Language

English

Publication Date

5-1-2026

Journal

Alzheimer's & Dementia

DOI

10.1002/alz.71388

PMID

42165338

PMCID

PMC13239731

PubMedCentral® Posted Date

5-21-2026

PubMedCentral® Full Text Version

Post-print

Abstract

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 (PM2.5), 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 PM2.5 concentration (µg/m3; β = -0.047; P = 4.0 × 10-4) and mediated the effect of PM2.5 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 (PM2.5), 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.

Keywords

Humans, Biomarkers, Alzheimer Disease, Male, Air Pollution, Female, tau Proteins, Aged, Particulate Matter, Amyloid beta-Peptides, Cohort Studies, Middle Aged, air pollution, Alzheimer's disease, Alzheimer's disease prevention, phosphorylated tau, PM2.5

Published Open-Access

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