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Microglia affect Alzheimer’s disease (AD) pathogenesis in opposing manners, by protecting against amyloid accumulation in early phases of the disease and promoting neuropathology in advanced stages. Recent research has identified specific microglial interactions with amyloid plaques that exert important protective functions including attenuation of early pathology. It is unknown how these protective microglial interactions with plaques are affected by apolipoprotein E ( APOE ) genotype and sex, two well-established AD risk factors that modulate microglial function. We investigated this question using quantitative confocal microscopy to compare microglial interactions with amyloid plaques in male and female EFAD mice across  APOE3  and  APOE4  genotypes at 6 months of age. We observed that microglial coverage of plaques is highest in male  APOE3  mice with significant reductions in coverage observed with both  APOE4  genotype and female sex. Plaque compaction, a beneficial consequence of microglial interactions with plaques, showed a similar pattern in which  APOE4  genotype and female sex were associated with significantly lower values. Within the plaque environment, microglial expression of triggering receptor expressed on myeloid cells 2 (TREM2), a known regulator of microglial plaque coverage, was highest in male  APOE3  mice and reduced by  APOE4  genotype and female sex. These differences in plaque interactions were unrelated to the number of microglial processes in the plaque environment across groups. Interestingly, the pattern of amyloid burden across groups was opposite to that of microglial plaque coverage, with  APOE4  genotype and female sex showing the highest amyloid levels. These findings suggest a possible mechanism by which microglia may contribute to the increased AD risk associated with  APOE4  genotype and female sex.   Electronic supplementary material  The online version of this article (10.1186/s40478-019-0729-z) contains supplementary material, which is available to authorized users.

APOE genotype and sex affect microglial interactions with plaques in Alzheimer’s disease mice