BACKGROUND: Pesticide residues have contaminated our environment and nutrition over the last century. Although these compounds arc present at very low concentrations, their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer's disease is not clear and difficult to establish. To date, no in vivo experiments have yet modeled the impact of this chronic contamination on neurodegenerative disorders. OBJECTIVES: We investigated the impact of fungicide residues on the pathological markers of Alzheimer's disease in a transgenic mouse model. METHODS: Transgenic (J20, hAPP(sw/Ind)) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil 0.1 mu g/L in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including A beta aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of A beta aggregation in vivo via a longitudinal study using two-photon microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of A beta peptides. RESULTS: We found that a chronic exposure to three fungicide residues exacerbated aggregation, microgliosis, and neuronal loss. These fungicides also increased vascular amyloid aggregates reminiscent of cerebral amyloid angiopathy between 6 and 9 months of treatment. The mechanism of action revealed that fungicides promoted A beta peptide fibril formation in vitro and involved an in vivo overexpression of the levels of the beta-secretase-cleaving enzyme (BACE1) combined with impairment of A beta clearance through neprylisin (NEP). CONCLUSIONS: Chronic exposure of the J20 mouse model of Alzheimer's disease to a cocktail of fungicides, at the regulatory concentration allowed in tap water (0.1 mu g/L), strengthened the preexisting pathological markers: neuroinflammation, A beta aggregation, and APP beta-processing. We hypothesize prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer's epidemic.