Ferrari-Souza, JP;
Lussier, FZ;
Leffa, DT;
Therriault, J;
Tissot, C;
Bellaver, B;
Ferreira, PCL;
... Pascoal, TA; + view all
(2023)
APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles.
Science Advances
, 9
(14)
, Article eade1474. 10.1126/sciadv.ade1474.
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Abstract
Animal studies suggest that the apolipoprotein E ε4 (APOEε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOEε4 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; [18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28). We found that APOEε4 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 APOEε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOEε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOEε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.
| Type: | Article |
|---|---|
| Title: | APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/sciadv.ade1474 |
| Publisher version: | https://doi.org/10.1126/sciadv.ade1474 |
| Language: | English |
| Additional information: | Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). See: https://creativecommons.org/licenses/by-nc/4.0/ |
| Keywords: | Animals, Alzheimer Disease, Amyloid beta-Peptides, Apolipoprotein E4, Brain, Microglia, Plaque, Amyloid, Positron-Emission Tomography, tau Proteins, Temporal Lobe, Apolipoproteins E |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10168598 |
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