In conclusion, our data link the protective effect of p.P522R in PLCG2 to lower CSF concentrations of pTau181 and tTau and slower cognitive decline in MCI patients, particularly in amyloid positive individuals and with an effect size similar to that of APOE. We present converging evidence, suggesting that the rare variant p.P522R in PLCG2 might reduce the effect of amyloidosis upon tau pathology and cognitive decline. Here, PLCG2 is linked to amyloidosis.