The interplay of air pollution with plasma neurodegenerative markers and metabolome for dementia, Parkinson’s disease and all-cause mortality risks and transitions: The UK Biobank study

Abstract

We investigated the joint associations of circulating neurodegeneration markers—neurofilament light (NfL) and glial fibrillary acidic protein (GFAP)—ambient air pollution, and plasma metabolomic profiles with transitions from a healthy state to dementia, Parkinson’s disease (PD), and all-cause mortality in the UK Biobank. The analytic sample included 19,645 participants aged ≥ 50 years with complete proteomic, metabolomic, and environmental data. Time-to-event analyses used Cox proportional hazards and multistate Weibull models to evaluate associations and statistical interactions across health transitions. Higher NfL concentrations were associated with increased risks of transitions from healthy to PD, dementia, and death, whereas higher GFAP concentrations were specifically associated with dementia (HR = 2.65, 95% CI: 2.17–3.25). At the nominal level, particulate matter (PM 2.5 , PM 10 ) showed positive statistical interactions with NfL for mortality, while nitrogen oxides (NO₂/NO x ) showed negative interactions with GFAP. There was little evidence of interaction between PM 2.5 and either biomarker for dementia. Metabolomic principal components reflecting lipid, amino acid, and energy pathways were associated with variation in the relationships of NfL and GFAP with dementia and mortality and interacted with PM 2.5 for PD and dementia. A branched-chain amino acid–related component showed a negative interaction with GFAP for dementia, indicating weaker associations at higher levels. These findings highlight complex relationships linking air pollution, metabolic dysregulation, and neurodegeneration, and support integrative multi-omics approaches to identify pathways relevant to prevention of neurodegenerative diseases and premature mortality.