APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition

Lesley R. Golden; Dahlia S. Siano; Isaiah O. Stephens; Steven M. MacLean; Kai Saito; Georgia L. Nolt; Jessica L. Funnell; Akhil V. Pallerla; Sangderk Lee; Cathryn Smith; Jing Chen; Haining Zhu; Clairity Voy; Callie M. Whitus; Gabriela Hernandez; Brandon C. Farmer; Kumar Pandya; Dale O. Cowley; Shannon L. Macauley; Scott M. Gordon; Josh M. Morganti; Lance A. Johnson

doi:10.1038/s41593-025-02094-y

APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition

Lesley R. Golden, Dahlia S. Siano, Isaiah O. Stephens, Steven M. MacLean, Kai Saito, Georgia L. Nolt, Jessica L. Funnell, Akhil V. Pallerla, Sangderk Lee, Cathryn Smith, Jing Chen, Haining Zhu, Clairity Voy, Callie M. Whitus, Gabriela Hernandez, Brandon C. Farmer, Kumar Pandya, Dale O. Cowley, Shannon L. Macauley, Scott M. GordonJosh M. Morganti, Lance A. Johnson

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English
Pages (from-to)	2461-2475
Number of pages	15
Journal	Nature Neuroscience
Volume	28
Issue number	12
DOIs	https://doi.org/10.1038/s41593-025-02094-y
State	Published - Dec 2025

Bibliographical note

Publisher Copyright:
© The Author(s) 2025.

Funding

We thank D. Adreon, C. Friday and H. Williams for their invaluable feedback. We thank the University of Kentucky Proteomics Core for their help with proteomics analysis and the Animal Behavior Core for their assistance with behavioral testing. This work was supported by the National Institute of Health (grant nos. R01AG062550, R01AG081421 and R01AG080589 to L.A.J.; grant nos. R01AG070830 and RF1NS118558 to J.M.M.; grant nos. R01AG068330 and R01AG093847 to S.L.M.; grant no. R01DK133184 to S.M.G.; grant no. T32AG057461 to L.R.G.), the CNS Metabolism COBRE P20 GM148326 (J.M.M., S.L.M. and L.A.J.), BrightFocus Foundation A20201775S (S.L.M.), Coins for Alzheimer’s Research Trust Grant (S.L.M.) and the Alzheimer’s Association (L.A.J., J.M.M., S.M.G.).

Funders	Funder number
Alzheimer's Association
Coins for Alzheimer's Research Trust
BrightFocus Foundation
University of Kentucky Proteomics Core
National Institutes of Health (NIH)	R01AG093847, R01DK133184, R01AG062550, R01AG068330, R01AG081421, RF1NS118558, R01AG070830, T32AG057461, R01AG080589
CNS Metabolism COBRE	P20 GM148326

ASJC Scopus subject areas

General Neuroscience

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Golden, L. R., Siano, D. S., Stephens, I. O., MacLean, S. M., Saito, K., Nolt, G. L., Funnell, J. L., Pallerla, A. V., Lee, S., Smith, C., Chen, J., Zhu, H., Voy, C., Whitus, C. M., Hernandez, G., Farmer, B. C., Pandya, K., Cowley, D. O., Macauley, S. L., ... Johnson, L. A. (2025). APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition. Nature Neuroscience, 28(12), 2461-2475. https://doi.org/10.1038/s41593-025-02094-y

@article{d082daaec5c74ea198e3881f9842afa4,

title = "APOE4 to APOE2 allelic switching in mice improves Alzheimer{\textquoteright}s disease-related metabolic signatures, neuropathology and cognition",

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{\textquoteright}s disease (AD) risk. Here we develop a knock-in model that allows for an inducible {\textquoteleft}switch{\textquoteright} 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.",

author = "Golden, \{Lesley R.\} and Siano, \{Dahlia S.\} and Stephens, \{Isaiah O.\} and MacLean, \{Steven M.\} and Kai Saito and Nolt, \{Georgia L.\} and Funnell, \{Jessica L.\} and Pallerla, \{Akhil V.\} and Sangderk Lee and Cathryn Smith and Jing Chen and Haining Zhu and Clairity Voy and Whitus, \{Callie M.\} and Gabriela Hernandez and Farmer, \{Brandon C.\} and Kumar Pandya and Cowley, \{Dale O.\} and Macauley, \{Shannon L.\} and Gordon, \{Scott M.\} and Morganti, \{Josh M.\} and Johnson, \{Lance A.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41593-025-02094-y",

language = "English",

volume = "28",

pages = "2461--2475",

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Golden, LR, Siano, DS, Stephens, IO, MacLean, SM, Saito, K, Nolt, GL, Funnell, JL, Pallerla, AV, Lee, S, Smith, C, Chen, J, Zhu, H, Voy, C, Whitus, CM, Hernandez, G, Farmer, BC, Pandya, K, Cowley, DO, Macauley, SL , Gordon, SM , Morganti, JM & Johnson, LA 2025, 'APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition', Nature Neuroscience, vol. 28, no. 12, pp. 2461-2475. https://doi.org/10.1038/s41593-025-02094-y

TY - JOUR

T1 - APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition

AU - Golden, Lesley R.

AU - Siano, Dahlia S.

AU - Stephens, Isaiah O.

AU - MacLean, Steven M.

AU - Saito, Kai

AU - Nolt, Georgia L.

AU - Funnell, Jessica L.

AU - Pallerla, Akhil V.

AU - Lee, Sangderk

AU - Smith, Cathryn

AU - Chen, Jing

AU - Zhu, Haining

AU - Voy, Clairity

AU - Whitus, Callie M.

AU - Hernandez, Gabriela

AU - Farmer, Brandon C.

AU - Pandya, Kumar

AU - Cowley, Dale O.

AU - Macauley, Shannon L.

AU - Gordon, Scott M.

AU - Morganti, Josh M.

AU - Johnson, Lance A.

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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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U2 - 10.1038/s41593-025-02094-y

DO - 10.1038/s41593-025-02094-y

M3 - Article

AN - SCOPUS:105021412169

SN - 1097-6256

VL - 28

SP - 2461

EP - 2475

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 12

ER -

APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition

Abstract

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