ArticleNature neuroscience2025
APOE4 to APOE2 allelic switching in mice improves Alzheimer's disease-related metabolic signatures, neuropathology and cognition.
Article in Nature neuroscience, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Lipid Metabolism in Central Nervous System Diseases: Pathological Mechanisms and Therapeutic Advances.CNS neuroscience & therapeutics · 2026Review
- Article
- Kinetic Lipidomics: QuantifyingbioRxiv : the preprint server for biology · 2026Article
- APOE*4 risk-modifying genes and drug targets in Alzheimer's disease through cell-type-specific genomic analyses.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Circulating lipids uncover early membrane disruption as a primary event preceding Alzheimer's disease onset.Research square · 2026Article
- Beyond Lipidation: CSF APOE4 Protein Burden, Not HDL Subclass, Drives Tau Associations in APOE4 Alzheimer's Disease.Research square · 2026Article
- Article
- Amyloid-Frontiers in neuroscience · 2026Review
- Astrocyte-blood-brain barrier crosstalk in cerebral small vessel disease: linking barrier dysfunction to neurovascular failure.Frontiers in neurology · 2026Review
- ApoE expression across the CNS: Who, What, Where, When, and How (much)?Molecular neurodegeneration advances · 2026Review
- Article
- High estrogen states enhance reinforcement learning.Nature neuroscience · 2025Article
- Flipping APOE to reverse Alzheimer's disease traits.Nature neuroscience · 2025Article
Corrections and comments
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Authors and funding
22 authors.
Funding
Abstract
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 from APOE4 to APOE2 can broadly affect the cerebral transcriptome and lipidome, and that astrocyte-specific APOE replacement may be a viable strategy for future gene editing approaches to simultaneously reduce multiple AD-associated pathologies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.