NSE in blood is considered to be a peripheral biomarker of neuronal injury38 and blood–brain barrier dysfunction,39 and PAI-1 has been strongly linked with aging,40 remitted depression41 and severe anxiety.42 Given the relationship we have shown between these three markers and REST plus their involvement in psychological disorders carrying increased risk for AD, in combination, REST, BDNF, NSE and PAI-1 may provide a more sensitive predictor of cognitive decline than a single peripheral protein. This evidence concerns the gene ENO2 and Anxiety.