This hypothesis proposes that coordinated activation of the entire TFEB transcription factor family (TFEB, TFE3, TFE4) can restore lysosomal biogenesis specifically at synaptic terminals during early Alzheimer's disease progression. While previous approaches have focused on individual TFEB activation, this strategy leverages the functional redundancy and synergistic effects of all three family members to maximize lysosomal restoration. The rationale is that synapses are the earliest sites of dysfunction in Alzheimer's disease, where impaired autophagy-lysosomal clearance leads to accumulation of amyloid-beta oligomers and early tau species that disrupt synaptic transmission before neuronal death occurs. By simultaneously enhancing nuclear translocation of TFEB, TFE3, and TFE4 through targeted mTORC1 inhibition or trehalose treatment, we can achieve robust upregulation of the complete lysosomal gene network including LAMP1, cathepsins, V-ATPase subunits, and lysosomal trafficking machinery.

This hypothesis proposes that coordinated activation of the entire TFEB transcription factor family (TFEB, TFE3, TFE4) can restore lysosomal biogenesis specifically at synaptic terminals during early Alzheimer's disease progression. While previous approaches have focused on individual TFEB activation, this strategy leverages the functional redundancy and synergistic effects of all three family members to maximize lysosomal restoration. The rationale is that synapses are the earliest sites of dysfunction in Alzheimer's disease, where impaired autophagy-lysosomal clearance leads to accumulation of amyloid-beta oligomers and early tau species that disrupt synaptic transmission before neuronal death occurs. By simultaneously enhancing nuclear translocation of TFEB, TFE3, and TFE4 through targeted mTORC1 inhibition or trehalose treatment, we can achieve robust upregulation of the complete lysosomal gene network including LAMP1, cathepsins, V-ATPase subunits, and lysosomal trafficking machinery. This comprehensive approach will be particularly effective in restoring synaptic autophagosome-lysosome fusion and clearance capacity at presynaptic terminals where protein aggregates first accumulate. The intervention targets the critical early window before irreversible synaptic loss occurs. Evidence will be gathered through detailed longitudinal studies in APP/PS1 and 3xTg-AD mouse models, focusing on synaptic-specific outcomes including electrophysiological measurements of synaptic strength, synaptosome protein clearance assays, and high-resolution imaging of synaptic autophagy flux. Clinical translation will utilize cerebrospinal fluid biomarkers of lysosomal enzyme activity and synaptic proteins, combined with advanced PET imaging to track amyloid clearance specifically at synaptic sites.