APOEϵ4 carriership associates with microglial activation independently of Aβ plaques and tau tangles

Microglial activation is an early phenomenon in Alzheimers disease (AD) that may occur prior to and independently of amyloid-{beta} (A{beta}) aggregation. Recent studies in transgenic animal models suggest that the apolipoprotein E {varepsilon}4 (APOE{varepsilon}4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the APOE{varepsilon}4 genotype is associated with microglial reactivity in the living human brain. Here, we tested whether APOE{varepsilon}4 carriership is associated with microglial activation in individuals across the aging and AD spectrum. We studied 118 individuals who had positron emission tomography (PET) for A{beta} ([18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28), as well as clinical, genetic, and magnetic resonance imaging data. We found that APOE{varepsilon}4 carriership was associated with increased microglial activation mainly in early Braak-staging regions within the medial temporal cortex, and this effect of APOE{varepsilon}4 was independent of A{beta} and tau deposition. Furthermore, microglial activation mediated the A{beta}-independent effects of APOE{varepsilon}4 on downstream tau accumulation, neurodegeneration, and clinical impairment. Interestingly, the physiological distribution of APOE mRNA expression, obtained from the Allen Human Atlas, predicted the patterns of APOE{varepsilon}4-related microglial activation in our population, suggesting that the deleterious effects of APOE{varepsilon}4 occur at the level of gene expression. These results support a model in which the APOE{varepsilon}4 has A{beta}-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition. Our findings provide a rationale for the development of novel AD therapies targeting the interplay between ApoE and neuroinflammation.