White Matter and Alzheimer's Disease: A Bidirectional Mendelian Randomization Study

Area of Science:

• Neuroscience
• Genetics
• Epidemiology

Background:

• Observational studies suggest a link between white matter (WM) lesions and Alzheimer's disease (AD) in the elderly.
• The causal relationship and directionality between WM lesions and AD remain unclear.

Purpose of the Study:

• To investigate the bidirectional causal relationship between white matter (WM) changes and Alzheimer's disease (AD) using a genetically informed approach.
• To examine the association between three WM phenotypes (WMH, FA, MD) and AD.

Main Methods:

• A bidirectional two-sample Mendelian randomization (MR) study was conducted.
• Summary statistics from genome-wide association studies (GWAS) for WM phenotypes (N > 17,000) and AD (N = 63,926) were utilized.
• Inverse variance weighted (IVW) method and sensitivity analyses were employed to assess causal estimates and test for heterogeneity and pleiotropy.

Main Results:

• No significant causal evidence was found for WM MRI markers influencing AD risk.
• Alzheimer's disease (AD) showed a significant causal effect on the risk of white matter hyperintensities (WMH) and mean diffusivity (MD).
• These causal effects were largely attenuated when single nucleotide polymorphisms (SNPs) near the APOE region were excluded, suggesting APOE mediation.

Conclusions:

• White matter injuries were not found to be associated with an increased risk of Alzheimer's disease (AD).
• Genetically predicted AD did not demonstrate a causal effect on white matter damage.
• The underlying mechanisms linking AD and white matter lesions may involve genetic factors near the APOE region.