Basic Science and Pathogenesis.

Area of Science:

• Environmental Epidemiology
• Genetic Epidemiology
• Neuroscience

Background:

• Environmental exposures like air pollution and occupational chemicals are linked to cognitive decline and dementia.
• Establishing causality for all-cause dementia (ACD) and vascular dementia (VAD) is challenging due to confounding in observational studies.

Purpose of the Study:

• To investigate the causal influence of genetically predicted exposure to fine particulate matter (PM2.5) and occupational chemicals on dementia risk using Mendelian Randomization (MR).

Main Methods:

• Utilized UK Biobank genome-wide association studies (GWAS) for genetic instruments of PM2.5 and chemical exposures.
• Applied inverse variance weighted (IVW), MR Egger, and Weighted Median MR methods with outcome data from large-scale ACD and VAD GWAS.
• Conducted sensitivity analyses (Cochran's Q, MR-Egger intercept, MR-PRESSO) to assess heterogeneity and pleiotropy.

Main Results:

• Genetically predicted PM2.5 exposure showed a causal association with a 51.7% increased risk of all-cause dementia (ACD).
• Frequent workplace chemical/fume exposure was associated with a significantly higher risk of vascular dementia (VAD), though with wide confidence intervals.
• Sensitivity analyses confirmed the robustness of the findings, with no significant evidence of heterogeneity or horizontal pleiotropy.

Conclusions:

• This MR study provides evidence for causal links between PM2.5 air pollution, occupational chemical exposures, and increased dementia risk.
• Findings suggest that vascular pathways may mediate the association between occupational exposures and VAD.
• Highlights the urgent need for public health interventions to reduce environmental exposures and lower dementia risk.