N Nature Neuroscience · Nov 11, 2025 APOE4toAPOE2allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition Compared to individuals carrying two copies of the ε4 allele of apolipoprotein E (APOE), ε2 homozygotes have an approximate 99% reduction in late-onset Alzheimer’s disease (AD) risk. Here we develop a knock-in model that allows for an inducible ‘switch’ between risk and protective alleles (APOE4s2). Gene expression and proteomic analyses confirm that APOE4s2 mice synthesize E4 at baseline and E2 after tamoxifen administration. A whole-body allelic switch results in a metabolic profile resembling E2/E2 humans and drives AD-relevant alterations in the lipidome and single-cell transcriptome, particularly in astrocytes. Finally, when crossed to the 5xFAD background, astrocyte-specific E4 to E2 switching improves cognition, decreases amyloid pathology, lowers gliosis and reduces plaque-associated apolipoprotein E. Together, these data show that a short-term transition fromAPOE4toAPOE2can broadly affect the cerebral transcriptome and lipidome, and that astrocyte-specificAPOEreplacement may be a viable strategy for future gene editing approaches to simultaneously reduce multiple AD-associated pathologies. Alzheimer's disease Astrocyte Genetic engineering Metabolism biology mouse experiments
