APOE ε4 associates with microglial activation independently of Aβ plaques and tau tangles
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Animal studies suggest that the apolipoprotein E ε4 ( APOE ε4) allele is a culprit of early microglial activation in Alzheimer’s disease (AD). Here, we tested the association between APOE ε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [ 18 F]AZD4694), tau ([ 18 F]MK6240), and microglial activation ([ 11 C]PBR28). We found that APOE ε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOE ε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOE ε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOE ε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.
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Using 11C-PBR28, Ferrari-Souza et al. found that APOE ε4 carriers present with increased microglial activation early in AD and independent of amyloid.
“Using 11C-PBR28 Ferrari-Souza et al. found that APOE ε4 carriers present with increased microglial activation early in AD and independent of amyloid [226].”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [226]
APOE4 drives Aβ- and tau-mediated neurodegeneration by inducing microglial and astrocytic activation.
“Studies have demonstrated that APOE4 drives Aβ- and tau-mediated neurodegeneration by inducing microglial and astrocytic activation.174–179”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [178]
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- Authors
- Ferrari-Souza, J. P., Lussier, F. Z., Leffa, D. T., Therriault, J., Tissot, C., Bellaver, B., Ferreira, P. C. L., Malpetti, M., Wang, Y.-T., Povala, G., Benedet, A. L., Ashton, N. J., Chamoun, M., Servaes, S., Bezgin, G., Kang, M. S., Stevenson, J., Rahmouni, N., Pallen, V., Poltronetti, N. M., O’Brien, J. T., Rowe, J. B., Cohen, A. D., Lopez, O. L., Tudorascu, D. L., Karikari, T. K., Klunk, W. E., Villemagne, V. L., Soucy, J.-P., Gauthier, S., Souza, D. O., Zetterberg, H., Blennow, K., Zimmer, E. R., Rosa-Neto, P., & Pascoal, T. A.
- Affiliations
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
- University of Pittsburgh (US)
- Centre intégré universitaire de santé et de services sociaux de l'Ouest-de-l’Île-de-Montréal (CA)
- Universidade Federal do Rio Grande do Sul (BR)
- University of Cambridge (GB)
- King's College London (GB)
- University of Toronto (CA)
- Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, UK.
- MRC Cognition and Brain Sciences Unit (GB)
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
- McGill University (CA)
- Sahlgrenska University Hospital (SE)
- Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal; Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
- Corresponding author
- Lussier, Firoza Z.
- Pascoal, Tharick A.
- ORCID
- Ferrari-Souza, João Pedro
- Lussier, Firoza Z.
- Leffa, Douglas T.
- Therriault, Joseph
- Tissot, Cécile
- Bellaver, Bruna
- Ferreira, Pâmela C. L.
- Malpetti, Maura
- Povala, Guilherme
- Benedet, Andréa L.
- Ashton, Nicholas J.
- Chamoun, Mira
- Servaes, Stijn
- Bezgin, Gleb
- Kang, Min Su
- Stevenson, Jenna
- Rahmouni, Nesrine
- O’Brien, John T.
- Rowe, James B.
- Cohen, Ann D.
- Lopez, Oscar L.
- Tudorascu, Dana L.
- Karikari, Thomas K.
- Klunk, William E.
- Villemagne, Victor L.
- Soucy, Jean-Paul
- Gauthier, Serge
- Souza, Diogo O.
- Zetterberg, Henrik
- Blennow, Kaj
- Zimmer, Eduardo R.
- Rosa-Neto, Pedro
- Pascoal, Tharick A.
- Venue
- Science Advances
- Published
- 2023-04-07
- Volume
- 9
- Issue
- 14
- Pages
- eade1474-eade1474
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC10075966
- OpenAlex
- W4362638452
- Cited by
- 81
- References
- 79
- Citations by year
- 2026: 15 · 2025: 25 · 2024: 26 · 2023: 14 · 2021: 1
- FWCI
- 14.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion, cc-by-nc)
- Apollo (University of Cambridge) (submittedVersion, cc-by-nc)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Apollo
- Funders
- Alzheimer's Association (NIRP-12-259245, AARGD-21-850670, #NIRG‐12‐92090, ALZ-NAN-22-928381, 34874, 33397, AACSF-20-648075, Serra-1912-31365)
- McGill University (162303, MOP-11-51-31, RFN 152985, 159815)
- Fondation Brain Canada (2020-VICO-279314, 34874, 33397)
- Weston Brain Institute
- National Institute for Health and Care Research ([IS-BRC-1215-20014, BRC1215-20014)
- Department of Health and Social Care
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (409066/2022-2, 312306/2021-0, 435642/2018- 9, 465671/2014‐4, 312410/2018‐2, 21/2551-0000673-0, 2014-4, 166407/2020-8)
- Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (2014-4, 21/2551- 0000673-0)
- Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção (# 465671/2014-4)
- Instituto Serrapilheira (Serra‐1912‐31365)
- National Institutes of Health
- Canadian Institutes of Health Research (#MOP-11-51-31, 152985, 159815, RFN 152,985, 162303, 92090)
- Medical Research Council (SUAG/092 116768, BRC-1215-20014)
- NIHR Cambridge Biomedical Research Centre ((BRC-1215-20014))
- National Institute on Aging (R01AG073267, R01AG075336)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, microglial activation, Alzheimer's disease, amyloid plaques, tau tangles, neuroinflammation, Braak stages, medial temporal cortex, neurodegeneration, genetic risk
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Brain, Temporal Lobe, Amyloid beta-Peptides, tau Proteins, Microglia, Positron-Emission Tomography, Apolipoprotein E4, Plaque, Amyloid
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