The Filamin A Proteomic Switch: Solubility States and Cytoskeletal Dynamics Explain the Inverse Epidemiological Relationship Between Cancer and Alzheimer's Disease

This manuscript unifies global registries with molecular kinetics to resolve the inverse comorbidity between cancer and Alzheimer’s disease. We propose this inversion represents a binary, tissue-specific allocation of cell survival strategies dictated by the solubility of the Filamin A (FLNA) cytoskeletal scaffolding network under systemic cobalamin insufficiency. Chronic exposure to trace environmental nitrous oxide (N2O) pollution passivates cobalamin, arresting the cell-autonomous one-carbon cycle. In post-mitotic neural architectures, this bioenergetic arrest forces membrane potential collapse and excitotoxic decay, activating caspase-3 to cleave the FLNA matrix into a divergent fragment pool. Specific cytosolic domains bind alpha-7 nicotinic acetylcholine receptors (α7nAChRs) to anchor toxic amyloid signaling, driving Alzheimer’s pathogenesis; concurrently, separate liberated 90-kDa C-terminal fragments (FLNA-90) translocate to the nucleus to execute a genomic tumor-suppressor checkpoint. Conversely, peripheral tissues with high metabolic plasticity escape collapse via malignant transformation. Upstream accumulation of the oncometabolite methylmalonic acid (MMA) acts as an epigenetic reprogrammer, driving TGF-β and SOX4 cascades to force KRAS transcription into constitutive overdrive. This active KRAS pool fuels downstream kinase networks that keep the peripheral FLNA matrix intact, soluble, and hyper-phosphorylated at Serine 2152 (pS2152) to complex with cytoplasmic Cyclin D1/CDK4 networks. This structural configuration shields the scaffold from caspase-3 cleavage, reconfiguring FLNA into an active motility engine driving invasive lamellipodia but stalls proteolytic processing and forces an absolute loss of the nuclear FLNA-90 tumor-suppressor brake, unleashing uninhibited c-Myc oncogenic transcription. Crucially, this malignant transformation functions as an active metabolic adaptation; the hyper-stabilization of the intact 280-kDa platform operates in tandem with the active downregulation of the MMAB protein via a direct, transcription-independent cytosolic protein interaction with SMAD4 to drive its proteasomal degradation entirely independent of canonical TGF-β signaling cascades. By shutting this internal gate, the cell prevents its own expanding somatic structure from natively consuming cobalamin cofactors, transforming the emerging biomass into a high-powered cytoplasmic motility engine and a strict systemic refinery sink. Using hyper-glycolytic GSH and NADPH reserves to forcefully reduce passivated corrin rings [Co(III) →Co(I)], the tumor coordinates active metastatic seeding to locate uncompromised nutrient sources and export bioavailable cobalamin via ABCC1 pumps, rescuing central neural networks from homeostatic collapse. Filamin A thus serves as the definitive structural, conformational, and proteomic switch governing this inverse disease matrix.