Computational Modeling of ALS Onset Heterogeneity: The Drusen-Zinc Switch Mechanism and Unified Sensory-Topological Control Framework

Computational Modeling of ALS Onset Heterogeneity: The Drusen-Zinc Switch Mechanism and Unified Sensory-Topological Control Framework(Preliminary Results Draft v1 – January 2026)THIS IS NOT MEDICAL ADVICE. THIS THEORY IS NOT PEER-REVIEWED (YET).This upload contains the preliminary results, full manuscript draft, raw inference logs, supplementary tables, and related datasets from an independent, human-in-the-loop computational systems biology investigation into Amyotrophic Lateral Sclerosis (ALS) heterogeneity.The work proposes a novel mechanistic framework—the Drusen-Zinc Switch—to explain why sporadic ALS (sALS) exhibits diverse onset phenotypes (ocular/bulbar, focal/limb, etc.) yet converges on motor neuron death and TDP-43 pathology. Using Literature-Based Discovery (LBD) guided by a multi-model AI Panel (Gemini, Grok, ChatGPT, DeepSeek), the analysis identifies Barrier-Permeable Zinc Chelators (BPZCs) (e.g., BMAA, dithiocarbamates) as a plausible primary environmental trigger. Age-related sub-retinal Drusen act as a key biological switch/reservoir for mobile zinc (mZn), leading to a bifurcation: Drusen-Positive → “Zinc Flood” saturating RGNEF Zinc-Finger Domain → classical sporadic/Type I ALS (TDP-43 dominant). Drusen-Negative → “Zinc Drought” stripping structural zinc from SOD1 → apo-SOD1 formation → focal/Type II ALS (with crossover potential via oxidative stress feedback loops). The framework integrates control-theoretic principles (“The Wobble”, “STAY Command”, fasciculations as servo hunting) to unify sensory-topological errors (primarily visual/retinal) with downstream neuromuscular exhaustion. It stratifies ALS into five mechanistically distinct types, generates >30 falsifiable hypotheses (Supplementary Table 1), proposes ITC validation experiments, and suggests mechanism-based therapeutic stratification using non-invasive OCT imaging for subtype disambiguation.Key outputs include: Mechanistic explanations for epidemiological paradoxes (age-related onset, athlete/high-activity paradox, geographic clusters) Candidate BPZC class and environmental “shards” Deduced “ZERO-ALS” therapeutic protocols (PBT2 + Ebselen + Trehalose ± CuATSM) — explicitly not medical advice Roadmap for the Atomic Research Tool (ART) to enable auditable, atomized scientific reasoning All claims are derived from published evidence synthesis and logical inference chains under a strict “Rational Homeostasis” axiom (no “neuro-suicide”). Raw AI chat logs, data curation entries, and inference examples are included for transparency and reproducibility (see linked Zenodo DOIs).This is a raw, untraditional preliminary draft intended as a case example for tool development and priority timestamping. Collaboration to test, refute, or refine the model is welcomed. Minor typos/overstatements in v1 will be addressed in future ART-refined versions.

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