2‐aminobutyrate mediates the impact of air pollution on blood biomarkers of Alzheimer's disease

INTRODUCTION We examined the impact of mid‐life metabolites on late‐life Alzheimer's disease (AD) plasma biomarkers and whether these metabolites mediate air pollution effects. METHODS In the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) cohort, we applied high‐dimensional regression and meditation models, adjusting for observed and latent confounders, with replication in the Atherosclerosis Risk in Communities (ARIC) study. Exposures included mid‐life fine particulate matter (PM 2.5 ), black carbon, metals, and metabolites. Outcomes were: late‐life plasma p‐tau(181, 217, and 231) and amyloid beta 42/40 (Simoa assays). RESULTS In the Heart SCORE study, seven lipid‐ and amnio acid‐pathway metabolites measured in mid‐life were significantly inversely associated with late‐life p‐tau181 levels (false discovery rate ≤ 15%) and showed a nominal inverse association with p‐tau217 and 231 ( P < 0.05). 2‐aminobutyrate was associated with mid‐life PM 2.5 concentration (µg/m 3 ; β = −0.047; P = 4.0 × 10−4) and mediated the effect of PM 2.5 on p‐tau181 ( P = 0.0057). Independent replication in the ARIC study confirmed the inverse association. DISCUSSION Mid‐life metabolite profiles, particularly 2‐aminobutyrate, may predict and mediate air pollution–related AD risk. Highlights Seven mid‐life metabolites were inversely linked to late‐life plasma phosphorylated tau (p‐tau)181. 2‐aminobutyrate was tied to fine particulate matter (PM 2.5 ), black carbon, and heavy metal exposure in two independent cohorts. 2‐aminobutyrate may link pollution to Alzheimer's disease (AD) via oxidative stress pathways. This effect is specific to p‐tau181, a marker of early AD changes. This is the evidence of a metabolic mediator between air pollution and AD risk.