As postmortem and in vivo brain imaging studies have demonstrated a reduced density of S1R in the brains of patients with AD (Jansen et al., 1993; Mishina et al., 2008) and S1R knockdown destabilizes mushroom spines (Tsai et al., 2009; Fisher et al., 2016; Ryskamp et al., 2019), downregulation of S1R may contribute to AD pathology. Here, TMBIM4 is linked to Alzheimer disease.