Environmental risk and genetic susceptibility in Alzheimer's disease: Impacts on cognitive function and biomarkers.

BackgroundAlzheimer's disease (AD) involves interactions among genetic, environmental, and lifestyle factors, yet the contribution of environmental exposures to cognitive decline and biomarker changes remains unclear. Detoxification genes such as EPHX1 may influence susceptibility to environmental neurotoxicants.ObjectiveTo evaluate associations between environmental risk, cognitive outcomes, and AD biomarkers, and to examine potential contributions of detoxification genes.MethodsWe analyzed 5101 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) across four study phases. Environmental exposure was summarized using a composite Environmental Risk Score (ERS) derived from Rural-Urban Continuum Codes, Rural-Urban Commuting Area codes, Risk-Screening Environmental Indicators, and occupational exposure. Cognitive outcomes included Mini-Mental State Examination, Clinical Dementia Rating, Montreal Cognitive Assessment, Neuropsychological Test Battery, Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Executive Dysfunction Cognitive Assessment. Biomarkers included PET amyloid/tau, MRI hippocampal volume, and cerebrospinal fluid amyloid-β, tau, and neurofilament light chain. Multivariable regression models adjusted for sociodemographic factors and APOE ε4 carrier status.ResultsERS was significantly associated with CDR (β = -1.13E-07; 95% CI -1.98E-07, -2.75E-08; p = 0.00956) but not with other cognitive measures. EPHX1 showed a significant main effect on ADAS-Cog (β = 0.479; 95% CI 0.0305, 0.927; p = 0.0356). ERS × gene interaction terms were not significant. ERS was not associated with amyloid PET SUVR.ConclusionsEnvironmental risk showed limited associations with AD-related outcomes, while EPHX1 demonstrated a significant main effect on cognitive performance. Longitudinal studies are needed to clarify mechanisms linking environmental exposure and AD.