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. To examine how switching from APOE4 to APOE2 globally influences cell-type specific changes to the brain transcriptome, we performed scRNAseq on whole brain tissue from 6-month-old APOE4s2G mice, Cre-negative APOE4s2 controls, and age- and sex-matched E2-TR and E4-TR mice. The APOE4s2G mice (E4 switched to E2 expression in all cell types) were switched one month prior to brain tissue isolation and single cell transcriptomic analysis.