Specifically, we showed that (i) GLOD4 mRNA and protein were downregulated in human AD patients compared to non-AD controls; (ii) Glod4 mRNA was similarly downregulated in Blmh–/–5xFAD mouse model of AD, mostly in females; (iii) The 5xFAD transgene downregulated Glod4 in Blmh–/– mice of both sexes and in Blmh+/+ males but not females; (iv) reduced Glod4 expression was associated with elevated Aβ and worsened memory/sensorimotor performance in Blmh–/–5xFAD mice (v); Glod4 silencing in N2a-APPswe cells upregulated AβPP and downregulated autophagy-related Atg5, p62, and LC3 genes. Here, SQSTM1 is linked to Alzheimer disease.