# Therapeutic Gene Editing of APOE4 in Sporadic Alzheimer's Disease via Prime Editor 7

Article · Kim Y, Lee G, An S, Park H, Kim H, Kim J, Kang S, Kim S, Kwon D, Park J, Hwang Y, Yuan X, Jeong J, Lee H, Kim HK

- Archive id: doi:10.1002/advs.76658
- Published: 2026-07-17
- Venue: Advanced science (Weinheim, Baden-Wurttemberg, Germany)
- DOI: https://doi.org/10.1002/advs.76658
- PMID: 42467931
- PMCID: PMC13379251
- Citations: 0
- Source URL: https://doi.org/10.1002/advs.76658
- PDF: https://europepmc.org/articles/PMC13379251/pdf
- Provenance: europepmc

## Abstract

The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), driving Aβ accumulation, tau pathology, and synaptic dysfunction. Allele-specific correction of APOE4 represents a promising therapeutic strategy to mitigate disease progression. In this study, we developed an APOE4-specific prime editing strategy based on an optimized APOE4-targeting pegRNA, enabling precise and efficient conversion of the APOE4 allele to the lower-risk APOE3 variant. We found that PE7 targeting the APOE4 allele achieved robust and specific editing without detectable off-target effects. This correction reduced ApoE4 protein levels and attenuated key AD-related pathologies, including Aβ42 accumulation, tau phosphorylation, and activation of the ERK1/2 pathway in APP/APOE4 knock-in (KI) mice. Notably, PE7 treatment enhanced neuronal survival and improved cognitive performance in these mice. Furthermore, in human induced neurons derived from APOE3/4 heterozygous AD patient fibroblasts, PE7 consistently corrected the APOE4 allele and suppressed both amyloid- and tau-associated pathologies. These findings establish PE7-mediated APOE4 correction as a precise and efficient therapeutic genome-editing strategy with translational potential for sporadic AD.

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [CRISPR & Gene-Editing Therapies](https://space-kitty.com/topics/gene-editing-therapies)

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