In summary, using a variety of in vivo mouse model systems, we have observed (1) that a deficiency of TYROBP in microglia is associated with increased phospho-tau stoichiometry and accelerated spread of tauopathy in mouse models; (2) that the deletion of Tyrobp induces a decrease of C1q, which may underlie the beneficial effects on memory and synaptic plasticity; (3) that TREM2 deficiency leads to an increased phosphorylation and diffusion of tau but without alteration of the complement cascade. Here, TYROBP is linked to tauopathy.