The article provides a comprehensive overview of the role of the endogenous detoxification system in the pathogenesis of age-related neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). It highlights epidemiological evidence linking environmental toxicant exposure to the onset and progression of these diseases, and discusses how dysfunction of detoxification pathways, including enzymes and transporters, can exacerbate neurodegenerative processes. The article also explores the potential of targeting nuclear receptor signaling pathways, such as the pregnane X receptor (PXR), as a promising therapeutic strategy to restore detoxification capacity and modify disease trajectories.