APOE4 to APOE2 allelic 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 a ~99% reduction in late-onset Alzheimer’s disease (AD) risk. Here, we developed a transgenic mice model which 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.