The impact of metals and polygenic risk on multiomics, brain aging, and ADRD outcomes

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Abstract. The goal of this project is to use genetically diverse mice that better model humans to determine the sex-specific consequences of exposure to toxic metals/metalloids (Pb, Cd, As, hereafter referred to as “metals”) on molecular, pathologic, and behavioral changes linked to Alzheimer’s Disease and Related Dementias (ADRD). While ADRD has a substantial genetic component, emerging research shows exposures, such as metals, are likely important modifiable risk factors. Exposures to Pb, Cd, and As are associated with cognitive decline or ADRD in epidemiology studies or ADRD-associated molecular changes, pathology, and behavior in toxicology studies. Major gaps remain to translate these findings into ADRD prevention and treatment: (1) Much of the existing toxicology is disproportionately focused on a single inbred mouse strain (C57BL/6J) rather than advanced models of ADRD genetic susceptibility, which better mimic human variability; (2) Comprehensive molecular maps of metals effects across brain regions do not exist to help us understand how metals perturb ADRD biology; (3) Data are limited about whether biomarkers from easily accessible tissues, like blood, reflect toxicant-associated changes in the brain, an important gap to fill for ADRD epidemiology. By bringing together a diverse team with expertise in metals toxicology, environmental health multiomics, genetic mouse models of ADRD, ADRD epidemiology, and data science, we are uniquely poised to address these gaps. Our long-term goal is to understand how exposure to toxic metals interact with genetics to drive ADRD. The objective of this proposal is to use AD-BXD mouse strains with widely varying risk for AD to comprehensively characterize how genetic risk interacts with exposure to Pb, Cd, and As to cause molecular, behavioral, and pathologic effects. We will test the impacts of lifestage timing of exposure and identify whether biomarkers measured surrogate tissues reflect ADRD-associated changes in the brain in a sex-specific manner. We will link our results to human ADRD molecular profiles to assess whether metals-associated changes are enriched in ADRD patient biological signatures. Our overall hypothesis is that early life metals exposure interacts with genetic susceptibility to promote ADRD phenotypes and changes in the brain in a sex- specific manner, which will be reflected by molecular signatures in surrogate tissues. We will test this hypothesis with three aims: (1) Generate multiomic maps of brain effects of perinatal and adult metals exposures; (2) Interrogate genetics and metals interactions on ADRD pathology and behavior in later life; (3) Test for interactions between metals exposure and aging in target and longitudinal surrogate tissues multiomic profiles. As part of the Precision Environmental Health in AD/ADRD Tri-Consortium, we will generate a robust, publicly available sample and data resource. We expect this work will have substantial impact on our understanding of how sex, genetic susceptibility, and timing of exposure influence how metals cause ADRD effects and whether earlier life signatures in the blood reflect metals-associated changes in the aging brain.