# Imaging brain iron and protein aggregation with MRI for assessing Alzheimer's disease pathology and progression

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2023 · $652,184

## Abstract

Abstract
 Alzheimer’s disease (AD) affects over 5 million Americans and is expected to affect 2-3-fold more in the next
few decades. AD is associated with aggregation of amyloid-beta (Ab) and phosphorylated tau proteins.
Curiously, burden of Aβ, classically considered the most important AD pathological hallmark is not enough to
indicate clinical decline or progression. For example, cognitive-normal elders may also carry high levels of Aβ
and recent clinical trials aiming to reduce Aβ have generally failed to improve patients’ conditions. Therefore,
developing biomarkers that can better predict clinical outcome and progression are needed. Confluent evidence
shows that regional brain magnetic susceptibility measured by MRI differs between AD patients and healthy
controls, and importantly such changes may predict cognitive decline. However, it is unclear what causes these
susceptibility changes in AD. While iron deposition has been widely suspected as the underlying cause, our
recent study has discovered that aggregation of Ab and tau by itself produces strong diamagnetic susceptibility,
opposite of the paramagnetic susceptibility generated by iron deposition. The opposing magnetic susceptibility
of iron and aggregated pathological proteins poses a significant challenge as current MRI-based magnetic
susceptibility mapping algorithms cannot differentiate iron from other colocalizing diamagnetic susceptibility
sources within the same voxel. Our goal is to develop a novel technique that can differentially quantify molecular
sources of magnetic susceptibility and test whether the resulting susceptibility components can serve as markers
of progressive AD pathology. We will test our techniques and hypothesis utilizing a unique capability that
combines in cranio MRI at autopsy with histological examinations. We have developed innovative histological
processing methods that allow voxel-to-voxel matching between MRI and histology in 3D, thus permitting the
examination of the relationship between magnetic susceptibility components and the neuropathology underlying
AD. If successful, our techniques and findings might ultimately allow the detection of AD-related neuropathology
at much earlier stages, permit intervention before neurons become irretrievably damaged and non-invasively
assess disease progression. These techniques, once standardized, will be highly cost-effective, widely
accessible and readily implementable in non-specialized clinical imaging centers, thus better serving the growing
population of AD patients.

## Key facts

- **NIH application ID:** 10563181
- **Project number:** 5R01AG070826-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Lea Tenenholz Grinberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $652,184
- **Award type:** 5
- **Project period:** 2021-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10563181

## Citation

> US National Institutes of Health, RePORTER application 10563181, Imaging brain iron and protein aggregation with MRI for assessing Alzheimer's disease pathology and progression (5R01AG070826-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10563181. Licensed CC0.

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