In Alzheimer’s disease (AD), synaptic connections are lost early and in specific areas of the brain, including the hippocampus, where memory is formed and stored; however, what makes synapses vulnerable in AD and other neurodegenerative diseases remains elusive. In the healthy developing brain, synaptic loss (also known as synaptic pruning) is a normal process required for proper brain development. We previously found a key role for a group of immune molecules called complement in synaptic pruning. These proteins localize to synapses during periods of active synapse elimination and are required for normal brain wiring. Interestingly, the function of complement proteins in the brain appears analogous to their function in the immune system: they “tag” cellular material to be eliminated. Synapses tagged with complement proteins are eliminated by microglia, resident immune cells that express complement receptors. We showed that synapse loss in AD mouse models is mediated by an abnormal reactivation of this developmental pruning pathway, and that blocking complement or microglial complement receptors resulted in protection of synapse loss and memory defects in AD models (Hong et al., Science 2016). We predict that proteins in this pruning pathway could serve as biomarkers in AD to detect the disease early. To test this hypothesis, we will determine whether complement and microglia localize to synapses in human brains of early stages of AD, and whether complement proteins are abnormally upregulated in the cerebrospinal fluid (CSF) of AD patients. Our preliminary data suggest that C1q, the initiating protein of the complement pathway, is associated with synapses in late stages of the disease. We plan to continue investigating the role of complement in earlier stages of human AD. Moreover, we aim to study the role of other microglial receptors in aberrant synapse loss. Recent genome-wide association studies have identified several microglial and complement proteins as AD susceptibility genes, including TREM2; however, it is not known whether TREM2 plays a role in synapse loss or dysfunction. Using established assays, we are investigating whether TREM2 acts as a receptor through which microglia engulf synapses in AD mouse models. We found that TREM2 is involved in activating microglia and may be involved in synaptic engulfment. Understanding the function of TREM2 and other immune-related risk genes in early synapse loss can provide novel insight into new biomarkers and therapeutic targets.