Child and adult Metal exposures, gene expression and neuropathologically confirmed Alzheimer's Disease

Harvard School Of Public Health, Boston MA

Investigators

Abstract

We propose to study the relation between early childhood and late life exposure to metals and neuropathological Alzheimer’s Disease and Related Dementias (ADRD) as well as clinical dementia, and whether early life metal exposures modify effects of late life metal exposures in a large, racially diverse population that will allow us to look separately by race and sex. We will also assess the relation between metal exposures and brain mRNA profiles (gene expression) and their possible relation to neuropathological ADRD and dementia, focusing, in particular, on AD-related genes found to be modified by early life lead exposure in animal studies. We will conduct this work in a population of decedents from autopsy centers in Brazil that see over 5,000 decedents per year as part of a government mandate to conduct autopsies resulting in a general population sample. We will leverage another ongoing study (PARDoS) that is collecting biomaterial from decedents to conduct whole genome sequencing and extensive neuropathology. Additional data is collected from knowledgeable informants including clinical dementia rating. For the current study, we will additionally collect bone, teeth, and additional brain tissue from 1,000 of the PARDoS decedents split equally among White and Black/Mixed race, and male and female decedents over 65 years of age. Early childhood exposure to several metals will be assessed by measuring metals in the teeth (using laser-ablation inductively coupled plasma mass spectrometry). Late life metal exposures will be assessed using X-Ray Fluorescence to measure metals in the bone samples. Brain tissue (frontal cortex) will be analyzed for mRNA expression levels. This Brazilian autopsy setting provides a unique opportunity that will allow us to leverage an ongoing study that is documenting neuropathology and clinical dementia, as well as performing whole genome sequencing, to have individual-level biomarkers of early life and late life metal exposures as well as brain gene expression data. This study setting allows us to have an unprecedented ability to examine whether early life metal exposures are related to ADRD—a hypothesis suggested for metals exposure from animal research, but extremely hard to test in humans without the biomarker of such early exposure that the teeth collected at autopsy can provide. Similarly, while some human literature exists suggesting a role for adult metal exposures in dementia risk, virtually none exists using individual biomarkers of cumulative exposure that our excised bone samples will provide, and none look at neuropathology.