# Influence of microglial cell depletion and repopulation on aducanumab induced ARIA and vascular lesions in APOE4 carriers with AD

> **NIH NIH R21** · ROSKAMP INSTITUTE, INC. · 2024 · $213,125

## Abstract

After many failed clinical trials, the FDA recently approved new breakthrough antibody therapy for use in early AD. But these
therapies have been revealed to increase the frequency of amyloid-related imaging abnormalities (ARIAs). Importantly, ARIA
occurs more frequently in APOE4 carriers. Although the mechanism is unclear, ARIA is thought to occur after removal of
amyloid from blood vessels with cerebral amyloid antipathy (CAA). APOE4 allele is one of the strongest risk factors for AD and
has been shown to promote cerebrovascular lesions such as CAA and microhemorrhages. Because CAA is universally observed
in AD, further investigation of APOE4-dependent mechanisms driving CAA and ARIA-events is needed. Activated microglia
have been shown to drive the outcome and pace of APOE-mediated neurodegeneration. Importantly, microglia can modulate
cerebrovascular integrity and cerebral blood flow, and release factors which contribute to BBB breakdown, cerebrovascular cell
damage and neurovascular injury. In our studies, we revealed an increase in inflammatory pathways in AD vs control human
cerebrovessels, and this was more prominent in APOE4 carriers, who also had higher CAA scores. Anti-Aβ antibody related
ARIA has also been associated with reactive microgliosis in a primate model of CAA. In humans, in vivo PET imaging of
microglial activation has been associated with the magnitude and severity of ARIA. No preclinical models have evaluated this
association between activated microglia response and ARIA-events, particularly in the context of APOE4 genotype. In this
proposal, we will address these unknowns by utilizing microglial ablation and repopulation techniques in a previously described
chronic anti-Aβ treated EFAD mouse model of AD expressing human APOE isoforms and AD mutations (i.e., aducanumab
treated E3FAD and E4FAD mice). From these studies, we will generate a detailed time-course of cognitive function, cerebral
blood flow and cerebrovascular reactivity, and characterize the histopathological and biochemical level changes to the
cerebrovasculature. No studies have characterized the cerebrovascular cell phenotypes in ARIA patients. We will thus employ a
single cell transcriptomic approach to characterize the phenotypic brain vascular cell type response(s) in our EFAD models
following aducanumab treatment with/without macrophage depletion and repopulation, and reveal key upstream regulators
driving these unique vascular cell responses at the single cell level. From this proposal, our goal is to reveal whether activated
microglia mediated cerebrovascular inflammation contributes to APOE4 mediated ARIA events following aducanumab
treatment, and ii) identify novel targets through which APOE4 confers these vascular-specific abnormalities, to reveal new
opportunities for improved antibodies and adjunct therapies that can one day minimize these complications in APOE4 patients
with AD.

## Key facts

- **NIH application ID:** 10985372
- **Project number:** 1R21AG089503-01
- **Recipient organization:** ROSKAMP INSTITUTE, INC.
- **Principal Investigator:** Joseph O Ojo
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $213,125
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985372

## Citation

> US National Institutes of Health, RePORTER application 10985372, Influence of microglial cell depletion and repopulation on aducanumab induced ARIA and vascular lesions in APOE4 carriers with AD (1R21AG089503-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10985372. Licensed CC0.

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