Alzheimer's disease (AD) is a major burden of aging populations--are we making any progress in understanding and treating it? Biomarker discoveries have revealed the decades-long natural history of the disease; human genetics studies have highlighted that glial cells rather than neurons lie at the root of pathogenesis. Synaptic dysfunction and synapse loss are hallmarks of Alzheimer’s disease (AD) and other tauopathies, yet the underlying molecular mechanisms remain largely undefined. We used unbiased proteomic analysis of postsynaptic density (PSD) proteins from wild-type versus Tau-P301S transgenic mice before the onset of overt neurodegeneration to identify early tau-dependent changes in the synapse. PSDs from tauopathy mice multiple changes, including a striking accumulation of C1q, the complement factor that initiates the classical complement cascade. C1q labels synapses damaged by tauopathy and mediates their engulfment by microglia. C1q-neutralizing antibodies suppressed microglial synapse clearance and rescued synapse density, suggesting a potential approach to mitigate synapse loss in AD.