Lipidomic reveals potential mediators of associations between lead exposure and Alzheimer’s disease

Previous studies have identified associations between lead (Pb) exposure and the incidence of Alzheimer's disease (AD), yet the underlying mechanisms are still missing. This investigation verified the association between Pb exposure burden and AD risk in a small case-control study. Using a nontargeted quantification lipidomic assay, the role of 3034 lipid metabolites in the associations between Pb exposure and AD risk was also explored. The results showed that serum Pb levels in AD patients were significantly higher than in control individuals. Meanwhile, serum Pb levels were positively associated with an increased risk of AD (OR = 1.10, 95% CI = 1.04-1.15). Lipidomic assay identified that four lipid metabolites, including phosphatidylcholine (PC) (33:2e), diacylglycerol (DG) (19:1e), sphingomyelins (SM) (d38:4), and phosphoserine (PS) (39:1), were significantly altered in the serum of AD patients. Among them, PC(33:2e) and SM(d38:4) were positively correlated with serum Pb levels. Moreover, PC(33:2e) and SM(d38:4) demonstrated mediation contributions of 60.49% and 20.38%, respectively, in the association between Pb exposure and AD incidence. Network toxicology suggests that Pb exposure may affect lipid metabolic processes in AD by modulating the activation of the MAPK, PI3K-Akt, AMPK, mTOR, and autophagy pathways. Our findings reveal novel insights into AD pathogenesis, suggesting that lipid metabolites may play a mediating role in the association between Pb exposure burden and AD risk.