. Apolipoprotein E4 and Insulin Resistance Interact to Impair Cognition and Alter the Epigenome and Metabolome. Sci Rep. 2017 Mar 8;7:43701. PubMed.


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  1. In the report by Johnson et al., the findings that lifestyle exposures leading to obesity, diabetes mellitus, and peripheral insulin resistance can interact with the ApoE4 genotype to exacerbate impairments in hippocampal function, and are associated with major alterations in metabolomics, are of interest and importance with regard to the increased risk of developing AD among individuals with ApoE3/E4 or ApoE4/E4 genotypes. One of the puzzling aspects about the heightened risk for developing AD in ApoE4+ individuals is why cognitive impairment and AD develop only later in life such that the incidence increases by age. The same question could be asked about sporadic AD (which accounts for most cases) since it is also linked to aging. Perhaps the answer lies in the facts that: 1) insulin resistance increases with age; 2) epidemiological and clinical data have convincingly shown that peripheral insulin resistance diseases increase risk for AD; and 3) human brain studies have documented AD-associated impairments in brain insulin and IGF signaling that worsen with severity of neurodegeneration. Johnson et al. illustrate that ApoE4 may increase risk for cognitive impairment due to multipronged dysregulation of energy metabolism mediated by differential 5’hydroxymethylation of DNA in the hippocampus. The reversibility of obesity, glucose intolerance, cognitive impairment, and DNA hydroxymethylation following rescue with a low-fat diet in the previously high-fat-diet fed (20 weeks) ApoE4 mice is particularly intriguing. The data suggest that mindful lifestyle measures may protect ApoE4 carriers from late onset MCI and AD.

    A significant limitation of this paper is the absence of correlative histopathology demonstrating ApoE4/insulin resistance effects on Aβ, phospho-tau, and neurodegeneration in the temporal lobe. In ApoE4+ humans, Aβ deposition in plaques is quite abundant when cognitive impairment is manifested. Caution is also needed with respect to the generalizable nature of the concepts expressed since the genetic background of the ApoE mice was C57BL/6. The C57BL/6 strain is highly susceptible to diet-induced obesity (especially visceral) mediated insulin resistance, systemic inflammation, metabolic syndrome, glucose intolerance, and cognitive impairment. Reproducing the observed effects in another mouse strain would help determine if the findings have broad-ranging significance.

    View all comments by Suzanne de la Monte

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  1. Do ApoE4 and Diabetes Conspire to Spur Cognitive Decline?