The goal of this proposal is to prospectively examine the exposome along with individual concentrations of multiple contaminants and their molecular mechanisms in relation to Alzheimer’s disease (AD) and AD-related dementias (ADRD) leveraging the Diabetes Prevention Program Outcomes Study (DPPOS) AD/ADRD project (U19AG078558; 09/01/22-08/31/27). This-well phenotyped cohort will add diversity and the high AD/ADRD-risk group of persons with PreD and T2D to the consortium formed in response to RFA-AG-24-022. We propose leveraging the unique DPPOS cohort and its biospecimen repository to study the role of environmental toxicants in AD/ADRD. The DPPOS AD/ADRD project is in its second year of funding and in the first of two waves of cognitive assessments. Led by a multidisciplinary team of experts in environmental health science, AD/ADRD, diabetes, and statistics, we propose to add (a) longitudinal untargeted exposomics and metabolomics using gas (GC) and liquid (LC) chromatography high-resolution mass spectrometry (HRMS), allowing detection of ≥ 1,000 environmental chemicals and full-scale analysis of ≥ 20,000 metabolites; (b) longitudinal measurement of metals with inductively coupled mass spectrometry (ICMS) in urine, er- and polyfluoroalkyl substances (PFAS) using on-line solid-phase extraction coupled to LC-tandem MS in plasma, and pesticides via LC-isotope dilution tandem mass spectrometry (MS) in urine; (c) measurement of DNA methylation in the first wave of DPPOS AD/ADRD; (d) characterization of microRNAs in neuronal EVs from the first wave of DPPOS AD/ADRD. Our proposed AD/ADRD outcomes are (a) cognitive decline (15-year changes in the Spanish English Verbal Learning Test and Digit Symbol Substitution Test); (b) NACC-UDS cognitive syndromes; (c) changes in plasma biomarkers of amyloid, neurodegeneration, and neuroinflammation; (d) amyloid, neurodegeneration, and cerebrovascular disease in the subsample with brain imaging; (e) insulin signaling dysregulation measured in neuronal EVs. We will characterize cognitive decline and cognitive syndromes as Alzheimer’s continuum and non-Alzheimer’s pathologic change following the National Institute on Aging NIA/Alzheimer’s Association (AA) research framework. We will explore effect modification by APOE-e4, sex, ethnic and racial group, PreD/T2D status, and cognitive reserve. Our specific aims are: (1) To examine the association of environmental toxicants with cognitive decline, cognitive impairment syndromes, AD/ADRD biomarkers in plasma and brain imaging, and neuronal insulin signaling using untargeted and targeted approaches; (2) To discover specific signatures in biologic intermediate mechanisms in relation to toxicant exposures and AD/ADRD outcomes; (3) To develop a causal model linking aggregate exposome profiles and individual exposures to environmental toxicants, biologic intermediate mechanisms, and neuropathologic and clinical outcomes, using systems biology approaches. We will also explore whe...