However, because the necessary concentration for Aβ to trigger phosphorylation was much higher than that of HMGB1 (Supplementary Figure 11d) and because Aβ was more prone to aggregate in the extracellular space than HMGB1 (Supplementary Figure 9a,b), HMGB1 may be the primary trigger of the pathological signalling via pSer46-MARCKS in AD. This evidence concerns the gene HMGB1 and Alzheimer disease.