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Disrupted neural activity patterns to novelty and effort in young adult APOE‐e4 carriers performing a subsequent memory task

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Evans, Simon, Dowell, Nicholas G., Tabet, Naji, King, Sarah L., Hutton, Samuel B., Rusted, Jennifer M.·2017·Brain and Behavior
DOI 10.1002/brb3.612PMC PMC5318365
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Abstract

Introduction: The APOE e4 allele has been linked to poorer cognitive aging and enhanced dementia risk. Previous imaging studies have used subsequent memory paradigms to probe hippocampal function in e4 carriers across the age range, and evidence suggests a pattern of hippocampal overactivation in young adult e4 carriers. Methods: In this study, we employed a word‐based subsequent memory task under fMRI; pupillometry data were also acquired as an index of cognitive effort. Participants (26 non‐e4 carriers and 28 e4 carriers) performed an incidental encoding task (presented as word categorization), followed by a surprise old/new recognition task after a 40 minute delay. Results: In e4 carriers only, subsequently remembered words were linked to increased hippocampal activity. Across all participants, increased pupil diameter differentiated subsequently remembered from forgotten words, and neural activity covaried with pupil diameter in cuneus and precuneus. These effects were weaker in e4 carriers, and e4 carriers did not show greater pupil diameter to remembered words. In the recognition phase, genotype status also modulated hippocampal activity: here, however, e4 carriers failed to show the conventional pattern of greater hippocampal activity to novel words. Conclusions: Overall, neural activity changes were unstable in e4 carriers, failed to respond to novelty, and did not link strongly to cognitive effort, as indexed by pupil diameter. This provides further evidence of abnormal hippocampal recruitment in young adult e4 carriers, manifesting as both up and downregulation of neural activity, in the absence of behavioral performance differences.

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  • Young APOE4 carriers or APOE4-knock-in mice with no apparent neurodegenerative pathology show increased brain metabolism and activity.

    “Interestingly, several studies in young APOE4 carriers or in APOE4-knock-in mice with no apparent neurodegenerative pathology, revealed increased brain metabolism and activity (Filippini et al., 2009; Evans et al., 2017; Nuriel et al., 2017; Venzi et al., 2017), indicating that the APOE4 effect on brain energy metabolism may differ depending on the degree of pathology.”

    From APOE genotype-dependent differences in human astrocytic energy metabolism (2025) · cites this paper as Evans et al., 2017

    The Discussion (page unavailable) reports hippocampal overactivation during word encoding in young adult APOE4 carriers, supporting the increased-activity part of the claim. It also reports underactivation during recognition and says the carriers do not show a consistent pattern of overactivity. The paper does not report increased brain metabolism or establish an absence of neurodegenerative pathology in its participants; the mouse studies are attributed to other citations. (LLM, conf=0.88)

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Cited by

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Authors
Evans, S., Dowell, N. G., Tabet, N., King, S. L., Hutton, S. B., & Rusted, J. M.
Affiliations
  • University of Sussex (GB)
  • Brighton and Sussex Medical School (GB)
Corresponding author
Rusted, Jennifer M.
ORCID
Venue
Brain and Behavior
Publisher
Wiley
Published
2017-01-05
Volume
7
Issue
2
Pages
e00612-e00612
ISSN
  • 2157-9032 (ISSN-L)
  • 2162-3279
DOI
10.1002/brb3.612
PMC
PMC5318365
OpenAlex
W2569854115
Cited by
20
References
3
Citations by year
2026: 1 · 2025: 5 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 4
FWCI
1.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain and Behavior (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
Funders
Biotechnology and Biological Sciences Research Council (BB/L009242/1)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
APOE ε4, subsequent memory, incidental encoding, old/new recognition, novelty, cognitive effort, pupil size, precuneus, cuneus, young adults, dementia risk
MeSH terms
Adolescent, Adult, Female, Heterozygote, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Occipital Lobe, Parietal Lobe, Pupil, Recognition, Psychology, Apolipoprotein E4, Young Adult, Functional Neuroimaging

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