The role of toxic and essential metal mixtures, and co-exposures to social stressors, in cognitive aging, mild cognitive impairment, and novel epigenetic age biomarkers: The Baltimore Memory Study

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PROJECT SUMMARY Environmental toxicants are understudied modifiable risk factors for cognitive decline and dementia. Toxic metals, and some essential trace elements, are well-known neurotoxicants and have been linked to cognitive decline. Evaluating the joint actions of environmental exposures may elucidate shared physiologic pathways and may inform policy. Populations with documented health disparities may be especially vulnerable to such pathways due to higher cumulative exposure to environmental hazards and social stressors like poverty, discrimination, or unsafe neighborhoods. Growing evidence suggests that novel epigenetic markers of DNA methylation age predict a host of aging-related outcomes. Few studies have examined whether environmental toxicants, individually or as a mixture, predict DNA methylation age acceleration. To address these gaps, the Candidate proposes new aims in the Baltimore Memory Study, a study of cognitive and cardiovascular aging in 50- to 70-year-old residents of Baltimore, with diversity in race/ethnicity and socioeconomic status. The overall objective of this proposal is to determine whether co-exposures to environmental toxicants and contextual (neighborhood) stressors are linked to cognitive function, mild cognitive impairment, novel epigenetic biomarkers. In the K99 phase, Dr. Moon will take advantage of existing bone lead biomarkers and chronic stress measures to estimate whether the causal association of lead on longitudinal cognitive function (Aim 1) or mild cognitive impairment (Aim 2) is modified by either a theory-based scale of neighborhood psychosocial hazards or hypothalamic-pituitary-adrenal-axis dysfunction, measured by saliva cortisol. To complete these aims and prepare for independence, Dr. Moon will train in four methodologic areas: cognitive aging epidemiology, mixture and causal inference models, co-exposures to social stressors, and epigenetics through formal coursework and mentoring. These training goals will be completed under the guidance of a strong mentoring and advisory team (Drs. Schwartz, Buckley, Gross, Dean, and Ladd-Acosta). This Pathway in Independence Award is critical to achieving Dr. Moon's long-term goal of becoming an independent investigator with expertise on the environmental determinants of aging-related disease, particularly cognitive aging outcomes, and evaluating how co-occurring social stressors contribute to health disparities. In the R00 phase, Dr. Moon will take advantage of stored biospecimens, measuring toxic and essential metals in urine and genome-scale DNA methylation in blood. Using this new data, she will determine the independent joint and effects of a mixture of metals on cognitive aging (cognitive function and mild cognitive impairment) (Aim 3) and on DNA methylation age acceleration (Aim 4). The proposed training and aims will provide further evidence that social and environmental factors must be addressed together to eliminate disparities in aging and preliminary data to support an R01 investigating the role of a mixture of metals and chronic stressors on DNA methylation-based biomarkers in aging.