Long-term exposure to fine particulate matter (PM_2.5) has been associated with increased risk of Alzheimer’s disease, yet the molecular pathways linking ambient particulate mixtures to disrupted amyloid-β (Aβ) handling remain poorly defined. Here, we combined decade-long nontarget molecular profiling of ambient PM_2.5 with protein binding assays, contribution analysis, and molecular simulations to resolve how water-soluble organic molecules (WSOM) interact with human serum albumin (HSA), a major carrier involved in peripheral Aβ sequestration. Across all samples, 11,848 WSOM were detected, of which 8,034 were associated with HSA and 5,237 attenuated HSA-Aβ binding. Interference was highly uneven across molecules, with reduced nitrogen-containing species contributing disproportionately to the total effect. Docking and molecular dynamics simulations showed that interfering WSOM preferentially bind HSA domain II and weaken Aβ association through long-range allosteric modulation rather than direct competition at the Aβ-binding site. These results identify a chemically resolved pathway by which ambient PM_2.5-derived organic mixtures perturb protein function relevant to peripheral Aβ handling and highlight nitrogen-containing organics as potentially important drivers of pollution-associated molecular interference.