APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer’s Disease Phenotypes in Human iPSC-Derived Brain Cell Types
Open accessAbstract
The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ 42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant. VIDEO ABSTRACT.
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iPSC-derived neurons from LOAD patients expressing ApoE4 secrete higher levels of Aβ compared to ApoE3-expressing neurons.
“induced pluripotent stem cells (iPSC)-derived neurons from LOAD patients expressing ApoE4 secrete higher levels of Aβ, when compared to ApoE3-expressing neurons”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [39]
The Results section on sAD patient-derived iPSCs reports no significant difference in secreted Aβ42 or Aβ40 between APOE4 neurons and their APOE3-edited counterparts (page unavailable). The reported 20% increase in Aβ42 came from a separate comparison using isogenic lines generated from unaffected parental cells, not the patient-derived neurons specified in the claim. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAPOE4 reduces the phagocytosis ability of glial cells, enhances microglia proinflammatory activation by Aβ plaques or tau aggregates, and promotes neurodegeneration in mouse models.
“In addition, APOE4 was found to reduce the phagocytosis ability of glial cells, enhance microglia proinflammatory activation by Aβ plaques or tau aggregates and promote neurodegeneration in the mouse models.176,177”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [177]
The Results section ('APOE4 microglia-like cells exhibit inflammatory gene activation and less efficient Aβ42 uptake'; page unavailable) reports slower Aβ42 uptake by APOE4 microglia-like cells and up-regulation of immune-response genes. The Discussion ('APOE4 effects on astrocytes'; page unavailable) also reports less efficient Aβ uptake by APOE4 astrocytes. These passages do not establish that plaques or tau aggregates trigger proinflammatory activation, or that this study found neurodegeneration in mouse models; its experiments used human iPSC-derived cells and organoids. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn 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 [8]
The Results section, “Converting APOE4 to APOE3,” reports that editing patient-derived iPSCs reduced astrocyte cholesterol accumulation and improved several neuronal and glial functional measures. It does not report an ε4-to-ε2 edit or show that the ε4-to-ε3 edit corrected glial transcriptomic profiles; the Discussion says APOE2’s effects warrant further study. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn disease models, ApoE4 perturbs cholesterol regulation, including expression of cholesterol metabolism-related genes, cholesterol transport and esterification.
“In disease models, ApoE4 perturbs cholesterol regulation, including expression of cholesterol metabolism-related genes, cholesterol transport and esterification10–13.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [11]
The Discussion (‘APOE4 effects on astrocytes’; page not supplied) reports altered expression of lipid-metabolism and transport genes and cholesterol accumulation in APOE4 astrocyte cultures. The Results (‘APOE4 astrocytes exhibit compromised Aβ uptake’; page not supplied) also report altered lipid-transport gene expression and cholesterol levels. Our copy does not report an effect on cholesterol esterification, so that specific part of the claim is unsupported. (LLM, conf=0.87)
Experimental — accuracy not yet measuredNeuronal APOE4 is associated with altered synaptic function, fatty acid accumulation and hyperexcitability in hiPSC-derived neurons.
“The characterization of hIPSC-derived neurons indicates that neuronal APOE4 is associated with altered synaptic function, fatty acid accumulation and hyperexcitability143.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [143]
The Results section, “Increased synapses, early endosomes and Aβ42 secretion in APOE4 neurons” (page unavailable), reports increased synapse number and excitatory postsynaptic current frequency in iPSC-derived APOE4 neurons, supporting altered synaptic function and increased synaptic activity. It does not establish neuronal hyperexcitability as such. The paper reports cholesterol accumulation in APOE4 astrocytes, not fatty acid accumulation in neurons. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Astrocytes derived from APOE4 human-inducible pluripotent stem cells are less efficient at secreting lipidated APOE particles and exhibit impaired cholesterol metabolism relative to APOE3 hiPSC-derived astrocytes.
“Astrocytes derived from APOE4 human-inducible pluripotent stem cells (hiPSCs) are less efficient at secreting lipidated APOE particles and exhibit impaired cholesterol metabolism relative to APOE3 hiPSC-derived astrocytes143,144.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [143]
The Results section ('APOE4 astrocytes exhibit compromised Aβ uptake'; page unavailable) reports less secreted APOE and altered cholesterol metabolism in APOE4 than APOE3 iPSC-derived astrocytes. It does not establish that the secreted APOE particles were lipidated or measure an efficiency of secreting such particles; it also reports increased, not decreased, cholesterol in APOE4 culture media. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAPOE4 astrocytes have an increased number of lipid droplets and impaired glucose utilization and mitochondrial function.
“APOE4 astrocytes have an increased number of lipid droplets and impaired glucose utilization and mitochondrial function, lending further support to this hypothesis143,146,147 (Fig. 2b).”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [143]
The Results section (‘APOE4 astrocytes exhibit compromised Aβ uptake’; page unavailable) reports increased cholesterol in APOE4 astrocytes, supporting altered lipid accumulation. It does not establish an increased number of lipid droplets or impaired glucose utilization or mitochondrial function in astrocytes. (LLM, conf=0.82)
Experimental — accuracy not yet measuredHuman 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 Lin et al 2018
The Results report increased Aβ42 secretion, but unchanged Aβ40 secretion, from APOE4 neurons; they do not establish an unqualified increase in Aβ production. The Results also show more Aβ aggregates in six-month-old APOE4 organoids and less Aβ42 clearance by APOE4 astrocytes. The Discussion describes increased neuronal Aβ generation as a possible contributor, rather than a confirmed mechanism. (LLM, conf=0.84)
Experimental — accuracy not yet measuredHuman 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 Lin et al 2018
The Results section on APOE4 organoids reports increased tau phosphorylation in six-month-old APOE4 organoids compared with APOE3 organoids (page unavailable). But the Results section on iPSC-derived neurons reports increased synapse numbers, not synapse loss, and the paper does not show that APOE4 exacerbates neurodegeneration in these models. (LLM, conf=0.90)
Experimental — accuracy not yet measuredRecent studies on human induced pluripotent stem cells with the APOE4 variant showed altered transcriptomic and metabolomic profiles toward the accumulation of cholesterol in glia, such as astrocytes and oligodendrocytes.
“Recent studies on human induced pluripotent stem cells (iPSCs) with the APOE4 variant showed altered transcriptomic and metabolomic profiles toward the accumulation of cholesterol in glia, such as astrocytes and oligodendrocytes.5”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [5]
The Results section (“APOE4 astrocytes exhibit compromised Aβ uptake”; page unavailable) reports altered lipid-metabolism gene expression and increased cholesterol in APOE4 iPSC-derived astrocytes. It does not report cholesterol accumulation in oligodendrocytes or a metabolomic profile; cholesterol was measured with targeted assays. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThree ApoE3 and ApoE4 isogenic iPSC pairs were used to determine the effect of APOE4 genotype without inter-donor variability.
“Three ApoE3 and ApoE4 isogenic iPSCs pairs were used to determine the effect of APOE4 genotype without inter-donor variability.5”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [5]
The Results sections on generating APOE4 iPSCs and converting APOE4 to APOE3 describe isogenic comparisons, which allow APOE genotype to be examined within a donor background. They describe one pair derived from an unaffected subject and another from a sporadic AD patient, not three pairs. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMultiple transcriptomic studies of APOE4-expressing iPSC-derived astrocytes and microglia demonstrate alterations in expression of lipid metabolic genes and defects in cholesterol trafficking and metabolism.
“Multiple transcriptomic studies of APOE4-expressing iPSC-derived astrocytes and microglia demonstrate alterations in the expression of lipid metabolic genes as well as defects in cholesterol trafficking and metabolism (Lin et al., 2018; de Leeuw et al., 2022; Tcw et al., 2022).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Lin et al., 2018
The Results section on APOE4 astrocytes reports altered expression of lipid-metabolism and transport genes and increased intracellular and secreted cholesterol. The microglia Results section reports transcriptomic changes, but the paper describes lipid-metabolism abnormalities in microglia as only potential; it does not demonstrate cholesterol-trafficking or metabolism defects in those cells. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCRISPR/Cas9 conversion of APOE ε4 into APOE ε3 in neuronal, astrocytic and microglial cells from iPSCs derived from LOAD patients led to attenuation of some AD-related pathologies, namely Aβ glial uptake.
“CRISPR/Cas9 technology, which allow precise genetic modifications, was used to convert APOE ε4 into APOE ε3 in neuronal, astrocytic and microglial cells types from iPSCs derived from LOAD patients, which led to the attenuation of some AD-related pathologies, namely Aβ glial uptake [39].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [39]
The Results section ('Converting APOE4 to APOE3 attenuates AD-related phenotypes') reports CRISPR/Cas9 editing of patient-derived iPSCs, followed by differentiation into neurons, astrocytes and microglia-like cells. It says the conversion enhanced Aβ uptake by astrocytes and microglia-like cells—not that Aβ glial uptake itself was attenuated. No page number is supplied in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe APOE genotype has a widespread impact on cell-autonomous and non-autonomous biological processes.
“The APOE genotype has a widespread impact on cell-autonomous and non-autonomous biological processes14.”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [14]
APOE ε4 disrupts lipid homeostasis and immune response and causes mitochondrial dysfunction.
“APOE ε4 is known to disrupt lipid homeostasis and immune response and to cause mitochondrial dysfunction [31–34]”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [32]
Astrocytes generated from hiPSC derived from fibroblasts of patients with CNS diseases show pathological phenotypes, including dysregulation of lipid metabolism, alteration in extracellular vesicles, reduced autophagy, or altered STAT3 signaling.
“Interestingly, astrocytes generated from hiPSC derived from fibroblasts obtained from patients with CNS diseases (usually with a genetic mutation causative of disease or a risk polymorphism) show pathological phenotypes, including dysregulation of lipid metabolism11, alteration in the contents of the extracellular vesicles released by astrocytes80, reduced autophagy81, or altered STAT3 signaling82”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [11]
hiPSC-derived astrocytes are rapidly becoming commonplace in basic research and therapy development.
“are rapidly becoming commonplace in basic research11,82 and therapy development109”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [11]
APOE4 microglia-like hiPSCs show decreased phagocytosis and increased inflammatory genes relative to APOE3 microglia.
“APOE4 microglia-like hiPSCs show decreased phagocytosis and increased inflammatory genes relative to APOE3 microglia143.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [143]
These results demonstrate an isoform-dependent regulation of APOE protein levels, as previously shown for E3 and E4 in vitro or in patient CSF.
“These results demonstrate an isoform-dependent regulation of APOE protein levels, as was previously shown for E3 and E4 in vitro, or in patient cerebrospinal fluid (CSF) (Lin et al., 2018; Mahley, 2016).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Lin et al., 2018
ApoE4 astrocytes display impaired Aβ clearance compared with ApoE3 astrocytes.
“ApoE4 astrocytes displayed reduced levels of ApoE and impaired Aβ clearance compared with ApoE3 astrocytes”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [5]
ApoE4 astrocytes display reduced levels of ApoE compared with ApoE3 astrocytes.
“ApoE4 astrocytes displayed reduced levels of ApoE and impaired Aβ clearance compared with ApoE3 astrocytes”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [5]
ApoE4 astrocytes show significant accumulation of cholesterol compared with ApoE3 astrocytes.
“we found a significant accumulation of cholesterol in ApoE4 astrocytes compared with ApoE3 astrocytes”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [5]
ApoE is expressed in neurons under stress conditions, in neurons cultured in vitro, and in neurons of selected brain regions in vivo.
“because ApoE is also expressed in neurons under stress conditions (Xu et al., 2006), neurons cultured in vitro (Lin et al., 2018; Xu et al., 1999b), and neurons of selected brain regions in vivo (Han et al., 1994; Xu et al., 1999a)”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Lin et al., 2018
The APOE ε4 variant associated with increased Alzheimer's disease risk causes functional changes in neurons, astrocytes, and microglia.
“and that the APOE ε4 variant associated with increased risk of Alzheimer’s Disease causes functional changes in neurons, astrocytes and microglia9.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [9]
iPSC-derived cells from different lineages can be combined into defined three-dimensional cultures called assembloids.
“Furthermore, iPSC-derived cell types from different lineages can be combined into defined three-dimensional cultures, termed assembloids9,94–98.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [9]
APOE ε4 alters iPSC-derived astrocytes and microglia, notably reducing their Aβ clearance.
“APOE ε4 also affects properties of iPSC-derived astrocytes and microglia, notably reducing their ability to clear Aβ9,102.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [9]
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- Authors
- Lin, Y.-T., Seo, J., Gao, F., Feldman, H. M., Wen, H.-L., Penney, J., Cam, H. P., Gjoneska, E., Raja, W. K., Cheng, J., Rueda, R., Kritskiy, O., Abdurrob, F., Peng, Z., Milo, B., Yu, C. J., Elmsaouri, S., Dey, D., Ko, T., Yankner, B. A., & Tsai, L.-H.
- Affiliations
- Massachusetts Institute of Technology (US)
- Harvard University (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 98
- Issue
- 6
- Pages
- 1141-1154.e7
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6023751
- OpenAlex
- W2805798400
- Cited by
- 1,125
- References
- 74
- Citations by year
- 2026: 94 · 2025: 152 · 2024: 175 · 2023: 167 · 2022: 159 · 2021: 151 · 2020: 142 · 2019: 66 · 2018: 18
- FWCI
- 64.81
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-06-27)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- IslandScholar (University of Prince Edward Island) (submittedVersion)
- Funders
- Basic Science Research Program (2014R1A6A3A03055359)
- NIH (RF1 AG048056, RC1 AG036106, RF1 AG048029)
- Glenn Foundation for Medical Research
- Robert A. and Renee E. Belfer Family Foundation
- Cure Alzheimer's Fund
- 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
- APOE ε4, sporadic Alzheimer's disease, induced pluripotent stem cells, APOE3, neurons, astrocytes, microglia-like cells, amyloid-beta, synaptic function, lipid metabolism, cholesterol accumulation, cell type-specific gene expression, CRISPR/Cas9 genome editing
- MeSH terms
- Alzheimer Disease, Astrocytes, Brain, Cell Differentiation, Humans, Synaptic Transmission, Neuroglia, Neurons, Organoids, Peptide Fragments, Phosphoproteins, Amyloid beta-Peptides, tau Proteins, Microglia, Lipid Metabolism, Apolipoprotein E3, Apolipoprotein E4, Induced Pluripotent Stem Cells, Transcriptome, CRISPR-Cas Systems
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