A naturally occurring variant of PLC-γ2 that is moderately active is strongly associated with protection from late-onset Alzheimer’s disease (Magno et al., 2019; Sims et al., 2017) and highlights the notion that aberrant PLC activity can be either deleterious or beneficial depending on the context. This evidence concerns the gene PLCG2 and early-onset autosomal dominant Alzheimer disease.