In this study, we explored lysosomal dysfunction and impaired autophagic flux in HFD‐fed 3xTg‐AD mice by assessing total and phosphorylated TFEB/TFE3 levels and ALP targets, including MAP1LC3B/LC3B, SQSTM1/p62, CTSD (cathepsin D), and LAMP1 in hippocampal lysates. The gene discussed is SQSTM1; the disease is Alzheimer disease.