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Distinct patterns of brain activity in young carriers of the APOE -ε4 allele
Open accessAbstract
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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“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]
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“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]
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“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]
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“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
In the citing paper
“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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“Healthy young and middle-aged adult apoE4 carriers show increased DMN activation at rest [179]”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [179]
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“and increased hippocampal activation during encoding task performance [179–181]”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [179]
In the citing paper
“Network hyperactivity is an overarching symptom of AD and is evident in human apoE4 carriers.”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [179]
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Magnetic vestibular stimulation modulates default mode network fluctuations
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Progression of brain functional connectivity and frontal cognitive dysfunction in ALS
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Extracting Reproducible Time-Resolved Resting State Networks Using Dynamic Mode Decomposition
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Metadata
- 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
- PMC
- PMC2678478
- OpenAlex
- W2041325253
- Cited by
- 1,613
- References
- 60
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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