in specific brain regions.
• Reverse MR confirmed no VaD subtype influenced the identified brain IDPs.

Conclusions:

• Robust genetic evidence supports distinct causal links between specific brain structural alterations and VaD subtypes.
• Subtype-specific neuroimaging signatures highlight divergent neuroanatomical substrates in VaD.
• Findings offer potential targets for developing diagnostic biomarkers for VaD.