Elevated serum pesticide levels and risk for Alzheimer disease

Abstract

Importance: The causes of late-onset Alzheimer disease (AD) are not yet understood but likely include a combination of genetic, environmental, and lifestyle factors. Limited epidemiological studies suggest that occupational pesticide exposures are associated with AD. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were elevated in a small number of patients with AD (n=20).

Objective: To evaluate the association between serum levels of DDE and AD and whether the apolipoprotein E (APOE) genotype modifies the association.

Design, setting, and participants: A case-control study consisting of existing samples from patients with AD and control participants from the Emory University Alzheimer's Disease Research Center and the University of Texas Southwestern Medical School's Alzheimer's Disease Center. Serum levels of DDE were measured in 79 control and 86 AD cases.

Main outcomes and measures: Serum DDE levels, AD diagnosis, severity of AD measured by the Mini-Mental State Examination score, and interaction with APOE4 status.

Results: Levels of DDE were 3.8-fold higher in the serum of those with AD (mean [SEM], 2.64 [0.35] ng/mg cholesterol) when compared with control participants (mean [SEM], 0.69 [0.1] ng/mg cholesterol; P < .001). The highest tertile of DDE levels was associated with an odds ratio of 4.18 for increased risk for AD (95% CI, 2.54-5.82; P < .001) and lower Mini-Mental State Examination scores (-1.605; range, -3.095 to -0.114; P < .0001). The Mini-Mental State Examination scores in the highest tertile of DDE were -1.753 points lower in the subpopulation carrying an APOE ε4 allele compared with those carrying an APOE ε3 allele (P interaction = .04). Serum levels of DDE were highly correlated with brain levels of DDE (ρ = 0.95). Exposure of human neuroblastoma cells to DDT or DDE increased levels of amyloid precursor protein.

Conclusions and relevance: Elevated serum DDE levels are associated with an increased risk for AD and carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE ε4 allele may lead to early identification of some cases of AD.

Figure 1. Serum Levels of Dichlorodiphenyldichloroethylene (DDE)

Serum levels of DDE are elevated in Alzheimer disease (AD). Data were pooled from University of Texas Southwestern Medical Center and Emory University. Levels of DDE are significantly higher in patients with AD (mean [SEM], 2.64 [0.35]) vs control participants (mean [SEM], 0.69 [0.10]; P < .001).

Figure 2. Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) Increase Levels of Amyloid Precursor Protein (APP) in Differentiated SH-SY5Y Cells

SY5Y cells were differentiated with retinoic acid and exposed to 1-μM DDT or DDE for 48 hours. Cells were fixed and stained with antimicrotubule-associated protein–2 (MAP-2) and anti-APP. Original magnification ×20.