APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles.
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Ferrari-Souza João Pedro, Lussier Firoza Z, Leffa Douglas T, Therriault Joseph, Tissot Cécile, Bellaver Bruna, Ferreira Pâmela C L, Malpetti Maura, Wang Yi-Ting, Povala Guilherme, Benedet Andréa L, Ashton Nicholas J, Chamoun Mira, Servaes Stijn, Bezgin Gleb, Kang Min Su, Stevenson Jenna, Rahmouni Nesrine, Pallen Vanessa, Poltronetti Nina Margherita, 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
Аннотация
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.