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Cited by 1,613Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsFunctional Brain Connectivity Studies

Distinct patterns of brain activity in young carriers of the APOE -ε4 allele

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Filippini, Nicola, MacIntosh, Bradley J., Hough, Morgan G., Goodwin, Guy M., Frisoni, Giovanni B., Smith, Stephen M., Matthews, Paul M., Beckmann, Christian F. +1 more·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0811879106PMC PMC2678478
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Abstract

The APOE ε4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects. We investigated structural and functional effects of the APOE polymorphism in 18 young healthy APOE ε4-carriers and 18 matched noncarriers (age range: 20–35 years). Brain activity was studied both at rest and during an encoding memory paradigm using blood oxygen level-dependent fMRI. Resting fMRI revealed increased “default mode network” (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) coactivation in ε4-carriers relative to noncarriers. The encoding task produced greater hippocampal activation in ε4-carriers relative to noncarriers. Neither result could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow. The APOE ε4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes.

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Crossref · 10.1073/pnas.0811879106

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  • Previous studies have already linked APOE4 to increased (hyper-)metabolism in young individuals.

    “However, previous studies have already linked APOE4 to increased (hyper-)metabolism in young individuals.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [45]

    The Abstract reports reduced resting glucose metabolism in young and middle-aged APOE ε4 carriers, contrary to the claim of increased metabolism. The paper does find increased BOLD activation in young carriers, but it distinguishes brain activation from glucose metabolism. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Studies in young adults, before the onset of a pathology, showed that APOE4 carriers display hypermetabolism and hyperactivity in distinct brain regions, such as the hippocampus, entorhinal cortex, and cortical regions.

    “Studies in young adults, before the onset of a pathology, showed that APOE4 carriers display hypermetabolism and hyperactivity in distinct brain regions, such as the hippocampus, entorhinal cortex, and cortical regions [44,45,46].”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [45]

    The Abstract and Discussion report increased resting coactivation and greater hippocampal activation during memory encoding in healthy young APOE ε4 carriers, including activity in a network with cortical regions. They do not establish increased entorhinal activation or hypermetabolism: the Abstract instead describes prior reports of reduced resting glucose metabolism, and the Discussion reports no difference in resting brain perfusion between the study groups. Page numbers are unavailable in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Young ApoE4 carriers showed increased brain activity in default network regions, as well as in the hippocampus and the temporal lobe, possibly due to increased aerobic glycolysis.

    “Young ApoE4 carriers showed increased brain activity in default network regions, as well as in the hippocampus and the temporal lobe, possibly due to increased aerobic glycolysis.34”

    From ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes (2023) · cites this paper as [35]

    The Results report greater default-mode-network coactivation in medial temporal, medial-prefrontal, and retrosplenial regions, as well as greater hippocampal activation during memory encoding in young APOE ε4 carriers. They do not establish a separate increase across the temporal lobe or suggest increased aerobic glycolysis as an explanation; the Discussion considers other possible mechanisms. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 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 Filippini et al., 2009

  • Dual regression is a reliable technique which allows for the identification of group differences in the spatial and temporal features of ICNs common to the entire sample.

    “Dual regression is a reliable technique which allows for the identification of group differences in the spatial and temporal features of ICNs common to the entire sample (Filippini et al., 2009; Zuo et al., 2010).”

    From Investigating functional brain network integrity using a traditional and novel categorical scheme for neurodevelopmental disorders (2019) · cites this paper as Filippini et al., 2009

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Authors
Filippini, N., MacIntosh, B. J., Hough, M. G., Goodwin, G. M., Frisoni, G. B., Smith, S. M., Matthews, P. M., Beckmann, C. F., & Mackay, C. E.
Affiliations
  • University of Oxford (GB)
  • University Department of Psychiatry and
  • Centro San Giovanni di Dio Fatebenefratelli (IT)
  • GlaxoSmithKline (United Kingdom) (GB)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-04-28
Volume
106
Issue
17
Pages
7209-7214
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0811879106
PMC
PMC2678478
OpenAlex
W2041325253
Cited by
1,613
References
11
Citations by year
2026: 41 · 2025: 60 · 2024: 48 · 2023: 53 · 2022: 61 · 2021: 82 · 2020: 99 · 2019: 104 · 2018: 110 · 2017: 142 · 2016: 136 · 2015: 160 · 2014: 140 · 2013: 125 · 2012: 110
FWCI
50.83
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor, 183 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • GlaxoSmithKline
  • Wellcome Trust
  • Engineering and Physical Sciences Research Council (EP/D001935/1)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
Keywords
APOE ε4, APOE polymorphism, default mode network, resting-state brain activity, hippocampal activation, memory encoding, neurodegeneration risk
MeSH terms
Adult, Alleles, Brain, Female, Humans, Magnetic Resonance Imaging, Male, Memory, Apolipoprotein E4

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