Uncoupling of synaptic loss from amyloid burden by an Alzheimer′s disease protective variant of PLCγ2.

A rare coding missense variant (rs72824905; P522R) in PLCG2 decreases the risk of late-onset Alzheimer’s disease, but how this protective effect is mediated is unclear. Here we demonstrate a mechanism for this protection, the R522 variant of PLCγ2 alters microglial activity leading to a marked preservation of synaptic integrity and reduced peri-plaque microglial engulfment of synapses independently of amyloid burden. Our data advocate for a direct central role of PLCγ2 in mediating synaptic loss as part of the pathological process of Alzheimer’s disease (AD), prioritising it as a therapeutic target and modulator of disease.