Complement and microglia mediate early synapse loss in Alzheimer's disease (AD) mouse models. Synapse loss in AD correlates with cognitive decline, and microglia and complement have been linked to neuroinflammation in late stages of the disease. This study shows that complement and microglia are involved in early synapse loss in AD. C1q, the first protein of the classical complement cascade, is increased and associated with synapses before plaque deposition. Inhibiting C1q, C3, or the microglial complement receptor CR3 reduces phagocytic microglia and early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation (LTP). Microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. These findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD. Genome-wide association studies (GWAS) implicate microglia and complement-related pathways in AD. Previous research has shown both beneficial and detrimental roles of complement and microglia in plaque-related neuropathology. However, their roles in synapse loss, a major pathological correlate of cognitive decline in AD, remain to be identified. Emerging research implicates microglia and immune-related mechanisms in brain wiring in the healthy brain. During development, C1q and C3 localize to synapses and mediate synapse elimination by phagocytic microglia. The study hypothesized that this normal developmental synaptic pruning pathway is activated early in the AD brain and mediates synapse loss. The degree of region-specific synapse loss is a stronger correlate of cognitive decline in AD than counts of plaques, tangles, and neuronal loss. To determine how early synapse loss occurs, the study used super-resolution structured illumination microscopy (SIM) to quantify synapse density in hippocampal CA1 stratum radiatum of familial AD-mutant hAPP (“J20”) transgenic mice. Quantification of colocalized pre- and postsynaptic puncta revealed a significant loss of synapses in J20 hippocampus at 3-4 months old, an age that precedes plaque deposition. Synapse loss in pre-plaque J20 CA1 was confirmed using electron microscopy. Confocal imaging also showed synapse loss in CA1, CA3, and dentate gyrus of 3 mo J20 hippocampus but not in striatum. Synapse levels were not altered in 1 mo J20 brains vs. wild-type (WT) littermates, suggesting that the hippocampal synaptic loss at 3 mo is likely not a result of abnormal synaptic development. The study found that C1q immunoreactivity wasComplement and microglia mediate early synapse loss in Alzheimer's disease (AD) mouse models. Synapse loss in AD correlates with cognitive decline, and microglia and complement have been linked to neuroinflammation in late stages of the disease. This study shows that complement and microglia are involved in early synapse loss in AD. C1q, the first protein of the classical complement cascade, is increased and associated with synapses before plaque deposition. Inhibiting C1q, C3, or the microglial complement receptor CR3 reduces phagocytic microglia and early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation (LTP). Microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. These findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD. Genome-wide association studies (GWAS) implicate microglia and complement-related pathways in AD. Previous research has shown both beneficial and detrimental roles of complement and microglia in plaque-related neuropathology. However, their roles in synapse loss, a major pathological correlate of cognitive decline in AD, remain to be identified. Emerging research implicates microglia and immune-related mechanisms in brain wiring in the healthy brain. During development, C1q and C3 localize to synapses and mediate synapse elimination by phagocytic microglia. The study hypothesized that this normal developmental synaptic pruning pathway is activated early in the AD brain and mediates synapse loss. The degree of region-specific synapse loss is a stronger correlate of cognitive decline in AD than counts of plaques, tangles, and neuronal loss. To determine how early synapse loss occurs, the study used super-resolution structured illumination microscopy (SIM) to quantify synapse density in hippocampal CA1 stratum radiatum of familial AD-mutant hAPP (“J20”) transgenic mice. Quantification of colocalized pre- and postsynaptic puncta revealed a significant loss of synapses in J20 hippocampus at 3-4 months old, an age that precedes plaque deposition. Synapse loss in pre-plaque J20 CA1 was confirmed using electron microscopy. Confocal imaging also showed synapse loss in CA1, CA3, and dentate gyrus of 3 mo J20 hippocampus but not in striatum. Synapse levels were not altered in 1 mo J20 brains vs. wild-type (WT) littermates, suggesting that the hippocampal synaptic loss at 3 mo is likely not a result of abnormal synaptic development. The study found that C1q immunoreactivity was