AbstractBackgroundLate‐onset Alzheimer’s disease (LOAD) is caused by interactions between genes and environment. However, current mouse models do not fully recapitulate LOAD phenotypes, limiting translatability to clinical needs. To address this, MODEL‐AD (Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease) Consortium was established to create and phenotype new mouse models. The IU/JAX/PITT MODEL‐AD Center focuses on developing models with combinations of genetic risk factors, as well as humanizing APP (hAb) and MAPT. One use of these models is to determine the contribution of environmental factors to LOAD risk. Studies show associations between LOAD risk and exposure to ubiquitous environmental neurotoxicants, including arsenic (As), lead (Pb), and cadmium (Cd). All three are ranked in the “Top 10 Toxicants” of public health concern (As #1, Pb #2, Cd #7; ATSDR Toxic Substance Priority List). However, mechanisms driving increased risk are unknown.MethodNovel mouse models were created by genetic engineering or editing in C57BL/6J. Four to 24 months old mice and controls were phenotyped using a human‐relevant battery that includes cognitive performance, imaging, biometrics, transcriptomics, proteomics, metabolomics, neuropathology, and fluid biomarkers. Toxicants (As, Pb, Cd) were delivered using human‐relevant doses in drinking water. Exogenous toxicants (Pb, Cd, As) and endogenous biometals (Zn, Cu, Fe) in brain and blood samples were analyzed by elemental mass spectrometry mapping.ResultMore than 40 mouse models have been created carrying combinations of genetic risk factors in genes including APOE, Trem2, Abca7 and Mthfr. One strain, LOAD2 (triple homozygous for APOE4, Trem2*R47H, and hAb) shows molecular and transcriptomic changes associated with human LOAD. Short‐term exposure to As, Cd, or Pb also modified expression of LOAD‐relevant genes in LOAD2 mice and controls, including App and Vgf, in a toxicant‐specific manner. Elevated toxicant levels were detected in both brain and blood samples from exposed mice.ConclusionThese data indicate that exposure to common environmental toxicants may increase LOAD risk by modifying expression of specific genes and molecular pathways previously implicated in human LOAD. Studies are underway using additional MODEL‐AD models to determine the long‐term effects of neurotoxicant exposures.