Impact of environmental toxicants on AD and ADRD risk in the Diabetes Prevention Program Outcomes study AD/ADRD project

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 whether differences in the exposome account for disparities in AD/ADRD by sex, race and ethnicity, and diabetes.