Gene Transfer of Human Apoe Isoforms Results in Differential Modulation of Amyloid Deposition and Neurotoxicity in Mouse Brain
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Introduction of different APOE isoforms modulates Aβ peptide aggregation and neurotoxicity after amyloid deposition in mouse brain.
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One strategy to prevent Alzheimer's disease in APOE4 carriers is to modify the central nervous system genetically to express APOE2, providing the CNS with the protective APOE2 to balance the Alzheimer's disease risk associated with expression of APOE4.
“Based on these observations, one strategy to prevent AD in APOE4 carriers is to modify the central nervous system (CNS) genetically to express APOE2, providing the CNS with the protective APOE2 to balance the AD risk associated with expression of APOE4.22–26”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [24]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
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 [33]
The Discussion (page unavailable) reports that previous studies replacing murine Apoe with human APOE2, APOE3, or APOE4 found isoform-dependent differences in amyloid deposits. It does not specify that those mice were homozygous or characterize those studies as essential, so those details are not supported by our copy. (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 [10]
The Results section reports that AAV4-delivered APOE2 reduced amyloid-plaque density in APP/PS1 mice, supporting the claim that exogenous E2 decreases amyloid burden. The Animals methods describe separate groups receiving APOE2 or APOE4 vectors; they do not establish that E2 was delivered to an E4-expressing brain, as the citing sentence suggests. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredExpression of apoE3 and apoE4 in the mouse brain results in diminished efflux of Aβ into the blood compared with apoE2.
“Expression of apoE3 and apoE4 in the mouse brain results in diminished efflux of A into the blood compared with apoE2 (Hudry et al., 2013).”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Hudry et al., 2013
The Results section reports lower plasma Aβ40 in mice expressing APOE3 or APOE4 than in those expressing APOE2 and says this suggests greater retention of Aβ in the CNS. The paper therefore supports the direction of the comparison, but diminished efflux is an inference from plasma concentrations, not a directly measured result. (LLM, conf=0.82)
Experimental — accuracy not yet measuredOverexpression of human APOE ε2 allele in APP/PS1 mice attenuated brain Aβ oligomerization and plaque deposition, as well as peri-plaque synapse loss and neurite dystrophy, in contrast to injection of ApoE4-encoding AAVs.
“overexpression of human APOE ε2 allele in APP/PS1 mice was able to attenuate brain Aβ oligomerization and plaque deposition, as well as peri-plaque synapse loss and neurite dystrophy, in contrast to the injection of ApoE4-encoding AAVs [79].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [79]
The Results sections on plaque deposition and peri-plaque neurotoxicity support the APOE2-versus-APOE4 comparison in APP/PS1 mice. However, the measured difference in Aβ oligomers comes from a separate experiment in Tg2576 mice, not APP/PS1 mice, so the claim extends that finding to the wrong model. Page numbers are unavailable in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measured
The protective effect of APOE2 genetic modification of the CNS was replicated by Hudry et al. using an adeno-associated virus serotype 4 (AAV4) vector to deliver APOE2 into the cerebrospinal fluid (CSF) of the lateral ventricle of mice overexpressing a mutant β-amyloid precursor protein (APP) transgene.
“The protective effect of APOE2 genetic modification of the CNS was replicated by Hudry et al.24 using an adeno-associated virus serotype 4 (AAV4) vector to deliver APOE2 into the cerebrospinal fluid (CSF) of the lateral ventricle of mice overexpressing a mutant β-amyloid precursor protein (APP) transgene”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [24]
The efficacy of this approach in AD transgenic mouse models has been demonstrated previously.
“The efficacy of this approach in AD transgenic mouse models has been demonstrated previously.23,24,26”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [24]
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 [33]
APOE exerts toxic effects on the cerebrovascular system and neurons and influences Aβ clearance, amyloid deposition, and tau-related neurodegeneration in an allele-dependent manner APOE4 > APOE3 > APOE2.
“APOE exerts toxic effects on the cerebrovascular system (694) and neurons (383, 384) and influences A 𝛃 clearance (60, 64, 98, 135, 256, 266, 278, 294, 315, 693), amyloid deposition (39, 256, 258, 266, 278, 314, 518, 612), and tau-related neurodegeneration (533) in an allele-dependent manner APOE4 > APOE3 > APOE2 .”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [266]
apoE4 markedly enhances the disease process.
“Epidemiological evidence and evidence from neuropathological assessment of the impact of apoE isoforms on the brain Aβ load, have suggested that apoE2 exerts a protective effect against Aβ pathology and AD morbidity [3,9,10], while apoE4, in contrast, markedly enhances the disease process [7,8,30].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [30]
ApoE plays an important role in amyloidosis progression.
“ApoE plays an important role in amyloidosis progression (Dodart et al., 2005;Hudry et al., 2013).”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Hudry et al., 2013
Consistent data appear to support apoE2's neuroprotective function.
“Unlike other two isoforms, apoE2 has not been studies extensively but consistent data appear to support its neuroprotective function (Hudry et al., 2013).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Hudry et al., 2013
The effect of APOE4 in Alzheimer disease is due not only to the increased propensity of proteins to aggregate in the presence of APOE4, but also to the way APOE4 modulates the brain response to those aggregates once formed.
“These results bear a striking resemblance to those from the Aβ plaque-depositing mice120,128 and indicate that the effect of APOE4 in AD is due not only to the increased propensity of proteins to aggregate in the presence of APOE4, but also to the way APOE4 modulates the brain response to those aggregates once formed.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [128]
The introduction of human APOE2 into plaque-depositing mice expressing endogenous mouse Apoe via AAV-mediated delivery was shown to prevent and even reverse the deposition of Aβ into plaques, whereas delivery of APOE4 had the opposite effect.
“The introduction of human APOE2 into plaque-depositing mice expressing endogenous mouse Apoe via AAV-mediated delivery was shown to prevent and even reverse the deposition of Aβ into plaques, whereas delivery of APOE4 had the opposite effect128”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [128]
Experiments suggest the order APOE4 > APOE3 > APOE2 for effects on amyloid deposition.
“In general, experiments suggest the order of APOE4 > APOE3 > APOE2 for effects on amyloid deposition (Fagan et al, 2002; Castellano et al, 2011; Hudry et al, 2013; Zhao et al, 2016)”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Hudry et al, 2013
Viral-vector mediated overexpression of APOE4 isoforms in AD mouse brains accelerates plaque formation.
“This has also been observed with viral-vector mediated overexpression of APOE4 isoforms in AD mouse brains (Dodart et al, 2005; Hudry et al, 2013; Zhao et al, 2016).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Hudry et al, 2013
A previously published split-luciferase complementation assay was employed.
“using a previously published split-luciferase complementation assay34”
From Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report (2019) · cites this paper as [34]
The Materials and Methods passages describe ELISA, immunoblotting, array tomography, and multiphoton imaging, but none describes a split-luciferase complementation assay. Searches for “split-luciferase complementation assay” and “luciferase protein complementation bioluminescence assay” found no passage addressing it. (LLM, conf=0.76)
Experimental — accuracy not yet measuredData support that ApoE2 expression may be protective using a gene transfer approach.
“While there is data to support the concept that ApoE2 expression may be protective using a gene transfer approach (Hu et al., 2015; Hudry et al., 2013), it would be useful to validate protective effects and lack of toxicity in a number of different models.”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Hudry et al., 2013
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Sultana, M. A., Hia, R. A., Akinsiku, O., & Hegde, V. K. (2023) · Biology · doi:10.3390/biology12071019 · Cited by 31 · see citing works
Onisiforou, A., Charalambous, E. G., & Zanos, P. (2025) · Microorganisms · doi:10.3390/microorganisms13010090 · Cited by 31 · see citing works
Neuronal Glial Crosstalk: Specific and Shared Mechanisms in Alzheimer’s Disease
Chavda, V. K., Singh, K., Patel, V., Mishra, M., & Mishra, A. K. (2022) · Brain Sciences · doi:10.3390/brainsci12010075 · Cited by 29 · see citing works
Opposing Roles of apolipoprotein E in aging and neurodegeneration
Hudry, E., Klickstein, J., Cannavo, C., Jackson, R., Muzikansky, A., Gandhi, S., Urick, D., Sargent, T., Wrobleski, L., Roe, A. D., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201900325 · Cited by 30 · see citing works
Self-citationCognitive resilience in Alzheimer’s disease: Mechanism and potential clinical intervention
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Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer’s disease?
Vecchio, F. L., Bisceglia, P., Imbimbo, B. P., Lozupone, M., Latino, R. R., Resta, E., Leone, M., Solfrizzi, V., Greco, A., Daniele, A., et al. (2022) · Therapeutic Advances in Chronic Disease · doi:10.1177/20406223221081605 · Cited by 28 · see citing works
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APOE4 is a Risk Factor and Potential Therapeutic Target for Alzheimer's Disease
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- Authors
- Hudry, E., Dashkoff, J., Roe, A. D., Takeda, S., Koffie, R. M., Hashimoto, T., Scheel, M., Spires-Jones, T., Arbel-Ornath, M., Betensky, R., Davidson, B. L., & Hyman, B. T.
- Affiliations
- MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
- Harvard University (US)
- University of Iowa (US)
- Corresponding author
- Hyman, Bradley T.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2013-11-20
- Volume
- 5
- Issue
- 212
- Pages
- 212ra161-212ra161
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4334150
- OpenAlex
- W2136199683
- Cited by
- 187
- References
- 55
- Citations by year
- 2026: 8 · 2025: 24 · 2024: 21 · 2023: 12 · 2022: 13 · 2021: 14 · 2020: 15 · 2019: 14 · 2018: 15 · 2017: 5 · 2016: 19 · 2015: 9 · 2014: 18
- FWCI
- 10.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (24800015)
- National Institute on Aging (R00AG033670, P50AG005134, 1RC1AG026265-01, R00AG33670, P30AG062421)
- National Institute on Drug Abuse (F32DA026265)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK54759, P30DK054759)
- National Institute of Neurological Disorders and Stroke (NS 34568, R01NS034568)
- National Institute of Environmental Health Sciences (P30ES005605)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-33531, R01HD033531)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- apolipoprotein E, APOE isoforms, APOE ε4, APOE2, Alzheimer's disease, amyloid-beta, synaptotoxicity, amyloid-beta oligomers, amyloid-beta clearance, dystrophic neurites, synaptic loss, gene transfer, transgenic mouse model, genetic risk
- MeSH terms
- Amyloid, Animals, Apolipoproteins E, Brain, Humans, Injections, Intraventricular, Mice, Transgenic, Transfection, Mice
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