Blood Biomarkers of Neurodegeneration Over Four Decades After Toxic Oil Syndrome: A Case‐Control Study

Toxic Oil Syndrome (TOS) was a multisystemic disease that emerged in Spain in 1981 due to the ingestion of aniline-contaminated rapeseed oil. Although neurological sequelae, including cognitive deficits, have been documented in long-term survivors, it remains unclear whether TOS leads to chronic or progressive neurodegeneration. In this case-control study, we measured blood concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau 217 (pTau217) in 50 individuals with clinically confirmed TOS and 50 matched healthy controls. Biomarkers were quantified using ultrasensitive immunoassay platforms (Quanterix SIMOA SR-X and Fujirebio Lumipulse G600II). Group differences were evaluated using non-parametric tests, and multiple linear regression was applied to assess associations between biomarkers and clinical variables. While NfL levels were slightly higher in TOS patients, the difference was not statistically significant. Similarly, no significant group differences were observed for pTau217 or GFAP. Age was a consistent predictor of biomarker levels, particularly for GFAP and pTau217, and female sex was independently associated with higher GFAP concentrations. Lower educational attainment was linked to increased NfL levels. Clinical status (TOS vs. control) did not significantly predict biomarker concentrations in any model. These findings suggest no evidence of overt or ongoing neurodegeneration in long-term TOS survivors as detected by current blood biomarkers. However, the possibility of subtle or slowly evolving neurotoxic processes cannot be excluded. Longitudinal studies incorporating neuroimaging are warranted to clarify the long-term neurological impact of TOS and to identify potential subclinical trajectories of neurodegeneration in this population.