APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease
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Abstract
Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do they have a later age of onset, milder clinical course, and less severe neuropathological findings than others with Alzheimer disease. The contrast is especially stark in comparison to the phenotype associated with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, as well as a more aggressive clinical course and notably more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Even one APOE ε2 allele improves phenotype, but it is uncertain if that is due to the replacement of a more toxic allele by APOE ε2, or if APOE ε2 has a protective, neuro-modulatory effect. Here, we demonstrate that brain exposure to APOE2 via a gene therapy approach which bathes the entire cortical mantle in the gene product after transduction of the ependyma, rapidly ameliorates established Aβ plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE4. This result suggests a promising protective effect of exogenous APOE2, revealing a cell non-autonomous effect of the protein on microglial activation. We also show that plaque associated microglia in the brain of patients who inherit APOE2 similarly have less microglial reactivity to plaques. These data raise the potential that an APOE2 therapeutic could be effective in Alzheimer disease even in individuals born with the risk ε4 allele. One Sentence Summary: Introduction of ApoE2 using an AAV that transduces the ependymal cells of the ventricle causes a reduction in amyloid load and plaque associated synapse loss, and reduces neuroinflammation by modulating microglial responsiveness to plaques.
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Viral APOE2 delivery, APOE2 gene therapy, and inducible APOE4 to APOE2 switching have demonstrated that increasing APOE2 expression or replacing APOE4 with APOE2 can ameliorate AD-related phenotypes.
“while viral APOE2 delivery, APOE2 gene therapy, and inducible APOE4 to APOE2 switching have demonstrated that increasing APOE2 expression or replacing APOE4 with APOE2 can ameliorate AD-related phenotypes 7,8,33,34 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [8]
The Introduction and Discussion report that APOE2 gene therapy ameliorated amyloid, neuroinflammatory, and neurodegenerative phenotypes in an AD mouse model. They do not support the sentence’s inducible APOE4-to-APOE2 switching or replacement claim: the Discussion says APOE4 expression continued unchanged. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPrevious studies using homozygous APOE knock-in mice have been essential for defining isoform-specific effects of APOE2, APOE3, and APOE4.
“Previous studies using homozygous APOE knock-in mice have been essential for de fi ning isoform-speci fi c effects of APOE2 , APOE3 , and APOE4”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [8]
The Introduction (page unavailable) reports that targeted-replacement animal models show different plaque deposition among APOE4, APOE3, and APOE2 carriers, supporting the claim that such models helped define isoform-specific effects. It does not specify that the mice in those previous comparisons were homozygous or characterize those studies as essential. (LLM, conf=0.82)
Experimental — accuracy not yet measuredExogenous E2 markedly decreases amyloid burden in mice.
“Moving in vivo, other studies have explored vector-mediated delivery to supplement the E4 brain with neuroprotective E2 protein, showing that exogenous E2 markedly decreases amyloid burden in mice9–12.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [12]
In mice, administration of APOE2 was found to be beneficial at reducing plaque deposition even in the presence of APOE4, indicating that APOE2 can reduce some of the negative effects of APOE4.
“in mice, administration of APOE2 was found to be beneficial at reducing plaque deposition even in the presence of APOE4, indicating that APOE2 can reduce some of the negative effects of APOE4 (refs. 202,203).”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [203]
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- Authors
- Jackson, R. J., Keiser, M. S., Meltzer, J. C., Fykstra, D. P., Dierksmeier, S. E., Hajizadeh, S., Kreuzer, J., Morris, R., Melloni, A., Nakajima, T., Tecedor, L., Ranum, P. T., Carrell, E., Chen, Y., Nishtar, M. A., Holtzman, D. M., Haas, W., Davidson, B. L., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Children's Hospital of Philadelphia (US)
- Broad Institute (US)
- Massachusetts General Hospital (US)
- Washington University in St. Louis (US)
- Corresponding author
- Jackson, Rosemary J.
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2024-05
- Volume
- 32
- Issue
- 5
- Pages
- 1373-1386
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC11081918
- OpenAlex
- W4392967616
- Cited by
- 86
- References
- 45
- Citations by year
- 2026: 29 · 2025: 36 · 2024: 20 · 2023: 1
- FWCI
- 24.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion)
- Funders
- JPB Foundation
- THE CHILDRENS HOSPITAL OF PHILADELPHIA
- NIH
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- APOE ε2, Alzheimer's disease, gene therapy, amyloid plaques, neuroinflammation, microglial activation, neurodegeneration, synaptic loss, APP/PS1 mice, APOE ε4, amyloid deposition
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