Quad-Platform Computational Architecture targeting Alzheimer's Neuroinflammation: Integrating Physical Biomodulation, Predictive Cheminformatics, Biological Foundation Models, and In Silico Bioenergetic Telemetries

Neuroinflammation driven by microglial dysfunction stands as a primary hallmark in the pathogenesis of Alzheimer's disease (AD). However, therapeutic breakthroughs remain bottlenecked by rigid blood-brain barrier (BBB) kinetics, inefficient intracellular vector programming, and poor small-molecule bioavailability. To address these systemic hurdles, this paper introduces a modular, quad-platform computational architecture designed to disrupt the neuroinflammatory cascade across distinct scales. Tier 1 establishes a standardized data infrastructure to optimize non-invasive physical therapies, calibrating Low-Intensity Pulsed Ultrasound (LIPUS) parameters for transient, safe BBB permeabilization. Tier 2 deploys deep learning-based cheminformatics pipelines to virtual-screen a dual-axis combination therapy: a Structural Axis targeting GSK inhibitors to maintain endothelial integrity, and an Immunological Axis utilizing STING inhibitors to arrest chronic innate immune activation. Tier 3 leverages Evo 2, a long-context genomic foundation model, to program single-nucleotide resolution intracellular genetic instructions capable of restoring homeostatic microglial phenotypes in the long term. Finally, Tier 4 introduces an in silico verification scheme driven by a non-linear double-Lorentzian signal processing pipeline; this module acts as a non-invasive telemetric sensor, deconvolving overlapping low-field Phosphorus Magnetic Resonance Spectroscopy (³¹P-MRS) peaks to quantitatively verify that downstream GSK/STING inhibition successfully rescues the cerebral NAD+/NADH matrix and ATP-synthetic machinery from neuroinflammatory decay. In an integrated pipeline, Tier 1’s biophysical parameters reshape Tier 2's chemical screening constraints—rescuing molecules previously discarded due to strict BBB limitations—while Tier 3's genomic vectors drive the biological recovery validated in real-time by Tier 4's closed-loop bioenergetic index. Ultimately, this modular framework bridges biomedical data engineering, predictive drug discovery, and synthetic biology, pioneering a multi-modal paradigm to halt neurodegeneration.