This hypothesis proposes that precise, neuron-specific TFEB modulation at optimal levels, combined with trehalose co-treatment, can restore lysosomal function in Alzheimer's disease while avoiding the detrimental effects of global TFEB activation. Building on the 'Goldilocks principle' that TFEB requires precise dosing to avoid toxicity, we will use neuron-specific promoters (such as CaMKII or synapsin) to drive moderate TFEB overexpression exclusively in excitatory neurons of AD-affected brain regions. This targeted approach circumvents the neuroinflammatory and microglial activation issues associated with global TFEB upregulation, while avoiding the α-synuclein-related APP processing defects seen with non-specific overexpression. Trehalose will be administered as a complementary TFEB-independent lysosomal enhancer, providing additive benefits through its chemical chaperone properties and alternative autophagy stimulation pathways. This dual intervention targets the fundamental cellular waste management deficits underlying amyloid-beta and tau accumulation at synapses, where lysosomal dysfunction is most critical for cognitive decline.

This hypothesis proposes that precise, neuron-specific TFEB modulation at optimal levels, combined with trehalose co-treatment, can restore lysosomal function in Alzheimer's disease while avoiding the detrimental effects of global TFEB activation. Building on the 'Goldilocks principle' that TFEB requires precise dosing to avoid toxicity, we will use neuron-specific promoters (such as CaMKII or synapsin) to drive moderate TFEB overexpression exclusively in excitatory neurons of AD-affected brain regions. This targeted approach circumvents the neuroinflammatory and microglial activation issues associated with global TFEB upregulation, while avoiding the α-synuclein-related APP processing defects seen with non-specific overexpression. Trehalose will be administered as a complementary TFEB-independent lysosomal enhancer, providing additive benefits through its chemical chaperone properties and alternative autophagy stimulation pathways. This dual intervention targets the fundamental cellular waste management deficits underlying amyloid-beta and tau accumulation at synapses, where lysosomal dysfunction is most critical for cognitive decline. The neuron-restricted TFEB expression will restore lysosomal biogenesis specifically where pathological proteins accumulate, while trehalose provides system-wide autophagy support without pleiotropic transcriptional effects. Evidence will be gathered through longitudinal analysis of APP/PS1 and 3xTg-AD mouse models using neuron-specific TFEB vectors plus trehalose treatment, measuring synaptic protein clearance, electrophysiological function, and cognitive performance. Biomarker studies will track lysosomal enzyme activity in cerebrospinal fluid and assess changes in brain amyloid and tau burden using PET imaging, focusing on early-stage intervention before extensive neuronal loss occurs.