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Association of pesticide exposure with plasma Aβ‐42/40 Ratio: Translational evidence from 5xFAD mice and the Child Health and Development Studies

Year: 2025

Type: article

Abstract: BACKGROUND: Environmental factors, including pesticides, are increasingly associated with an increased risk of Alzheimer's disease (AD). Although banned in 1972, DDT remains persistent due to its long half-life, bioaccumulation, and residual dumpsites. However ubiquitous, its metabolite, dichlorodiphenyldichloroethylene (DDE), is considered non-neurotoxic. We previously reported that serum DDE levels were nearly 4x higher in AD patients compared to healthy individuals. Here, we assessed: i) effects of subchronic DDE exposure on serum Aβ-42/40, brain Aβ pathology, and cognition in 5xFAD mice, and ii) impact of prenatal DDE exposure on midlife plasma Aβ-42/40 in humans. METHOD: Six-week-old male 5xFAD mice were exposed to 3 mg/kg p,p'-DDE or corn oil every 3 days for 90 days. At 4.5 months, mice were sacrificed post-behavioral testing; brains were drop-fixed for staining, hippocampi dissected, and serum collected for biochemical assays. For prenatal p,p'-DDE exposure, offspring born into the Child Health and Development Studies (CHDS) were recruited in 2010 for follow-up (∼50 years), completing cognitive tests and providing blood samples. Plasma Aβ-42/40 ratio in midlife was measured using the Quanterix N3PA kit (N = 160). RESULT: In DDE-exposed 5xFAD mice, MSD analysis showed significantly elevated Guanidine-HCl (GuHCl)-soluble Aβ42 (∼100-fold) and formic acid (FA)-soluble Aβ42 (∼5-fold), indicating increased insoluble Aβ. Serum Aβ-42/40 was significantly reduced by 31% in DDE-exposed mice and was correlated with elevated brain Aβ42 in the GuHCl (r = -0.42) and FA fractions (r = -0.40). DDE-exposed mice displayed working memory deficits, performing 20% worse in Y-maze, which correlated with low serum Aβ-42/40 (r = 0.42). In the CHDS cohort, higher prenatal DDE was associated with lower midlife Aβ-42/40. In logistic models, the Odds Ratio for estimating lower Aβ-42/40 was 2.6 and 3.2 for DDE tertiles 2 and 3, respectively. The test for trend across DDE tertiles was significant (p = 0.04). Higher prenatal DDE was also associated with lower midlife Wechsler Digit Symbol Substitution Task score (β = -0.0221). CONCLUSION: These findings show that DDE is an active metabolite of DDT and has lasting neurological effects on the amyloid system and cognition. This translational evidence highlights the role of early-life environmental exposures in AD risk and opportunities for early interventions to prevent disease progression.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz70856_106002