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APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis

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Farmer, Brandon C., Williams, Holden C., Devanney, Nicholas A., Piron, Margaret A., Nation, Grant K., Carter, David J., Walsh, Adeline E., Khanal, Rebika +14 more·2021·Molecular Neurodegeneration
DOI 10.1186/s13024-021-00483-yPMC PMC8420022

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Abstract

Background: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer’s disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. Methods: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. Results: Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13 C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. Conclusions: Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a ‘Warburg like’ endophenotype that is observable in young females decades prior to clinically manifest AD.

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  • Altered brain metabolism, especially increased aerobic glycolysis and impaired oxygen consumption in the brains of ApoE4 carriers, is suggested by studies from human plasma and humanized mouse models.

    “Altered brain metabolism, especially increased aerobic glycolysis and impaired oxygen consumption in the brains of ApoE4 carriers, is suggested in studies from human plasma and humanized mouse models.2”

    From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [4]

    The Results and Discussion report increased aerobic glycolysis in brains of mice expressing human APOE4, alongside decreased oxygen consumption in E4 astrocytes. In human participants, the paper measured plasma metabolites and whole-body oxygen consumption, not oxygen consumption in carriers’ brains. The claim therefore extends the oxygen-consumption finding beyond the tissue measured. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Previous studies reported altered glucose metabolism, dysregulated lipid homeostasis, and lysosomal/autophagosomal impairments by ApoE4 in various cell types, including neurons and astrocytes.

    “altered glucose metabolism, dysregulated lipid homeostasis, and lysosomal/autophagosomal impairments by ApoE4 in various cell types, including neurons and astrocytes.”

    From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [4]

    The Discussion (page unavailable) reports altered glucose metabolism in APOE4-expressing neurons and astrocytes. The Results section on single-cell sequencing also reports lower expression of mitochondrial beta-oxidation genes in E4 astrocytes, offering limited support for altered lipid metabolism. The passages do not establish dysregulated lipid homeostasis broadly, and a search for lysosomal, autophagosomal, and autophagy impairments found no supporting passage. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • None of the previous studies attempted to provide causality among these pathological features and to restore the defects by ApoE4, especially in human astrocytes.

    “However, none of these studies attempted to provide the causality among these pathological features and to restore the defects by ApoE4, especially in human astrocytes.”

    From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [4]

    The Materials and methods (Cell culture; page unavailable) describe mouse-derived astrocytes expressing human APOE alleles, not human astrocytes. The Results (Stable isotope resolved metabolomics; page unavailable) compare metabolic changes in E3 and E4 mice and astrocytes; the passages do not describe restoring those defects. This supports the characterization of this paper, but it cannot establish the broader claim about what none of the other studies attempted, or which pathological features they investigated for causality. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Pathways 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 [24]

    The Results section (Fig. 1; page unavailable) reports altered oxidative-phosphorylation-related gene expression in brain astrocytes and lower expression of genes related to mitochondrial beta-oxidation in APOE4 mice. It also describes astrocyte-directed glycolysis changes, but reports no significant difference in the glycolysis genes measured in whole-brain tissue (Results, Fig. 2; page unavailable). The evidence is therefore narrower than a claim of altered brain expression profiles across all three pathways and their proteins. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Some studies found that APOE4 reduced glycolysis, whereas others observed a shift from oxidative to glycolytic metabolism in APOE4 cells with higher glycolytic activity in APOE4 than APOE3.

    “Some studies found that APOE4 reduced glycolysis [28,39], whereas others observed a shift from oxidative to glycolytic metabolism in APOE4 cells with higher glycolytic activity in APOE4 than APOE3 [40,41,42].”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [41]

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Authors
Farmer, B. C., Williams, H. C., Devanney, N. A., Piron, M. A., Nation, G. K., Carter, D. J., Walsh, A. E., Khanal, R., Young, L. E. A., Kluemper, J. C., Hernandez, G., Allenger, E. J., Mooney, R., Golden, L. R., Smith, C. T., Brandon, J. A., Gupta, V. A., Kern, P. A., Gentry, M. S., Morganti, J. M., Sun, R. C., & Johnson, L. A.
Affiliations
  • University of Kentucky (US)
  • University of Kentucky HealthCare (US)
Corresponding author
Johnson, Lance A.
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2021-09-06
Volume
16
Issue
1
Pages
62-62
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-021-00483-y
PMC
PMC8420022
OpenAlex
W3196375294
Cited by
87
References
15
Citations by year
2026: 21 · 2025: 14 · 2024: 24 · 2023: 12 · 2022: 13 · 2021: 3
FWCI
7.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging (R01 AG060056, R01 AG062550)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
APOE ε4, Alzheimer's disease, aerobic glycolysis, Warburg effect, cerebral glucose hypometabolism, astrocytes, energy expenditure, oxygen consumption, glucose oxidation, lactate, plasma metabolome, sex differences, metabolic reprogramming, TCA cycle
MeSH terms
Adolescent, Adult, Aerobiosis, Aged, Alzheimer Disease, Animals, Astrocytes, Base Sequence, Brain Chemistry, Cells, Cultured, Energy Metabolism, Female, Glucose, Glycolysis, Humans, Gas Chromatography-Mass Spectrometry, Mice, Transgenic, Middle Aged, Nerve Tissue Proteins, Oxidation-Reduction, Oxidative Phosphorylation, Oxygen Consumption, Sex Characteristics, Early Diagnosis, Mice, Apolipoprotein E4, Metabolomics, Young Adult, Gene Knock-In Techniques, Single-Cell Analysis, Prodromal Symptoms

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