In a simple case of direct interaction, sHsps would need to be located outside of cells in order to associate with and reduce toxicity of extracellular misfolded proteins, like Aβ (Ojha et al., 2011b; Cameron et al., 2017); which has been described for HspB1, HspB5, and HspB8 in extracellular, classic, senile plaques in AD brain (Wilhelmus et al., 2006b; Wilhelmus et al., 2006c). This evidence concerns the gene HSPB1 and Alzheimer disease.