Taken together, these results suggest that it is feasible to reduce the risk of AD associated with the APOE4 allele without inducing off-target effects using the high-fidelity FNLS-YE1 editor via sequential conversion of APOE4 into the neutral APOE3r or APOE3 into the protective APOE2 alleles. This evidence concerns the gene APOE and Alzheimer disease.