A moderated mediation of tau phosphorylated sites in the association between occupational aluminum exposure and...

This study aimed to elucidate the associations among occupational aluminum exposure, plasma phosphorylated tau (P-tau), and cognitive function, with particular attention to the modulatory effects of key factors involved in tau protein synthesis and degradation. A total of 208 aluminum plant workers were enrolled, with assessments conducted for plasma aluminum concentrations, cognitive performance, levels of phosphorylated tau (P-tau181 and P-tau231), and biomarkers related to tau synthesis and degradation pathways. Elevated plasma aluminum levels were inversely associated with scores on cognitive assessments, including the MMSE, DSP, DSR, DS, FOM, and CDT, while showing positive associations with STRA and STRF scores. Higher plasma aluminum concentrations were also significantly associated with increased levels of P-tau181 and P-tau231. P-tau181 and P-tau 231 concentrations are negatively correlated with MMSE, DSP, DSR, DS, and FOM scores, and positively correlated with STRA, STRF, and CDT scores. Mediation analysis revealed that P-tau181 and P-tau231 were statistically consistent with mediating 16.6 % and 35.9 % of the association between aluminum exposure and MMSE scores, respectively, with P-tau231 demonstrating a stronger mediating effect. Moderated mediation analysis further indicated that factors regulating tau synthesis had a more pronounced influence on this mediating role than those involved in degradation[ΔR²(PP2A, CDK5)= 0.016 > ΔR²(CHIP, Ub)= 0; ΔR²(PP2A, CDK5)= 0.027 > ΔR²(CHIP, Ub)= 0], with PP2A-mediated regulation exerting a greater effect than CDK5[ΔR²(PP2A)= 0.021 > ΔR²(CDK5)= 0.006; ΔR²(PP2A)= 0.016 > ΔR²(CDK5)= 0.008]. These results are statistically consistent with the hypothesis that P-tau231 and PP2A are critical targets for early intervention and biomonitoring in the context of aluminum-related cognitive impairment, offering novel directions for occupational health risk management and protection.