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Astrocytic lipidopathy and bioenergetic failure in ApoE4-associated late-onset Alzheimer's disease: A unifying hypothesis

Garrahy, James P·2025·Journal of Alzheimer’s Disease
DOI 10.1177/13872877251350338
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Abstract

Late-onset Alzheimer's disease (LOAD) is traditionally attributed to amyloid-β (Aβ) accumulation and tau pathology as primary drivers of neurodegeneration. However, growing evidence suggests these may be secondary events arising from earlier disturbances in brain metabolism and lipid homeostasis. The ε4 allele of apolipoprotein E (ApoE4) remains the strongest genetic risk factor for LOAD, with carriers exhibiting both increased lifetime risk and earlier age of onset compared to ε2 or ε3 carriers. ApoE4 disrupts lipid metabolism and is associated with increased lipid droplet accumulation within astrocytes, implicating astrocytic lipidopathy in disease pathogenesis. Here, we propose a self-reinforcing pathogenic feedback loop—driven by dysregulated lipid homeostasis, chronic neuroinflammation, impaired glucose-handling, and cerebrovascular dysfunction—that culminates in astrocytic bioenergetic failure. This framework helps explain why ApoE4 carriers reach a critical bioenergetic threshold earlier in life, triggering the clinical onset of LOAD. Targeting astrocytic lipid homeostasis, through interventions such as blood-brain barrier-permeable statins, choline supplementation, or metabolic therapies, may offer novel strategies to delay disease progression or onset. Beyond AD, the framework proposed here, if validated, may have broader implications for unifying the cellular origins of age-related degenerative diseases and cancer through a shared vulnerability to progressive bioenergetic collapse.

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Crossref · 10.1177/13872877251350338

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  • Astrocytes expressing ApoE4 typically have more lipid droplets compared to those expressing ApoE2 or ApoE3.

    “Astrocytes expressing ApoE4 typically have more lipid droplets compared to those expressing ApoE2 or ApoE3 [49][50][51][52][53] .”

    From ApoE4 impairs astrocyte lipid droplet formation via endolysosomal dysfunction (2026) · cites this paper as [53]

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Metadata

Authors
Garrahy, J. P.
Venue
Journal of Alzheimer’s Disease
Publisher
SAGE Publications
Published
2025-06-26
Volume
106
Issue
3
Pages
890-902
ISSN
  • 1387-2877
  • 1875-8908
DOI
10.1177/13872877251350338
Cited by
6
References
18
Language
en
Licence
journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)

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