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Cited by 103Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeurological Disease Mechanisms and Treatments

Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome

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Johnson, Lance A., Torres, Eileen Ruth S., Impey, Soren, Stevens, Jan F., Raber, Jacob·2017·Scientific Reports
DOI 10.1038/srep43701PMC PMC5341123
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Abstract

Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer’s disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in hippocampal-dependent spatial learning and memory were exaggerated in E4 mice. Combining genome-wide measures of DNA hydroxymethylation with comprehensive untargeted metabolomics, we identified novel alterations in purine metabolism, glutamate metabolism, and the pentose phosphate pathway. Finally, in E4 mice, the metabolic and cognitive deficiencies caused by HFD were rescued by switching to a low fat diet for one month, suggesting a functional role was associated with reversal of the same metabolic pathways described above. These results suggest a susceptibility of E4 carriers to metabolic impairments brought on by IR, and may guide development of novel therapies for cognitive decline and dementia.

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  • APOE4 expression causes reduced cerebral blood volume and cognitive function in response to a high fat diet.

    “reduced cerebral blood volume and cognitive function in response to a high fat diet (HFD)21,22”

    From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [22]

    The Results (page unavailable) report that high-fat-diet-induced deficits in spatial learning and memory were more pronounced in E4 mice than E3 mice. The paper does not report reduced cerebral blood volume in response to the diet; its Discussion raises vascular dysfunction only as a possibility. (LLM, conf=0.88)

    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 [20]

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Cited by

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Authors
Johnson, L. A., Torres, E. R. S., Impey, S., Stevens, J. F., & Raber, J.
Affiliations
  • Oregon Health & Science University (US)
  • Oregon State University (US)
Corresponding author
Raber, Jacob
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-03-08
Volume
7
Issue
1
Pages
43701-43701
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep43701
PMC
PMC5341123
OpenAlex
W2592011417
Cited by
103
References
6
Citations by year
2026: 11 · 2025: 11 · 2024: 11 · 2023: 13 · 2022: 9 · 2021: 13 · 2020: 11 · 2019: 10 · 2018: 11 · 2017: 3
FWCI
7.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion, cc-by)
Funders
  • National Science Foundation (1408653, ES07060)
  • Collins Medical Trust
  • Oregon Health and Science University
  • National Institutes of Health
  • National Institute on Aging (R21AG043857)
  • National Heart, Lung, and Blood Institute (T32HL094294)
  • National Institute on Drug Abuse (T32DA007262)
  • National Institute of Environmental Health Sciences (ES-07060, P30ES000210, T32ES007060)
  • National Center for Research Resources (S10RR027878)
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 › Neurological Disease Mechanisms and Treatments
Keywords
APOE ε4, insulin resistance, cognitive decline, Alzheimer's disease, type 2 diabetes, high-fat diet, DNA hydroxymethylation, epigenome, untargeted metabolomics, purine metabolism, glutamate metabolism, pentose phosphate pathway, low-fat diet, brain metabolism, APOE isoforms
MeSH terms
Animals, Body Weight, Disease Susceptibility, Genotype, Hippocampus, Insulin Resistance, Models, Biological, Glucose Intolerance, DNA Methylation, Epigenesis, Genetic, Mice, Apolipoprotein E4, Metabolic Networks and Pathways, Metabolome, Diet, High-Fat, Cognitive Dysfunction, Spatial Memory, Spatial Learning

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