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Cited by 25Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Fueling the brain - the role of apolipoprotein E in brain energy metabolism and its implications for Alzheimer's disease

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Budny, Vanessa, Ruminot, Iván, Wybitul, Maha, Treyer, Valerie, Barros, L. Felipe, Tackenberg, Christian·2025·Translational Psychiatry
DOI 10.1038/s41398-025-03550-wPMC PMC12379154
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Abstract

The human brain has high energy demands and tightly regulated mechanisms ensure its activity-dependent energy supply. Glucose hypometabolism is associated with brain aging and has also been linked to neurodegenerative diseases such as Alzheimer's disease (AD). The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for AD while APOE2 reduces the risk and APOE3 has been referred to as risk neutral allele. APOE is a major lipid carrier in the brain and is not only involved in the build-up of the two AD hallmark pathologies, β-amyloid (Aβ) plaques and neurofibrillary tangles, but also in several other (patho-)physiological processes including immune response, neuronal growth, synaptic plasticity and energy metabolism. Although there has been recent progress in understanding APOE biology, the exact mechanisms of how APOE (especially APOE4) affects brain energy metabolism are still largely unclear. This review highlights the recent evidence of how APOE isoforms differentially affect the bioenergetic homeostasis of the brain, thereby affecting AD etiology and pathophysiology, and identifies critical questions and emerging topics that require further investigation.

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  • Prior work shows that E4 impairs microglial metabolism/immune reactivity and can exaggerate cytokine reactivity to LPS.

    “Prior work shows that E4 impairs microglial metabolism/immune reactivity and can exaggerate cytokine reactivity to LPS”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Budny et al., 2025

    The APOE section (page unavailable) says that APOE is involved in immune response and is produced to some extent by microglia, but does not describe E4 impairing microglial metabolism or immune reactivity. Searches for microglia, LPS, lipopolysaccharide, and cytokine reactivity found no passage in our copy reporting an exaggerated cytokine response to LPS. (LLM, conf=0.76)

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Cited by

Sorted by citations

Authors
Budny, V., Ruminot, I., Wybitul, M., Treyer, V., Barros, L. F., & Tackenberg, C.
Affiliations
  • University of Zurich (CH)
  • Universidad San Sebastián (CL)
Corresponding author
Tackenberg, Christian
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2025-08-25
Volume
15
Issue
1
Pages
316-316
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-025-03550-w
PMC
PMC12379154
OpenAlex
W4413552555
Cited by
25
References
23
Citations by year
2026: 23 · 2025: 2
FWCI
2.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-nd)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc-nd)
  • ETH Zürich Research Collection
Funders
Hartmann Müller-Stiftung für Medizinische Forschung
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 › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, APOE ε4, brain energy metabolism, Alzheimer's disease, glucose hypometabolism, APOE isoforms, APOE2, APOE3, neurodegeneration, amyloid plaques, neurofibrillary tangles, brain bioenergetics, genetic risk factors
MeSH terms
Alzheimer Disease, Apolipoproteins E, Brain, Energy Metabolism, Humans, Apolipoprotein E4

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