APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer’s disease

Brookhouser, Nicholas; Raman, Sreedevi; Frisch, Carlye; Srinivasan, Gayathri; Brafman, David A.

doi:10.1038/s41380-021-01076-3

Cited by 33Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer’s disease

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Brookhouser, Nicholas, Raman, Sreedevi, Frisch, Carlye, Srinivasan, Gayathri, Brafman, David A.·2021·Molecular Psychiatry

DOI 10.1038/s41380-021-01076-3PMC PMC8501163

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Abstract

Genome-wide association studies (GWAS) have identified polymorphism in the Apolipoprotein E gene (APOE) to be the most prominent risk factor for Alzheimer’s disease (AD). Compared to individuals homozygous for the APOE3 variant, individuals with the APOE4 variant have a significantly elevated risk of AD. On the other hand, longitudinal studies have shown that the presence of the APOE2 variant reduces the lifetime risk of developing AD by 40 percent. While there has been significant research that has identified the risk-inducing effects of APOE4, the underlying mechanisms by which APOE2 influences AD onset and progression have not been extensively explored. In this study, we utilize an isogenic human induced pluripotent stem cell (hiPSC)-based system to demonstrate that conversion of APOE3 to APOE2 greatly reduced the production of amyloid-beta (Aβ) peptides in hiPSC-derived neural cultures. Mechanistically, analysis of pure populations of neurons and astrocytes derived from these neural cultures revealed that mitigating effects of APOE2 are mediated by cell autonomous and non-autonomous effects. In particular, we demonstrated the reduction in Aβ is potentially driven by a mechanism related to non-amyloidogenic processing of amyloid precursor protein (APP), suggesting a gain of the protective function of the APOE2 variant. Together, this study provides insights into the risk-modifying effects associated with the APOE2 allele and establishes a platform to probe the mechanisms by which APOE2 enhances neuroprotection against AD.

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In vitro editing of ε4 to ε3 or ε2 simultaneously corrects several phenotypes, including glial transcriptomic profiles, lipid metabolism and other functional measures.
“Studies that have successfully targeted APOE using gene editing in induced pluripotent stem cells (iPSCs) provide strong proof of concept that in vitro editing of ε4 to ε3 or ε2 simultaneously ‘corrects’ several phenotypes, including glial transcriptomic profiles, lipid metabolism and other functional measures7,8.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [7]
The Discussion and Results report editing APOE3 to APOE2 in hiPSC-derived cultures, with reductions in amyloid secretion and, in some cultures, phosphorylated tau. This paper does not report editing APOE4 to APOE3 or APOE2. Its Results use astrocyte RNA sequencing to identify cell populations, not to demonstrate correction of glial transcriptomic profiles or lipid metabolism (pages not specified in our copy). (LLM, conf=0.90)
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Compared with APOE3, APOE4 increases and APOE2 decreases levels of secreted Aβ in isogenic hiPSCs.
“Similarly, our work with isogenic hiPSCs has shown that, compared with APOE3, APOE4 increases and APOE2 decreases levels of secreted Aβ (Brookhouser et al., 2021; Zhao et al., 2020).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Brookhouser et al., 2021
The Results section (‘APOE2 modulates AD-related phenotypes in hiPSC-derived neural cultures’; page unavailable) reports that APOE2 reduced secreted Aβ40 and Aβ42 relative to APOE3 in isogenic cultures with familial AD mutations. It also reports no reduction in non-demented control cultures. This paper does not report an APOE4-versus-APOE3 increase in secreted Aβ from its isogenic hiPSC experiments, so it supports the APOE2 portion but not the full unqualified claim. (LLM, conf=0.86)
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[71]Chiang GC Insel PS Tosun D Schuff N Truran-Sacrey D Raptentsetsang ST Hippocampal atrophy rates and CSF biomarkers in elderly APOE2 normal subjects Neurology 2010 75 1976 81 20980669 PMC3014234
[74]Serrano-Pozo A Qian J Monsell SE Betensky RA Hyman BT APOEε2 is associated with milder clinical and pathological Alzheimer disease Ann Neurol 2015 77 917 29 25623662 PMC4447539

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Authors: Brookhouser, N., Raman, S., Frisch, C., Srinivasan, G., & Brafman, D. A.
Affiliations: University of Arizona College of Medicine- Phoenix (US)
Arizona State University (US)
Corresponding author: Brafman, David A.
ORCID: Srinivasan, Gayathri
Brafman, David A.
Venue: Molecular Psychiatry
Publisher: Springer Science and Business Media LLC
Published: 2021-04-09
Volume: 26
Issue: 10
Pages: 5715-5732
ISSN: 1359-4184 (ISSN-L)
1476-5578
DOI: 10.1038/s41380-021-01076-3
PMC: PMC8501163
OpenAlex: W3143443901
Cited by: 33
References: 98
Citations by year: 2026: 4 · 2025: 10 · 2024: 6 · 2023: 5 · 2022: 6 · 2021: 2
FWCI: 2.98
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Molecular Psychiatry (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: U.S. Department of Health & Human Services | NIH | National Institute on Aging (5R21AG056706, 5R21AG063358)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: APOE2, Alzheimer's disease, APOE ε4, APOE3, amyloid-beta production, APP processing, non-amyloidogenic pathway, hiPSC-derived neurons, isogenic cell models, neuroprotection, genetic risk factors
MeSH terms: Alzheimer Disease, Apolipoproteins E, Humans, Phenotype, Amyloid beta-Peptides, Apolipoprotein E4, Apolipoprotein E2, Genome-Wide Association Study, Induced Pluripotent Stem Cells

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APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer’s disease

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