biostudies-literatureGolden LRU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesNIA NIH HHSNIDDK NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on AgingNINDS NIH HHSU.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)Alzheimer's AssociationNIGMS NIH HHS2461-2475https://www.ebi.ac.uk/biostudies/studies/S-EPMC12672373biostudies-literatureUnknown28(12)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-associatNature neuroscienceAPOE4 to APOE2 allelic switching in mice improves Alzheimer's disease-related metabolic signatures, neuropathology and cognition.PMC12672373R01 AG080589P20 GM148326R01 AG062550T32 AG057461R01 AG068330R01AG081421R01 AG093847R01 DK133184R01 AG070830R01 AG081421RF1 NS118558Lee SSmith CChen JPallerla AVSaito KZhu HNolt GLFunnell JLFarmer BCStephens IOMacauley SLMacLean SMWhitus CMMorganti JMVoy CHernandez GPandya KJohnson LASiano DSCowley DOGordon SMGolden LRfalseAPOE4 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 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-associat2025-01-01T00:00:00Z2025 Dec2026-06-05T22:19:02.808Z2026-05-22T03:15:52.761ZS-EPMC126723734121950710.1038/s41593-025-02094-y