APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia
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APOE4 -disrupted intracellular lipid homeostasis in human and yeast cells was reversed by promoting phospholipid synthesis through choline supplementation.
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The effects of APOE on the composition of lipid droplets themselves remain unexplored.
“the effects of APOE on the composition of LDs themselves remains unexplored”
From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Sienski et al., 2021
The Introduction reports that APOE4 astrocytes accumulated more unsaturated triacylglycerides stored in lipid droplets than APOE3 astrocytes, contrary to the unqualified claim that APOE’s effects on droplet composition remain unexplored. The Results clarify that the lipid composition was measured by whole-cell lipidomics, not by directly analyzing isolated droplets. (LLM, conf=0.76)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAPOE 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 [34]
The Abstract reports that APOE4 disrupted lipid homeostasis in human iPSC-derived astrocytes and yeast, supporting that part of the claim. The passages retrieved for immune response and mitochondrial dysfunction do not report either effect; the References mention a study of mitochondria-associated membranes, but that does not establish mitochondrial dysfunction in this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIncreased lipid droplet accumulation in ApoE4-expressing astrocytes has been thought to result from dysregulation of lipid homeostasis in neuroinflammation.
“Increased LD accumulation in ApoE4-expressing astrocytes has been thought to result from the dysregulation of lipid homeostasis in neuroinflammation (20)(21)(22).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [21]
The Results section reports greater lipid-droplet accumulation and altered lipid composition in APOE4-expressing human iPSC-derived astrocytes than in APOE3 counterparts. It does not establish that this occurs in neuroinflammation; the reported interferon-gamma stimulation involved microglia, not astrocytes. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBlocking fatty acid desaturation through inhibition of stearoyl-CoA desaturase 1 or supplementing cells with choline reduces lipid droplet accumulation in APOE4 iPSCs.
“Blocking fatty acid desaturation through inhibition of stearoyl-CoA desaturase 1, an enzyme elevated in Alzheimer's disease patient brains, or supplementing cells with choline reduced LD accumulation in APOE4 iPSCs (Astarita et al., 2011; Sienski et al., 2021).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Sienski et al., 2021
The Results sections on lipid desaturation and choline supplementation report that SCD1 inhibition and CDP-choline treatment each reduced lipid droplet numbers. The experiments used APOE4-expressing human iPSC-derived astrocytes, not undifferentiated APOE4 iPSCs as the claim states. (LLM, conf=0.86)
Experimental — accuracy not yet measuredStudies have shown benefits of dietary choline intake and supplementation on cognitive performance in human individuals and in animal models.
“This finding aligns with studies showing benefits of dietary choline intake and supplementation on cognitive performance in human individuals and in animal models71–78.”
From Single-cell multiregion dissection of Alzheimer’s disease (2024) · cites this paper as [78]
The Discussion (page not provided) reports greater efficacy of choline supplementation in clinical trials involving people with Alzheimer’s disease who carry APOE4; the cited trial’s title identifies cognitive performance as an outcome. The paper’s own Results concern lipid defects in cultured cells, while the animal-related study listed in its References reports improved Alzheimer’s pathology, not cognitive performance. The claim’s animal-cognition component is therefore not supported by our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured
APOE4 promotes the accumulation of unsaturated triglycerides and lipid droplets in iPSC-derived astrocytes.
“Recent in vitro studies discovered that APOE4 promotes the accumulation of unsaturated triglycerides and lipid droplets in iPSC-derived astrocytes10”
From APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes (2022) · cites this paper as [10]
Lipid droplets (LDs) have important roles in ageing and Alzheimer's disease (AD).
“Moreover, LDs—cellular organelles containing lipids such as glycerolipids and cholesterol—were recently found to have important roles in ageing and Alzheimer's disease (AD)10–15.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [12]
Live cell microscopy showed greater lipid droplet accumulation in APOE4/4 iMG compared with isogenic APOE3/3 iMG.
“Live cell microscopy of iMG with a fluorescent dye for neutral lipids (LipidSpot) showed greater LD accumulation in APOE4/4 iMG compared with isogenic APOE3/3 iMG, similar to recent reports in isogenic iMG4 and astrocytes20.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [20]
ApoE4 disrupts intracellular lipid homeostasis.
“ApoE4 disrupts intracellular lipid homeostais [50]”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [50]
E4-expressing astrocytes and E4 microglia accumulate more lipid droplets than E3-expressing cells.
“E4 expressing astrocytes (Windham et al., 2024; Farmer et al., 2019; Sienski et al., 2021) and E4 microglia (Machlovi et al., 2022; Victor et al., 2022; Haney et al., 2024) both accumulate more lipid droplets than neutral AD-risk ε3/ε3 (E3) expressing cells.”
From APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses (2025) · cites this paper as Sienski et al., 2021
Previous work has identified that the APOE genotype correlates with changes in fatty acid saturation in whole cell lipidomics measurements.
“Previous work has identified that the APOE genotype correlates with changes in fatty acid saturation in whole cell lipidomics measurements16,24,30.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [24]
Astrocytic lipid droplets accumulate in an APOE genotype-dependent manner.
“Astrocytic lipid droplets also accumulate in an APOE genotype-dependent manner.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [24]
Studies in various model systems have linked APOE4 with increased astrocytic lipid droplets.
“studies in various model systems have linked APOE4 with increased astrocytic lipid droplets15,16,20,24.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [24]
APOE4 astrocytes accumulate unsaturated triglycerides in lipid droplets in both mouse and human iPSC-derived astrocytes.
“APOE4 astrocytes accumulate unsaturated triglycerides in lipid droplets in both mouse15,16 and human iPSC-derived astrocytes24,30.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [24]
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“The normalized (FPKM) gene count matrix is reported in Supplementary Table 10.”
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“Right, unnormalized mean gene expression (counts) of different gene modules (81, 45, 47, 27) in affected and unaffected supertypes (Top).”
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Self-citationEffects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice
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“Interestingly, supplementation with choline, a precursor of PC, restores APOE4-induced lipid defects and highlights the therapeutical potential of dietary interventions targeting lipid metabolism [72].”
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PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia
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Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4
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Self-citationAlzheimer’s disease pathogenesis: standing at the crossroad of lipid metabolism and immune response
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Astrocyte in Neurological Disease: Pathogenesis and Therapy
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Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity
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Leisure Activities, APOE ε4, and Cognitive Decline: A Longitudinal Cohort Study
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Mechanistic insights into the role of herpes simplex virus 1 in Alzheimer’s disease
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Intracellular Cholesterol TraffickingPreprint
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The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases
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Mechanistic Insights into Selective Autophagy Subtypes in Alzheimer’s Disease
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A Dichotomous Role for FABP7 in Sleep and Alzheimer’s Disease Pathogenesis: A Hypothesis
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Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline
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- Authors
- Sienski, G., Narayan, P., Bonner, J. M., Kory, N., Boland, S., Arczewska, A. A., Ralvenius, W. T., Akay, L., Lockshin, E., He, L., Milo, B., Graziosi, A., Baru, V., Lewis, C. A., Kellis, M., Sabatini, D. M., Tsai, L.-H., & Lindquist, S.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- National Institutes of Health (US)
- Harvard University (US)
- Massachusetts Institute of Technology (US)
- Duke University (US)
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sienski, Grzegorz
- Narayan, Priyanka
- Bonner, Julia Maeve
- Tsai, Li-Huei
- Lindquist, Susan
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2021-03-03
- Volume
- 13
- Issue
- 583
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC8218593
- OpenAlex
- W3135225782
- Cited by
- 336
- References
- 97
- Citations by year
- 2026: 59 · 2025: 80 · 2024: 72 · 2023: 65 · 2022: 42 · 2021: 18
- FWCI
- 30.90
- Type
- journal article
- Language
- en
- Update notices
- correction (2026-01-21)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health
- Howard Hughes Medical Institute
- National Institute of Mental Health
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute
- National Institute of Neurological Disorders and Stroke (ALTF 829-2015, NIH/NIA K99, AG055697-03, R01 CA103866, RF1 AG048029, RF1 AG062377, U01 NS110453, R01 AG062335, R01 AG058002)
- NIH Office of the Director (AG055697-03)
- National Cancer Institute, Cairo University
- National Institute of Development Administration
- Neurodegeneration Consortium
- NIH Clinical Center (R01 CA103866)
- Damon Runyon Cancer Research Foundation
- European Molecular Biology Organization (ALTF 829-2015)
- Helen Hay Whitney Foundation
- Alzheimer’s Association (AARF-19-616816)
- NIH Blueprint for Neuroscience Research (R01 AG062335, R01 AG058002, RF1 AG048029, RF1 AG062377)
- Robert A. and Renee E. Belfer Family Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- APOE ε4, glial cells, induced pluripotent stem cells, phospholipid synthesis, choline supplementation, Alzheimer's disease, lipid metabolism
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Homeostasis, Humans, Neuroglia, Apolipoprotein E3, Apolipoprotein E4, Induced Pluripotent Stem Cells
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