Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder defined by amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), yet approximately 20-30% of aged individuals exhibit these hallmark lesions without developing cognitive impairment-a clinically silent condition termed asymptomatic AD (AsymAD). The molecular basis of this cognitive resilience remains poorly understood due to a lack of mechanistic models. Here, we integrate systems-level Boolean network modeling with in vivo validation to define the transcriptomic logic of AsymAD and uncover a novel preclinical model. Using Boolean implication networks trained on large-scale human cortical RNA-seq datasets, we identified a robust and invariant AD gene signature that accurately stratifies disease states across independent datasets. Application of this signature to Chromogranin A-deficient PS19 mice (CgA-KO/PS19) revealed a unique resilience phenotype: male mice developed AD-like molecular and neuropathological profiles in the pre-frontal cortex yet retained intact learning and memory. Female CgA-KO/PS19 mice displayed even greater protection, including reduced Tau phosphorylation and preserved synaptic ultrastructure. These findings establish the first validated murine model of AsymAD and identify CgA as a modifiable node linking neuroendocrine signaling, Tauopathy, and cognitive preservation. This work provides a scalable platform to probe sex-specific resilience, uncover early-stage biomarkers, and accelerate preventive therapeutic development in AD.