ε4 associates with microglial activation independently of Aβ plaques and tau tangles.

Animal studies suggest that the apolipoprotein E ε4 (ε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between ε4 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; [F]AZD4694), tau ([F]MK6240), and microglial activation ([C]PBR28). We found that ε4 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 ε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of mRNA expression predicted the patterns of ε4-related microglial activation in our population, suggesting that gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the ε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.