APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge
Open accessPublished version of a preprint
Abstract
The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses in mice expressing human APOE to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1α expression and a disrupted tricarboxylic acid (TCA) cycle and are inherently pro-glycolytic, while spatial transcriptomics and mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism and provide valuable, interactive resources for discovery and validation research.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
APOE is a lipid transporter expressed in astrocytes and microglia and affects microglial functions including neuroinflammation and phagocytosis.
“APOE is a lipid transporter expressed in astrocytes and microglia and has been shown to affect microglial functions including neuroinflammation and phagocytosis7–9.”
From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [7]
The Results section on APOE expression reports that APOE is predominantly expressed by astrocytes and is also expressed by microglia. The Introduction and Discussion link APOE4 to heightened neuroinflammation and a pro-inflammatory microglial phenotype. The passages found do not show that APOE affects microglial phagocytosis, and they discuss lipid metabolism without explicitly identifying APOE as a lipid transporter. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAPOE4 astrocytes and microglia have increased glycolytic activity when compared with the same cells expressing APOE3.
“APOE4 astrocytes and microglia have increased glycolytic activity when compared with the same cells expressing APOE3 (refs. 175,176).”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [176]
The Results section (‘E4 microglia have increased aerobic glycolysis and higher HIF1α expression’) reports higher basal and compensatory glycolysis in E4 than E3 microglia. But the Results section (‘APOE4 drives immunometabolic changes across the glial transcriptome’) describes E4-associated increases in oxidative phosphorylation and branched-chain amino acid metabolism in astrocytes, not increased astrocyte glycolysis. Page numbers were not provided. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAPOE is a lipid transporter expressed on astrocytes and microglia and affects numerous microglial functions including neuroinflammation and phagocytosis.
“APOE is a lipid transporter expressed on astrocytes and microglia and has been shown to affect numerous microglial functions including neuroinflammation and phagocytosis8–10.”
From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [8]
The Results section on APOE expression reports that APOE is predominantly expressed by astrocytes and is also expressed by microglia. The Results and Discussion link APOE4 to changes in microglial immune responses and a pro-inflammatory phenotype. The Discussion mentions phagocytosis as a trigger for a microglial state, but does not show that APOE affects phagocytosis; the searched passages also do not explicitly call APOE a lipid transporter. No page numbers were available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredE4 is associated with dysregulated immuno-metabolic function in microglia compared to E3 and E2.
“in which E4 is associated with an impaired phagocytic response and dysregulated immuno-metabolic function compared to E3 and E2 microglia”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Lee et al., 2023
The Results section (“E4 microglia have increased aerobic glycolysis and higher HIF1α expression”; page unavailable) reports altered metabolism in E4 microglia compared with E3, supporting the immunometabolic part of the claim. The passages found do not establish the same comparison with E2 microglia. (LLM, conf=0.87)
Experimental — accuracy not yet measuredE4 is associated with an impaired phagocytic response in microglia compared to E3 and E2.
“in which E4 is associated with an impaired phagocytic response and dysregulated immuno-metabolic function compared to E3 and E2 microglia”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Lee et al., 2023
The Discussion ('A single-cell view of APOE immunometabolism'; page unavailable) reports lower expression of some phagocytic genes in young E4 microglia relative to E3, but it does not establish an impaired phagocytic response. The Results ('E4 microglia have increased aerobic glycolysis and higher HIF1α expression'; page unavailable) support altered immunometabolism relative to E3. The cited passages do not support the comparison with E2. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Prior lipidomic, metabolomic, and magnetic resonance spectroscopy studies in mouse models show that APOE genetic variation modifies brain metabolite levels.
“Prior lipidomic, metabolomic, and magnetic resonance spectroscopy (MRS) studies in mouse models show that genetic variation in APOE modify brain metabolite levels [20][21][22][23] .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [22]
The Results section on MALDI mass spectrometry imaging reports APOE-associated changes in lipid concentrations across mouse brain regions, and the microglia Results section reports APOE-dependent metabolite differences. These findings support the lipidomic and metabolomic parts of the sentence, but our copy does not report magnetic resonance spectroscopy findings. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPathways and proteins associated with oxidative phosphorylation, glycolysis, and lipid metabolism have altered brain expression profiles in APOE4 humanized mice.
“Pathways and proteins associated with oxidative phosphorylation, glycolysis, and lipid metabolism demonstrate altered brain expression profiles in APOE4 humanized mice 21,22,24 .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [22]
The Results section on the glial transcriptome reports altered expression of oxidative-phosphorylation and glycolysis pathways in brains of mice expressing human APOE4; the lipid-metabolism Results and Discussion sections also describe APOE4-associated changes. The cited passages establish gene-expression and lipid changes, but not altered expression profiles of the associated proteins. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMicroglia from APOE4 mouse models, as well as human microglia from post-mortem brain tissue in AD and APOE4 carriers, exhibit lipid dysregulation and upregulation of neutral lipid storage.
“Microglia from APOE4 mouse models, as well as human microglia from post-mortem brain tissue in AD and APOE4 carriers, exhibit lipid dysregulation and upregulation of neutral lipid storage17,27–29.”
From APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics (2026) · cites this paper as [29]
The Results section on MALDI MSI reports altered lipid metabolism in APOE4 mouse brains, with changes most pronounced in microglia at the single-cell level. The Discussion’s spatial-view section also reports lipid changes in post-mortem human AD brain and notes an association between APOE4 and lipid-droplet accumulation. It does not establish increased neutral-lipid storage specifically in microglia isolated from post-mortem human AD brains or APOE4 carriers. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia exhibit distinct APOE-genotype dependent transcriptional diversity.
“They also exhibit distinct APOE-genotype dependent transcriptional diversity”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Lee et al., 2023
Microglia from LPS-treated mice exhibit distinct APOE genotype-dependent metabolic profiles.
“Moreover, microglia from LPS-treated mice exhibit distinct APOE genotype–dependent metabolic profiles”
From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Lee et al., 2023
Microglia and astrocytes have APOE genotype-dependent immune and inflammatory metabolic changes.
“Additionally, microglia and astrocytes, which have been extensively studied in vivo, have APOE genotype dependent immune and inflammatory metabolic changes 22,25,26 .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [22]
Cass4 is predominantly expressed by microglia in the brain.
“As previously reported, we found that Cass4 is predominantly expressed by microglia in the brain (Fig. S1 G; Lee et al., 2023; Podlesny-Drabiniok et al., 2020).”
From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Lee et al., 2023
The Results passages describe APOE expression and microglial gene-expression patterns, but do not address Cass4. A search of our copy for “Cass4” and for predominant expression in microglia found no passage establishing which brain cell type predominantly expresses Cass4. (LLM, conf=0.74)
Experimental — accuracy not yet measuredCass4 appears to be expressed only by microglia among brain-resident cell types.
“Of the brain-resident cell types, Cass4 appears to be ex pressed only by microglia (Lee et al., 2023; Podlesny-Drabiniok et al., 2020; Zhang et al., 2014).”
From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Lee et al., 2023
The Methods section lists cell-type markers, and the Results discuss microglial gene-expression patterns, but neither identifies Cass4 as microglia-specific. Searches for “Cass4” and for its expression across brain-resident cell types found no passage addressing the claim in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measuredAPOE4 drives Aβ- and tau-mediated neurodegeneration by inducing microglial and astrocytic activation.
“Studies have demonstrated that APOE4 drives Aβ- and tau-mediated neurodegeneration by inducing microglial and astrocytic activation.174–179”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [179]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 125 · Cited by 203
- Authors
- Lee, S., Devanney, N. A., Golden, L. R., Smith, C. T., Schwartz, J. L., Walsh, A. E., Clarke, H. A., Goulding, D. S., Allenger, E. J., Morillo-Segovia, G., Friday, C. M., Gorman, A. A., Hawkinson, T. R., MacLean, S. M., Williams, H. C., Sun, R. C., Morganti, J. M., & Johnson, L. A.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Morganti, Josh M.
- Johnson, Lance A.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 42
- Issue
- 3
- Pages
- 112196
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC10117631
- OpenAlex
- W4323037201
- Cited by
- 203
- References
- 125
- Citations by year
- 2026: 56 · 2025: 66 · 2024: 64 · 2023: 16 · 2022: 1
- FWCI
- 21.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Cancer Society (16-182-28)
- Cure Alzheimer's Fund
- National Institute on Aging (R01AG062550-03S1, T32GM118292, T32AG057461, F31AG076282, RF1NS118558, R01AG060056, R01AG066653, R01AG080589, R01AG070830)
- Alzheimer's Association
- St. Baldrick's Foundation
- National Cancer Institute (P30 CA177558)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- APOE ε4, microglia, immunometabolism, neuroinflammation, Alzheimer's disease, amyloid pathology, aging, HIF-1α, TCA cycle, glycolysis, lipid metabolism, single-cell transcriptomics, spatial transcriptomics, mass spectrometry imaging, humanized mice
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain, Humans, Mice, Transgenic, Neuroglia, Amyloid beta-Peptides, Microglia, Mice, Apolipoprotein E3, Apolipoprotein E4, Amyloidogenic Proteins
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
