# Investigating the Effects of APOE Genotype on AD Pathology in a Novel AD Mouse Model

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $243,000

## Abstract

Project Summary
Carriers of the apolipoprotein E (APOE) ε4 gene are at a significantly increased risk of developing Alzheimer’s
disease (AD). Although numerous theories have been proposed, the cause of this association remains unclear.
Our own research has uncovered novel effects of APOE4 expression on important processes in the brain,
including neuronal activity, the endosomal-lysosomal system and bioenergetic regulation. However, substantial
questions remain about these effects of APOE4 expression. Most importantly, it is unclear what effects these
and other APOE4-associated pathway deficits have on the development of the hallmark pathologies that are
observed in the brains of AD patients. In order to answer this question effectively, the AD field requires new
mouse models that more faithfully replicate both the genetics and the pathology of AD patients. As a first step in
that direction, we are proposing to generate and characterize a novel mouse model that expresses either the
APOE2, APOE3 or APOE4, alongside KI versions of a pro-aggregating humanized mutant APP gene and a
human MAPT gene. These APOE/hAPP/hTau mice will be aged and characterized using both traditional
experiments, such as immunohistochemistry (IHC) and behavior, as well as cutting-edge structural and
functional MRI (sfMRI)-based techniques. We anticipate that the full study proposed herein will result in the
creation of a valuable new AD mouse model and that the characterization studies will elucidate the effects of
differential APOE isoform expression on the development of AD pathology and the behavioral changes they
induce. In total, this study will be an important breakthrough in our quest to understand how APOE isoform
differences affect an individual’s susceptibility to AD, potentially leading to new therapeutic strategies for AD,
especially among APOE4 carriers.

## Key facts

- **NIH application ID:** 10487591
- **Project number:** 5R21AG074308-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jia Guo
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $243,000
- **Award type:** 5
- **Project period:** 2021-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487591

## Citation

> US National Institutes of Health, RePORTER application 10487591, Investigating the Effects of APOE Genotype on AD Pathology in a Novel AD Mouse Model (5R21AG074308-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10487591. Licensed CC0.

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