Metals Exposure, Dementia, and Longitudinal Trajectories of Cognition, Functioning, and Neuropsychiatric Symptoms

PROJECT SUMMARY/ABSTRACT Dementia is a disorder of multiple cognitive domains severe enough to affect activities of daily living and often occurs with more than one neuropathology, including the most common Alzheimer's disease (AD), vascular dementia, Lewy body disease (LBD), and frontotemporal dementia (FTD). To postpone the onset or prevent

dementia, identifying modifiable risk factors is pivotal. Exposure to metals shows toxicologic evidence of disruption of multiple neuropathological pathways, as well as suggestive cross-sectional associations in human studies. However, relatively little is known about the impact of metals exposure on incident dementia and

longitudinal trajectories of functioning of multiple domains in the human populations. Using neurological examination and clinical diagnosis from the National Alzheimer’s Coordinating Center (NACC) and repository plasma samples from the National Centralized Repository for Alzheimer’s Disease and Related Dementias

(NCRAD), this K01 award application will determine metal concentrations and investigate their associations with dementia. The Principal Investigator, Xin Wang, Ph.D., M.P.H., commits to a career in environmental epidemiology and dementia research. The proposed training will build upon his research foundation in

environmental epidemiology with four training goals to enhance his trajectory to become an independent investigator: (1) Gaining knowledge in principles of neuroscience, neurobiology in aging, and dementia pathology; (2) Receiving training in clinical evaluation of dementia; (3) Developing expertise in neurogenetics;

and (4) Professional development activities. Dr. Wang will be mentored by Dr. Kelly Bakulski, an expert in genetic and environmental epidemiology and the Data Management and Statistical Core Lead of the Michigan Alzheimer’s Disease Research Center (MADRC), and Dr. Henry Paulson, an expert in clinical neurology and

neuropathology and the MADRC Director. Dr. Wang will also collaborate with Drs. Roger Albin (MADRC Research Education Core Lead), Bruno Giordani (MADRC Associate Director), and Bhramar Mukherjee (Chair of Biostatistics), and leverage resources available in the MADRC and NACC network. Aim 1 will examine the

associations of metals with dementia at the baseline (prevalence) and during the follow-up (incidence). Aim 2 will assess the associations of metals with baseline levels and longitudinal trajectories of cognition, functioning, and neuropsychiatric domains. Aim 3 will evaluate effect modification of the associations of metals with

dementia and related clinical outcomes by APOE-ε4 genotype. The expected outcome is a comprehensive evaluation of effects of metals exposure on dementia and related outcomes, and potential effect modifications by APOE-ε4. Metals are modifiable and widespread exposures, therefore, findings from this proposal may play

an important role in dementia prevention and intervention. The outstanding training opportunities will greatly enhance the skills and capabilities of the candidate and position him for a successful independent career to develop his own research program to explore the intersection of environmental epidemiology and dementia.