We show that (a) intracerebral expression of both sIl10R and sIl4R effectively prevent Aβ deposition when present prior to plaque onset; (b) sIl10R and sIl4R have opposing effects on astrocyte and microglial proliferation in an AD-amyloidosis model; (c) sIl4R preferentially reduced Aβ when expressed after plaque onset, indicating therapeutic efficacy; (d) RNAseq analysis indicates that sIl10R and sIl4R mediated plaque reduction was associated with unique immune profiles; and (e) neither sIl10R nor Il10 had measurable effects on tau proteinopathy. Here, IL10 is linked to Alzheimer disease.