Associations of environmental factors with neurodegeneration: An exposome-wide Mendelian randomization investigation

Neurodegenerative diseases (NDDs) remain a global health challenge. Previous studies have reported potential links between environmental factors and NDDs, however, findings remain controversial across studies and elusive to be interpreted as evidence of robust causal associations. In this study, we comprehensively explored the causal associations of the common environmental factors with major NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), based on updated large-scale genome-wide association study data through two-sample Mendelian randomization (MR) approach. Our results indicated that, overall, 28 significant sets of exposure-outcome causal association evidence were detected, 12 of which were previously underestimated and newly identified, including average weekly beer plus cider intake, strenuous sports or other exercises, diastolic blood pressure, and body fat percentage with AD, alcohol intake frequency with PD, apolipoprotein B, systolic blood pressure, and forced expiratory volume in 1 s (FEV₁) with ALS, and alcohol intake frequency, hip circumference, forced vital capacity, and FEV₁ with MS. Moreover, the causal effects of several environmental factors on NDDs were found to overlap. From a triangulation perspective, our investigation provided insights into understanding the associations of environmental factors with NDDs, providing causality-oriented evidence to establish the risk profile of NDDs.