However, chronic elevation of TMAO in AD mouse models promotes tau conformational changes and aggregation (Tseng and Graves, 1998), increases hippocampal β-secretase activity and amyloid-β deposition (Gao et al., 2019), activates the PERK–EIF2α–ER stress pathway (Govindarajulu et al., 2020), impairs hippocampal synaptic plasticity via the mTOR/P70S6K/4EBP1 axis (Li et al., 2018; Zhou et al., 2023), and upregulates circulating clusterin, potentially driving neuroinflammation and β-secretase–dependent Aβ pathology (Yu et al., 2013). Here, MAPT is linked to Alzheimer disease.