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

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.