# Contribution of Cerebral Iron Load to Cognitive Function in Older Adults with High Risk to Develop Alzheimer's Disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $561,693

## Abstract

Project Summary: Dementia has a high global prevalence due to the aging population and places an
enormous burden on health care systems. Alzheimer’s disease (AD) is the most common cause of
dementia, and it is widely believed that the accumulation of Amyloid beta (Aβ) peptide is a key event in the
pathogenesis of AD, representing preclinical disease stages. Cerebral iron is also strongly implicated as a
cofactor in the pathogenesis of AD, and its overload accelerates Aβ production and promotes the toxicity of
the Aβ peptide. However, the impact of brain iron load, and its combined effect with regional Aβ-plaque-load
on cognitive impairment in AD and its precursor, mild cognitive impairment (MCI), is lacking. Our overall aim
is to study the role of brain iron load and its possible synergistic effect with Aβ-plaque-load in the
development of cognitive decline, MCI and dementia, in particular AD. We will perform such study using data
from two prospective cohort studies: the Atherosclerosis Risk in Communities (ARIC) study, which has
collected clinical data from cohort participants over the past 30 years and the UK biobank study, which
collects extensive clinical, imaging and genetic data in the UK adult population. In the ARIC study, a biracial
sample of elderly adults was evaluated by brain MRI, florbetapir positron emission tomography (PET), and
cognitive tests at study visit 5 with repeat testing underway at visit 6. We will utilize the phase signal from
gradient echo MRI data at visit 6 (n=1,000) to compute quantitative susceptibility mapping (QSM). Brain iron
load will be automatically quantified using our recent developed susceptibility multi-atlas tool. We will then
for Aim 1 determine if increased cerebral iron measures are independently associated with cognitive
performance with the presence of MCI or dementia in these ARIC participants aged 73-94 years. We will
also assess possible associations between known midlife vascular risk factors with cerebral iron as
measured in late-life. For Aim 2, we will estimate the combined effects of Aβ-plaque-load as measured by
florbetapir PET in the ARIC-PET study (n=300) and increased cerebral iron-load as measured by QSM on
the progression of cognitive impairment with adjustment for contributions from demographic, contemporary
vascular risk factors, small vessel diseases and APOE-e4 status. To further establish the causality between
brain iron and cognitive function in Aim 3, we will perform a genome-wide association study (GWAS) with
Mendelian randomization to find genetic determinants of cerebral iron and their association with cognitive
function. Cerebral iron as measured by QSM will be calculated from UK biobank brain MRI data
(n~=35,000), while genetic variants associated with cerebral iron load will tested against the cognitive
function measures in the remaining ~465,000 independent samples.

## Key facts

- **NIH application ID:** 10255995
- **Project number:** 5R01AG063842-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Xu Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $561,693
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10255995

## Citation

> US National Institutes of Health, RePORTER application 10255995, Contribution of Cerebral Iron Load to Cognitive Function in Older Adults with High Risk to Develop Alzheimer's Disease (5R01AG063842-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10255995. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*