Alzheimer’s disease (AD) and AD-related dementias (ADRDs) are leading causes of cognitive decline and major contributors to morbidity, mortality, and healthcare costs. Cardinal hallmarks of AD brain pathology include amyloid-β (Aβ) plaques, neurofibrillary tangles (hyperphosphorylated tau), neurodegeneration, cerebro- vasculopathy, and neuroinflammation. AD risk is modulated by interaction of genetics (e.g., APOE-ε4 allele) and environmental factors, including high-fat diet, sedentary lifestyle, and exposures to environmental toxicants (exposome). Despite strong evidence for the role of environmental factors in AD/ADRD risk, the specific mechanisms driving the underlying biology remain elusive. A major reason for this knowledge gap is the absence of resource-based studies to identify age-, sex-, and toxicant-dependent molecular processes that modulate AD/ADRD pathobiology. This U01 preclinical project addresses this gap responsive to NIA exposome initiatives (RFA-AG-24-023) by leveraging a multidisciplinary collaborative team led by MPIs Lee Goldstein, MD, PhD (Boston University Alzheimer’s Disease Research Center, BU-ADRC), Gareth Howell, PhD (The Jackson Laboratory, JAX; MODEL-AD), Paul Territo, PhD (Indiana University, IU; MODEL-AD, TREAT-AD). Collectively, our team brings broad expertise and decades of experience in AD/ADRD research and resource generation using advanced AD/ADRD mouse models to investigate brain health, AD pathobiology, gene by exposome (GxE) interactions, and biometallomics. The project team includes: Dr. Greg Carter, PhD (JAX, MODEL-AD, TREAT- AD, MARMO-AD), David Aylor, PhD (North Carolina State University, NIEHS-TaRGET), and Greg Crawford, PhD (Duke, TaRGET). This U01 project will generate resources to identify mechanisms by which AD-relevant genetic factors interact with exposures to ubiquitous neurotoxic metals/metalloid (lead, Pb; cadmium, Cd; arsenic, As) to modulate AD/ADRDs pathobiology. We will expose male and female mice carrying humanized genetic risk factors (hAβ, hMAPT; APOE4 or APOE3; MODEL-AD) to Pb, Cd, or As in drinking water at human toxicant-relevant doses during two clinically-relevant exposure windows: (prenatal-early adult, developing brain; early adult-aged, mature brain). Exposed mice and non-exposed controls will be assessed across the lifespan using an enhanced MODEL-AD phenotyping pipeline (behavior/cognition, PET/CT, BBB integrity, metallomic imaging MS brain mapping, multi-omics, epigenomics, neuropathology, blood-based biomarkers) following a combined longitudinal/cross-sectional study design. Data will be integrated, aligned to human data resources, and made available to the scientific community via the AD Knowledge Portal (Sage Bionetworks). Molecular processes predicted to drive toxicant/exposure-dependent effects relevant to AD/ADRD risk will be validated using JAX, MODEL-AD, BU-ADRC resources. Strong links with MODEL-AD, AMP-AD, TREAT-AD, NIEHS- TaRGET, ADRCs, and a network of interactions with other research teams (via companion RFAs) position our team to serve as a pivotal resource to address AD/ADRD risks posed by modifiable environmental exposures.

Alzheimer’s disease (AD) and AD-related dementias (ADRDs) are the leading causes of dementia and major contributors to morbidity, mortality, and healthcare costs. Exposure to environmental toxicants increases risk for AD/ADRDs and is common in disadvantaged groups, raising concerns about health disparities, socioeconomic inequities, and environmental justice. This project (responsive to RFA-AG-24-023) leverages innovative mouse models (NIA MODEL-AD) that carry human AD/ADRD genetic risk factors to generate vital resources with the goal of identifying mechanisms by which three ubiquitous metal/metalloid neurotoxicants (lead, cadmium, arsenic) impact brain health and increase risk for AD/ADRDs.