APOE and metabolic dysfunction in Alzheimer's disease
Abstract
The strongest genetic risk factor for sporadic Alzheimer's disease (AD) is carriage of the E4 allele of APOE. Metabolic dysfunction also increases risk of dementia and AD. Facing a need for effective therapies and an aging global population, studies aimed at uncovering new therapeutic targets for AD have become critical. Insight into the biology underlying the effects of E4 and metabolic impairment on the brain may lead to novel therapies to reduce AD risk. An understudied hallmark of both AD patients and E4 individuals is a common metabolic impairment-cerebral glucose hypometabolism. This is a robust and replicated finding in humans, and begins decades prior to cognitive decline. Possession of E4 also appears to alter several other aspects of cerebral glucose metabolism, fatty acid metabolism, and management of oxidative stress through the pentose phosphate pathway. A critical knowledge gap in AD is the mechanism by which APOE alters cerebral metabolism and clarification as to its relevance to AD risk. Facing a need for effective therapies, studies aimed at uncovering new therapeutic targets have become critical. One such approach is to gain a better understanding of the metabolic mechanisms that may underlie E4-associated cognitive dysfunction and AD risk.
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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 [2]
Proteomics of AD brains revealed strong upregulation of glial proteins associated with glucose metabolism.
“Proteomics of AD brains revealed strong upregulation of glial proteins associated with glucose metabolism.30”
From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [30]
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- Authors
- Johnson, L. A.
- Affiliations
- University of Kentucky HealthCare (US)
- Corresponding author
- Lance A. Johnson
- ORCID
- Lance A. Johnson
- Venue
- International Review of Neurobiology
- Publisher
- Elsevier
- Published
- 2020
- Volume
- 154
- Pages
- 131-151
- ISSN
- 0074-7742 (ISSN-L)
- OpenAlex
- W3041498416
- Cited by
- 31
- References
- 10
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 6 · 2022: 7 · 2021: 2
- FWCI
- 15.50
- Type
- book chapter
- Language
- en
- Open access
- closed
- Locations
- International review of neurobiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG062550)
- 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
- apolipoprotein E, APOE ε4, Alzheimer's disease, cerebral glucose hypometabolism, brain glucose metabolism, fatty acid metabolism, oxidative stress, pentose phosphate pathway, metabolic dysfunction, dementia risk, therapeutic target
- MeSH terms
- Alzheimer Disease, Brain Diseases, Metabolic, Fatty Acids, Humans, Pentose Phosphate Pathway, Apolipoprotein E4, Cognitive Dysfunction
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