The cell biology of APOE in the brain
Open accessAbstract
Apolipoprotein E (APOE) traffics lipids in the central nervous system. The E4 variant of APOE is a major genetic risk factor for Alzheimer's disease (AD) and a multitude of other neurodegenerative diseases, yet the molecular mechanisms by which APOE4 drives disease are still unclear. A growing collection of studies in iPSC models, knock-in mice, and human postmortem brain tissue have demonstrated that APOE4 expression in astrocytes and microglia is associated with the accumulation of cytoplasmic lipid droplets, defects in endolysosomal trafficking, impaired mitochondrial metabolism, upregulation of innate immune pathways, and a transition into a reactive state. In this review, we collate these developments and suggest testable mechanistic hypotheses that could explain common APOE4 phenotypes.
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ApoE has been implicated in various cellular pathways linked to AD pathogenesis, including amyloid-β (Aβ) clearance and aggregation, tau pathology, metabolism, endolysosomal trafficking, and neuroinflammation.
“Apolipoprotein E (ApoE) has been implicated in various cellular pathways linked to AD pathogenesis, including amyloid-β (Aβ) clearance and aggregation, tau pathology, metabolism, endolysosomal trafficking, and neuroinflammation1–3.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [3]
Column-purified recombinant ApoE is invariably prepared as apoprotein.
“Mammalian expression systems retain physiologically relevant secretory, folding and post-translational modification mechanisms, but column-purified recombinant ApoE is invariably prepared as apoprotein.22–25”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [22]
Mammalian expression systems retain physiologically relevant secretory, folding and post-translational modification mechanisms.
“Mammalian expression systems retain physiologically relevant secretory, folding and post-translational modification mechanisms, but column-purified recombinant ApoE is invariably prepared as apoprotein.22–25”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [22]
Secreted ApoE is generally presumed to be converted into HDL-like LNPs by astrocytes.
“As the major lipid carrier in the brain, secreted ApoE is generally presumed to be converted into HDL-like LNPs by astrocytes.”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [22]
These LNPs undergo receptor-mediated endocytosis in neurons and glia cells where their lipid constituents are disassembled in lysosomes to supply these constituents to recipient cells.
“In turn, these LNPs undergo receptor-mediated endocytosis in neurons and glia cells where their lipid constituents are disassembled in lysosomes to supply these constituents to the recipient cells.22, 44–47”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [22]
To date all reports describing the biochemical properties of this recombinant protein have deployed lipid-free biosynthetic materials.
“Although ApoE is not detected in appreciable quantities in its apo form in physiological fluids, to date all reports describing the biochemical properties of this recombinant protein have deployed lipid-free biosynthetic materials.21–25”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [22]
ApoE is not detected in appreciable quantities in its apo form in physiological fluids.
“Although ApoE is not detected in appreciable quantities in its apo form in physiological fluids, to date all reports describing the biochemical properties of this recombinant protein have deployed lipid-free biosynthetic materials.21–25”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [22]
Nascent APOE lipoproteins are assembled in the lumen of the ER prior to secretion.
“Nascent APOE lipoproteins are assembled in the lumen of endoplasmic reticulum (ER) prior to secretion, although the mechanism for this stage of biogenesis is unknown (Windham and Cohen, 2023).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Windham and Cohen, 2023
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Ferrari-Souza, J. P., Lussier, F. Z., Leffa, D. T., Therriault, J., Tissot, C., Bellaver, B., Ferreira, P. C. L., Malpetti, M., Wang, Y.-T., Povala, G., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade1474 · Cited by 81 · see citing works
PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4
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APOE4 confers transcriptomic and functional alterations to primary mouse microglia
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LCAT synthesized by primary astrocytes esterifies cholesterol on glia-derived lipoproteins
Hirsch‐Reinshagen, V., Donkin, J. J., Stukas, S. K., Chan, J., Wilkinson, A., Fan, J., Parks, J. S., Kuivenhoven, J. A., ̈tjohann, D. L., Pritchard, H., et al. (2008) · Journal of Lipid Research · doi:10.1194/jlr.m800584-jlr200 · Cited by 72 · see citing works
Common human genetic variants of APOE impact murine COVID-19 mortality
Ostendorf, B. N., Patel, M. A., Bilanovic, J., Hoffmann, H.-H., Carrasco, S. E., Rice, C. M., & Tavazoie, S. F. (2022) · Nature · doi:10.1038/s41586-022-05344-2 · Cited by 65 · see citing works
Hamilton, L. K., Moquin‐Beaudry, G., Mangahas, C. L., Pratesi, F., Aubin, M., Aumont, A., Joppé, S. E., Légiot, A., Vachon, A., Plourde, M., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29506-y · Cited by 62 · see citing works
NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
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Henry, N., Krammer, E., Stengel, F., Adams, Q., Liefferinge, F. V., Hubin, E., Chaves, R. C., Efremov, R. G., Aebersold, R. H., Vandenbussche, G., et al. (2018) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1006165 · Cited by 41 · see citing works
APOE expression and secretion are modulated by mitochondrial dysfunction
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APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size
Windham, I. A., Powers, A. E., Ragusa, J. V., Wallace, E. D., Zanellati, M. C., Williams, V. H., Wagner, C. H., White, K. K., & Cohen, S. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202305003 · Cited by 96 · see citing works
Self-citationGuo, J. L., Braun, D., Fitzgerald, G. A., Hsieh, Y.-T., Rougé, L., Litvinchuk, A., Steffek, M., Propson, N. E., Heffner, C. M., Discenza, C., et al. (2025) · Cell · doi:10.1016/j.cell.2024.10.027 · Cited by 91 · see citing works
Protective ApoE variants support neuronal function by effluxing oxidized phospholipids
Ralhan, I., Do, A. D., Bae, J.-Y., Feringa, F. M., Cai, W., Chang, J., Chik, K., Lee, N. Y. J., Gerry, C. J., van der Kant, R., et al. (2026) · Neuron · doi:10.1016/j.neuron.2025.10.040 · Cited by 23 · see citing works
Protective ApoE variants support neuronal function by extracting peroxidated lipids
Ralhan, I., Do, A. D., Bae, J.-Y., Feringa, F. M., Cai, W., Chang, J., Chik, K., Lee, N. Y., Gerry, C., van der Kant, R., et al. (2025) · bioRxiv · doi:10.1101/2025.03.05.641722 · Cited by 4 · see citing works
ApoE expression across the CNS: Who, What, Where, When, and How (much)?
Nolt, G. L., Lucido, C. C., Smith, L. M., & Johnson, L. A. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00028-x · Cited by 2 · see citing works
Hernandez Arriaza, R., Reil, D., Fatuzzo, N., Fu, M., Dai, Y., Fernandez Martinez, D., Jiang, H., Holtzman, D. M., Greicius, M. D., & Khosla, C. (2025) · Biochemistry · doi:10.1021/acs.biochem.5c00503 · Cited by 2 · see citing works
- Authors
- Windham, I. A., & Cohen, S.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Cohen, Sarah
- Venue
- Trends in Cell Biology
- Publisher
- Elsevier BV
- Published
- 2024-04
- Volume
- 34
- Issue
- 4
- Pages
- 338-348
- ISSN
- 0962-8924 (ISSN-L)
- PMC
- PMC10995109
- OpenAlex
- W4387375802
- Cited by
- 103
- References
- 89
- Citations by year
- 2026: 40 · 2025: 54 · 2024: 7 · 2023: 2
- FWCI
- 5.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Trends in Cell Biology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (F31 AG069419, R01 AG081421)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- apolipoprotein E, APOE ε4, Alzheimer's disease, lipid trafficking, astrocytes, microglia, lipid droplets, endolysosomal trafficking, mitochondrial metabolism, innate immunity, neuroinflammation, neurodegeneration, iPSC models, knock-in mice
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Brain, Humans, Neurodegenerative Diseases, Mice, Apolipoprotein E4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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