From Metabolic Endotoxemia to Calcium-Mediated Synaptic and Vascular Collapse: Reassessing Neurological Divergence through a Barrier-Failure Model

This article examines whether Alzheimer's disease and fibromyalgia, conditions traditionally separated by clinical taxonomy and treated within distinct medical specialties, share partial pathophysiological ground through an interacting pathway involving metabolic endotoxemia, endothelin-dependent vascular dysfunction, and disturbed intracellular calcium homeostasis. Drawing on human epidemiological data linking ultra-processed food consumption to systemic inflammatory and metabolic disturbance, mechanistic animal work on dietary emulsifiers and intestinal barrier regulation, and neurophysiological research on calcium compartmentalization and synaptic precision, the article proposes a model of partial mechanistic convergence rather than unified etiology. The central argument identifies a plausible feed-forward loop in which diet-associated barrier dysfunction contributes to chronic low-grade lipopolysaccharide translocation, incomplete hepatic clearance permits systemic inflammatory signaling, endothelial imbalance shifts endothelin activity toward vasoconstriction and impaired neurovascular regulation, and destabilized calcium handling degrades the spatiotemporal precision required for synaptic transmission and plasticity. In Alzheimer's disease, this framework aligns with early synaptic failure that precedes structural atrophy and with evidence linking peripheral inflammatory events to accelerated cognitive decline. In fibromyalgia, the same molecular logic applies to central sensitization and pain-processing network hyperexcitability, supported indirectly by the clinical utility of alpha-2-delta ligands that modulate voltage-gated calcium channel activity. The article distinguishes throughout between demonstrated human association, longitudinal human evidence, experimental animal mechanism, and theoretical inference, and explicitly excludes autism spectrum disorder and cerebral palsy from its scope on evidentiary grounds. It concludes that current published evidence supports biological connections among the proposed elements but does not establish metabolic endotoxemia as a necessary or sufficient cause of either disorder. The model is therefore presented as a testable hypothesis rather than a validated causal chain, with specific conditions under which longitudinal biomarker studies and controlled interventional research could confirm, narrow, or refute its central claims.