Microglial activation impacts amyloid‐β effects on reactive astrogliosis

Abstract Background Glial reactivity is a key phenomenon in Alzheimer’s disease (AD) and is closely associated with amyloid‐β (Aβ) pathology. Although compelling experimental data suggest that microglial activation modulates reactive astrogliosis, it remains to be elucidated whether microglial activation influences the association of Aβ pathology with reactive astrogliosis in the living AD human brain. Here, we tested the association of microglial activation and Aβ pathology with reactive astrogliosis in individuals across the aging and AD clinical spectrum. Method We studied 101 participants (62 cognitively unimpaired [CU], 26 with mild cognitive impairment [MCI], and 13 with AD dementia) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort. Individuals had available positron emission tomography (PET) for Aβ ([ 18 F]AZD4694) and microglial activation ([ 11 C]PBR28), as well as magnetic resonance imaging. We further assessed reactive astrogliosis with plasma glial fibrillary acidic protein (GFAP). Linear regression analyses were used to investigate the associations between Aβ, microglial activation and GFAP. Result Demographic characteristics of the study population are reported in Table 1. Regression analyses revealed a significant positive association between Aβ PET burden and plasma GFAP levels in microglial activation‐positive but not in microglial activation‐negative individuals (Figure 1A). A significant interaction between continuous values of Aβ PET burden and [ 11 C]PBR28 PET uptake on plasma GFAP levels (Figure 1B) supported that microglial activation affects the association of Aβ pathology with reactive astrogliosis. Analysis of variance further confirmed that the model with the interaction term was the most adequate to describe the association of Aβ PET and microglial activation PET with plasma GFAP ( P = 0.007). In additional analyses investigating the topography of the observed findings, we found that higher Aβ PET burden was associated with higher plasma GFAP levels only in the presence of microglial activation positivity across Aβ‐vulnerable cortical brain regions (Figure 1C). Conclusion Our results suggest that microglial activation impacts Aβ‐dependent reactive astrogliosis in the living AD brain. This can help to better understand the complementary roles of glial cells in neurodegenerative diseases, as well as provide insights for the development of novel therapeutic strategies for AD targeting the interplay between Aβ and glial reactivity.