João Pedro Ferrari‐Souza, Guilherme Povala, Nesrine Rahmouni, Bruna Bellaver, Pâmela C.L. Ferreira, Marco Antônio De Bastiani, Douglas Teixeira Leffa, Firoza Z Lussier, Cristiano Schaffer Aguzzoli, Wagner S. Brum, Giovanna Carello‐Collar, Wyllians Vendramini Borelli, Joseph Therriault, Arthur C. Macedo, Stijn Servaes, Jenna Stevenson, Ilaria Pola, Serge Gauthier, Diogo O. Souza, Lucas Porcello Schilling, Mychael V. Lourenco, Gallen Triana‐Baltzer, Hartmuth C. Kolb, Andréa L. Benedet, Nicholas J. Ashton, Dana Tudorascu, Henrik Zetterberg, Kaj Blennow, Sterling C. Johnson, Tharick A. Pascoal, Pedro Rosa‐Neto, Eduardo R. Zimmer
Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer’s disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([18F]AZD4694), tau aggregation ([18F]MK-6240) and microglial activation ([11C]PBR28), along with plasma biomarkers for astrocyte reactivity (GFAP) and tau phosphorylation (p-tau217). We further evaluated 251 individuals with cerebrospinal fluid levels of the microglial marker sTREM2. We found that Aβ pathology was associated with astrocyte reactivity across cortical brain regions only in the presence of microglial activation. The microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Our results suggest that microglial activation plays a key role in Aβ-related astrocyte reactivity, which, in turn, contributes to downstream pathological features of AD. Microglia influence amyloid-β effects on astrocyte reactivity in the living brain of individuals with Alzheimer’s disease. This phenomenon further contributes to cognitive impairment via tau phosphorylation and aggregation.