# APOE Allele Switching as a Therapeutic Approach for Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $642,264

## Abstract

Abstract
In comparison to the highly protective E2 allele of Apolipoprotein E (APOE), the E4 allele has
been associated with a host of detrimental effects, including, but not limited to, increased
amyloid deposition, more severe tau pathology, heightened neuroinflammation, cerebrovascular
dysfunction, and various metabolic deficits. With its strong risk profile and varied biological
mechanisms, APOE itself has emerged as an attractive candidate for gene therapy. In addition
to providing a much-needed preclinical model for ongoing and future trials, exploration of E4 to
E2 allele ‘switching’ has the potential to help answer several fundamental and longstanding
biological questions in the field. For example, which ApoE-synthesizing cell-type(s) drive AD
pathogenesis in E4 carriers and which are most protective in those with E2? Are E4-associated
deficits set in stone at birth (developmentally), or is later-life APOE editing a feasible approach
to mitigate AD neuropathology and cognitive dysfunction? To this end, we have generated a
series of novel APOE ‘switch’ (4s2) mouse models that allow for temporal and cell-specific allele
switching from E4 to E2. Our preliminary data confirms that these 4s2 mice synthesize a full-
length human ApoE4 at baseline, and importantly, when crossed to various inducible CreERT2
strains, the switch successfully leads to efficient recombination and expression of human ApoE2
in cell types of interest. Given the remarkable protective effects of E2 carriage and the various
roles of ApoE at differing steps of AD pathogenesis, we hypothesize that astrocyte-specific
allelic switching to E2 will simultaneously rescue multiple metabolic, immune, and
neuropathological deficits associated with E4. We propose to leverage these unique mouse
models to determine the therapeutic window for CNS-specific E4 to E2 allele switching to
simultaneously mitigate metabolic deficits, neuroinflammation, cerebrovascular dysfunction,
amyloid pathology, and cognitive dysfunction. If successful, this proposal will provide an
essential preclinical model for ongoing and future clinical trials, and will provide critical new
information regarding ideal cell-, region- and temporally-specific opportunities for therapeutic
ApoE modulation.

## Key facts

- **NIH application ID:** 10745738
- **Project number:** 5R01AG080589-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Lance Allen Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $642,264
- **Award type:** 5
- **Project period:** 2022-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745738

## Citation

> US National Institutes of Health, RePORTER application 10745738, APOE Allele Switching as a Therapeutic Approach for Alzheimer's Disease (5R01AG080589-02). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10745738. Licensed CC0.

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