# Leveraging novel mouse models to investigate toxic metal exposures on brain aging and Alzheimer's disease

> **NIH NIH U01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $2,122,961

## Abstract

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...

## Key facts

- **NIH application ID:** 10973886
- **Project number:** 1U01AG088683-01
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** LEE E. GOLDSTEIN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,122,961
- **Award type:** 1
- **Project period:** 2024-09-30 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10973886

## Citation

> US National Institutes of Health, RePORTER application 10973886, Leveraging novel mouse models to investigate toxic metal exposures on brain aging and Alzheimer's disease (1U01AG088683-01). Retrieved via MORVS 2026-10-27 from https://api.morvs.ai/grant/nih/10973886. Licensed CC0.

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