Endocrine disruptors, immune dysregulation, and Alzheimer's disease: A multi-omics approach to uncovering environmental neurogenetics

Alzheimer's disease (AD) is a progressive neurodegenerative disorder influenced by both genetic and environmental factors. Endocrine-disrupting chemicals (EDCs), which are widely present in consumer products and industrial waste, have been implicated in neurotoxicity, but their causal role in AD remains unclear. In this study, we integrated chemical-gene interaction data, blood-based cis-eQTLs, and genome-wide association study (GWAS) summary statistics to investigate whether EDC-regulated gene expression is causally linked to AD risk. Using Mendelian randomization (MR) and Bayesian colocalization analyses, we identified 27 genes with significant associations, of which 12, including CCNE2 , SEMA4G , and NDUFS2 , showed strong evidence of colocalization with AD risk loci. Enrichment analyses revealed that these genes are involved in immune regulation and mitochondrial function, particularly natural killer cell cytotoxicity and mitochondrial ribosomal pathways. Single-cell RNA sequencing of peripheral blood mononuclear cells further demonstrated that colocalized genes were differentially expressed in specific immune cell subsets in AD patients, particularly NK and T cells. Our findings provide genetic evidence that EDCs may influence AD pathogenesis through immune and mitochondrial dysregulation. This study highlights the importance of environmental factors in AD and offers novel insights into molecular targets for prevention and therapeutic development. • Integrated eQTL, GWAS, and scRNA-seq to study EDC-regulated gene expression in AD. • Immune dysregulation and mitochondrial dysfunction were key enriched pathways in AD. • Bisphenols, heavy metals, and POPs showed strong gene connectivity and potential mechanistic relevance to AD. • Real-world exposure modeling and biomonitoring are needed to prioritize high-risk EDCs. • This framework offers a scalable approach for investigating environmental risk factors.