White-Matter Structural Connectivity and Alzheimer's Disease: A Mendelian Randomization Study

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Observational studies suggest a link between Alzheimer's disease (AD) and white-matter structural connectivity.
• The causal relationship between white-matter structural connectivity and AD remains unclear.

Purpose of the Study:

• To investigate the impact of white-matter structural connectivity on Alzheimer's disease (AD) using a two-sample multivariate Mendelian randomization (MR) approach.
• To determine if specific white-matter connections causally influence AD risk.

Main Methods:

• Utilized genome-wide association study (GWAS) data for white-matter structural connectivity (Wainberg et al.) and AD (Bellenguez et al.).
• Employed various MR methods including inverse variance weighted, MR-Egger, simple mode, weighted median, and weighted mode.
• Assessed robustness through heterogeneity, horizontal pleiotropy, and leave-one-out analyses; conducted reverse MR analysis.

Main Results:

• Identified 10 out of 206 white-matter structural connections significantly associated with genetic susceptibility to AD.
• Right-hemisphere limbic network to thalamus and salience-ventral attention network to accumbens connections were positively correlated with AD likelihood.
• Eight other connections showed a negative correlation with AD; no reverse causal relationship was found.

Conclusions:

• The MR study demonstrates a significant association between specific white-matter structural connectivity patterns and Alzheimer's disease.
• Findings may inform future diagnostic and therapeutic strategies for AD.
• Highlights the potential role of specific brain network connections in AD pathogenesis.