학술논문
APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles
Document Type
Author
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.; Lessa Benedet, Andréa; Ashton, Nicholas J.; Chamoun, M.; Servaes, S.; Bezgin, G.; Kang, M. S.; Stevenson, J.; Rahmouni, N.; Pallen, V.; Poltronetti, N. M.; O'Brlen, J. T.; Rowe, J. B.; Cohen, A. D.; Lopez, O. L.; Tudorascu, D. L.; Karikari, Thomas; Klunk, W. E.; Villemagne, V. L.; Soucy, J. P.; Gauthier, S.; Souza, D. O.; Zetterberg, Henrik, 1973; Blennow, Kaj, 1958; Zimmer, E. R.; Rosa-Neto, P.; Pascoal, T. A.
Source
Science Advances. 9(14)
Subject
Language
English
ISSN
2375-2548
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.