The causal relationship between immune cells, white matter microstructure and dementia: a Mendelian randomization study and co-localization analysis.

With the advancement of global aging, the prevalence of dementia is on the rise. Peripheral immune dysregulation and white matter microstructural changes are potential inducing factors for dementia. However, it is not yet clear which specific types of immune cells and parameters of white matter microstructure have a causal relationship with dementia. This study used Mendelian randomization (MR) to assess causal relationships and mediating pathways among immune cell-related phenotypes, white matter microstructure-related phenotypes, and dementia-related phenotypes, and used co-localization analysis to explore shared genetic variants. We identified potential causal associations between multiple immune cell phenotypes, white matter microstructure phenotypes, and dementia risk. Mediation MR analysis identified four possible causal pathways from immune cells to white matter microstructure to dementia, highlighting the potential mediating role of white matter microstructural changes in the relationship between immune cells and dementia risk. Co-localization analysis further clarified the genetic association between CCR2 on plasmacytoid dendritic cells and the mean RD of the superior fronto-occipital fasciculus, identifying TRIM39 as the possible core gene. Meanwhile, evidence was provided for common causal variations between the mean MO of the superior corona radiata and Any dementia, as well as between the MD of the anterior limb of the internal capsule and Alzheimer's disease. These results provide potential insights into regulating peripheral immunity and protecting the white matter microstructure to prevent and alleviate cognitive decline and dementia.