<i>APOE</i>ε4 associates with microglial activation independently of Aβ plaques and tau tangles.

Abstract

Animal studies suggest that the apolipoprotein E ε4 (<i>APOE</i>ε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between <i>APOE</i>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; [¹⁸F]AZD4694), tau ([¹⁸F]MK6240), and microglial activation ([¹¹C]PBR28). We found that <i>APOE</i>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 <i>APOE</i>ε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of <i>APOE</i> mRNA expression predicted the patterns of <i>APOE</i>ε4-related microglial activation in our population, suggesting that <i>APOE</i> gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the <i>APOE</i>ε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.