APOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
Open accessAbstract
APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4 -related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4 -related phenotypes and suggests APOE4 -related degenerative pathways contributing to AD pathogenesis.
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Human iPSC-derived neurons and organoids confirm that apoE4 increases Aβ production and aggregation and decreases Aβ clearance.
“Studies with human iPSC-derived neurons and organoids confirm that apoE4 increases Aβ production and aggregation as well as decreases Aβ clearance”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Zhao et al 2020
The Results section (‘Increased Aβ amounts in cerebral organoids from AD-iPSCs’; page not provided) says Aβ increases in AD organoids were independent of APOE4, APP processing was unaffected, and insoluble Aβ was undetectable. The Discussion likewise says neither APOE4 nor apoE amounts influenced Aβ levels in these organoids; it raises impaired clearance as a possibility for AD organoids, not as an established effect of APOE4. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredPluripotency and karyotype of iPSC line MC0020 have been validated in a previous study.
“The pluripotency and karyotype of the iPSC line MC0020 have been validated in a previous study [28].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [28]
The Results section, “Characterization of human iPSC-derived cerebral organoids” (page unavailable), reports pluripotency validation and normal karyotypes for iPSC lines studied. Our copy does not identify MC0020 among those lines, so it does not establish that these findings apply to MC0020 specifically. (LLM, conf=0.77)
Experimental — accuracy not yet measuredCompared 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 Zhao et al., 2020
The Results section on isogenic conversion (Fig. 7; page unavailable) reports lower Aβ40 and Aβ42 in APOE3 cerebral organoids than in their APOE4 parental line, supporting the APOE4-versus-APOE3 direction. Those measurements were from organoid lysates, not secreted Aβ, and the paper does not report an APOE2 comparison. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe study also observed apoptotic pathways, including activation of BH3-only proteins and apoptosis, suggesting a potential role of APOE in cell death.
“We also observe apoptotic pathways, including activation of BH3-only proteins (Reactome:R-HSA-114452) and apoptosis (Reactome:R-HSA-109581, Supp. Table S36), suggesting a potential role of APOE40–42 in cell death.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [40]
The Results (Fig. 2) report increased apoptosis in APOE4 cerebral organoids, supporting a potential role for APOE4 in cell death. The paper does not report activation of BH3-only proteins or identify the specified Reactome apoptotic pathways; its pathway analysis used MetaCore. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe APOE4 allele is associated with altered synaptic density.
“Additionally, upregulation of synaptogenesis suggests a compensatory effect in APOE4 mice as previous work has found the APOE4 allele is associated with altered synaptic density [39][40][41] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [40]
The Discussion reports that APOE4 exacerbated synaptic loss in AD patient-derived cerebral organoids at week 12. However, the Results measured synaptic protein levels rather than synaptic density and found no significant overall APOE4 effect on those levels. The source therefore supports an APOE4-related synaptic change in this model, but not the claim at its broader level of specificity. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Human iPSC-derived neurons and cerebral organoids demonstrate that apoE4 enhances tau phosphorylation and exacerbates synapse loss and neurodegeneration.
“Studies with human iPSC-derived neurons and cerebral organoids demonstrate that apoE4 enhances tau phosphorylation and exacerbates synapse loss and neurodegeneration”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Zhao et al 2020
ApoE4 is the strongest genetic risk factor for sporadic Alzheimer's disease.
“APOE ε4 allele (ApoE4) is the strongest genetic risk factor for sporadic AD [15]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [15]
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Self-citationAPOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology
Lysaker, C. R., Johnson, C. N., Csikos, V., Franczak, E., Benson, M., Gilmore, C. A., Birky, C. J., Davis, X., McCoin, C. S., Smith, K. P., et al. (2026) · npj Dementia · doi:10.1038/s44400-026-00105-8 · Cited by 1 · see citing works
Frisch, C., Baker, L., Srinivasan, G., Mintah, A. E., Leyasi, S., Pedroza, M., Galyon, B., & Brafman, D. A. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1856154
Self-citation
- Authors
- Zhao, J., Fu, Y., Yamazaki, Y., Ren, Y., Davis, M. D., Liu, C.-C., Lu, W., Wang, X., Chen, K., Cherukuri, Y., Jia, L., Martens, Y. A., Job, L., Shue, F., Nguyen, T. T., Younkin, S. G., Graff-Radford, N. R., Wszolek, Z. K., Brafman, D. A., Asmann, Y. W., Ertekin-Taner, N., Kanekiyo, T., & Bu, G.
- Affiliations
- Mayo Clinic (US)
- Arizona State University (US)
- Mayo Clinic in Florida (US)
- Corresponding author
- Bu, Guojun
- ORCID
- Venue
- Nature Communications
- Published
- 2020-11-02
- Volume
- 11
- Issue
- 1
- Pages
- 5540-5540
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7608683
- OpenAlex
- W3095784700
- Cited by
- 374
- References
- 27
- Citations by year
- 2026: 50 · 2025: 83 · 2024: 73 · 2023: 68 · 2022: 61 · 2021: 37 · 2020: 2
- FWCI
- 26.02
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-05-05)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Alzheimer’s Association (2018-AARF-592302)
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1AG051504, R37AG027924, RF1AG046205, RF1AG057181)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, Alzheimer's disease, brain organoids, induced pluripotent stem cells, synaptic loss, neurodegeneration, tau pathology, amyloid-beta, apoptosis, stress granules, RNA metabolism, iPSC-derived neurons
- MeSH terms
- Alzheimer Disease, Gene Expression Regulation, Genotype, Humans, Organoids, RNA, Synapses, Apolipoprotein E3, Apolipoprotein E4, Induced Pluripotent Stem Cells, Transcriptome
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