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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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“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]
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In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
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In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“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]
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In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
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In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The fact that human iPSC-derived APOE4/E4 astrocytes were recently reported to accumulate endolysosomal cholesterol”
From TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge (2020) · cites this paper as Lin et al., 2018
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“ApoE4 drives the accumulation of lipids and increased inflammatory cytokine production in vitro in human induced pluripotent stem cell (iPSC)-derived astrocytes, microglia, and oligodendrocytes.”
From Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist (2024) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Multiple studies on astrocytes, microglia, and oligodendrocytes derived from iPSCs demonstrate an important role for ApoE4 in cholesterol metabolism pathways.6”
From Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist (2024) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Along the same lines, ApoE4 increased the number and size of early endosomes in AD patients (Cataldo et al., 2000) and in neurons derived from induced pluripotent stem cells (Lin et al., 2018).”
From Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease (2018) · cites this paper as Lin et al., 2018
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In the citing paper
“In this regard, transcriptomic studies of ApoE4 astrocytes deriving from human-induced pluripotent stem cells (hiPSCs) of AD patients demonstrated that lipid metabolism is one of main altered processes [15,16].”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Recently, it has been shown that cholesterol homeostasis is also impaired in ApoE4 astrocytes, although controversial data concerning intracellular and secreted cholesterol levels are present in literature depending on the different experimental model employed [15,16,24].”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“studies suggest that lower levels of ApoE receptors in the astrocytic membrane may lead to the reduced ability of ApoE4 astrocytes to clear Aβ [16,73].”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [16]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Similarly, although both groups could perform phagocytosis, both the percentage of phagocytic cells and the phagocytic index were lower in AD than in healthy control iMGs (Fig. 2H, Supplementary Fig. 2F), as has been previously reported in human iPSC-derived microglia with altered expression of AD risk genes [60–64].”
From microRNA-132 attenuates inflammation in induced pluripotent stem cell-derived microglia from Alzheimer’s disease patients (2026) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Notable shared features include reduced phagocytosis, previously reported in human iPSC-derived microglia with altered expression of AD risk genes [60–64], and increased expression of inflammatory genes (such as complement C3), consistent with findings from human AD brain and APOE4/4 iPSC-derived microglia [52, 60, 61].”
From microRNA-132 attenuates inflammation in induced pluripotent stem cell-derived microglia from Alzheimer’s disease patients (2026) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Notably, iPSC-derived microglia with altered expression of the sAD risk genes APOE4 and TREM2 display pronounced phenotypic differences from control microglia, such as impaired phagocytosis, whereas mutations involved in familial AD have a more limited impact on microglial function [51, 60–63, 119–122].”
From microRNA-132 attenuates inflammation in induced pluripotent stem cell-derived microglia from Alzheimer’s disease patients (2026) · cites this paper as [60]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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 cited source says what the claim attributes to it.
In the citing paper
“In agreement with our data, significantly reduced ApoE levels were also observed in hiPSC-derived ApoE4 astrocytes [15,16,24], as well as in brain homogenates from mouse models expressing the human ApoE4 isoform [43,44].”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [16]
The cited source says what the claim attributes to it.
In the citing paper
“These results, together with those obtained by transcriptomic and proteomic analyses of hiPSC-derived astrocytes [15,16], further confirm that lipid metabolism is one of the main altered processes in ApoE4 astrocytes.”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [16]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“Alterations of ApoE synthesis and release have been shown to characterize hiPSCs-derived ApoE4 astrocytes [15,16,24].”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [16]
In the citing paper
“ApoE4 has been shown to impact on many physiological functions played by astrocytes, affecting their ability to clear Aβ, to uptake glutamate, to promote neuronal synaptogenesis, and to maintain lipid homeostasis [15,16,42].”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [16]
In the citing paper
“Our results further highlight the link between cholesterol metabolism, astrocyte dysfunction and neurodegeneration, emphasizing the role of cholesterol exposure in driving astrocyte-mediated neurotoxicity70–72.”
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Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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