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- Ferrari-Souza, J. P., et al.
(author)
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APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles
- 2023
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In: Science Advances. - 2375-2548. ; 9:14
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Journal article (peer-reviewed)abstract
- Animal studies suggest that the apolipoprotein E epsilon 4 (APOE epsilon 4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOE epsilon 4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomog-raphy for amyloid-beta (A beta; [18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28). We found that APOE epsilon 4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for A beta and tau deposition. Furthermore, microglial acti-vation mediated the A beta-independent effects of APOE epsilon 4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOE epsilon 4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOE epsilon 4 genotype exerts A beta-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.
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