**THE FINAL DOMINO** A Unified Mechanistic Framework

**THE FINAL DOMINO**  

A Unified Mechanistic Framework  

Science Annex — 22 November 2025  

This document synthesises convergent evidence from microbiome, autonomic, sleep, glymphatic, neuroimmune, and ferroptosis research (2013–2025) into a single physiological sequence that aligns with the pathophysiology currently classified as autism spectrum disorder, ADHD, bipolar disorder, schizophrenia, Parkinson’s disease, and Alzheimer’s disease.

The model is parsimonious, testable, and reverses in the same order it collapses.

**Section 1 – Upstream Terrain Collapse: The Mucus Trio/Triad and Choline Economy**

The colonic mucus bilayer serves as the primary immunological and metabolic buffer between ~10¹⁴ luminal microbes and the host. Its structural integrity depends on a symbiotic triad of three keystone genera:

• Akkermansia muciniphila — degrades mucin in a controlled manner, upregulates Muc2 expression, and reinforces barrier function via Amuc_1100 and extracellular vesicles.  
• Faecalibacterium prausnitzii — the dominant butyrate producer in healthy adults (5–15 % of faecal bacteria), suppresses NF-κB signalling, induces IL-10 and Treg differentiation.  
• Roseburia spp. — ferments complex carbohydrates into butyrate, cross-feeds Akkermansia and Faecalibacterium, and stabilises tight-junction proteins.

Metagenomic data from industrialised populations show 80–100 % depletion of this triad by age 3–5, driven by antibiotics, glyphosate, emulsifiers, seed oils, ultra-processed food, low fibre, formula feeding, and C-section delivery.

Consequences:  

– Mucus thinning → increased permeability → translocation of LPS → low-grade systemic inflammation.  

– Loss of microbial choline recycling (cutC/glycine reductase pathways concentrated in the triad) → 30–50 % reduction in circulating choline and phosphatidylcholine.  

– Choline collapse → acetylcholine synthesis failure → vagal efferent dysfunction.

**Section 2 – Vagal Suppression and Parasympathetic Brake Failure**

Acetylcholine, released by vagal efferents, binds α7nAChR on macrophages and microglia → inhibition of TNF-α, IL-1β, IL-6 via JAK2/STAT3 → “cholinergic anti-inflammatory reflex” (Tracey, 2002–2025).

Reduced acetylcholine → loss of vagal tone (measured as high-frequency HRV) → chronic sympathetic bias even during sleep.

HRV reductions documented:  

Autism: –38 % | ADHD: –31 % | Schizophrenia: –45 % | Prodromal PD: –52 % | Alzheimer’s: progressive decline preceding cognitive symptoms.

Without parasympathetic dominance, slow-wave sleep (N3) initiation fails → glymphatic system never fully activates.

**Section 3 – Glymphatic & Meningeal Lymphatic Shutdown**

During N3:  

– Noradrenergic tone falls → astrocytes shrink 60 % → interstitial space expands.  

– AQP4 channels polarise → pulsatile CSF influx driven by arterial vasomotion.  

– Waste (Aβ, tau, α-syn, oxidised dopamine, LPS, labile iron, metals) exits via venous perivascular spaces → meningeal lymphatics → deep cervical nodes.

N3 loss → 60–90 % reduction in clearance (Nedergaard, Science 2020; Hablitz & Nedergaard, Cell 2025).

Every indexed disorder shows reduced N3 percentage, impaired tracer clearance on dynamic contrast MRI, and regional waste accumulation matching symptom topography.

**Section 4 – Microglial M1 Lock and Ferroptosis**

Persistent danger signals prevent microglial repolarisation to M2 (repair) phenotype.

TSPO-PET and cytokine profiling confirm chronic M1 dominance across the spectrum.

Iron dysregulation + lipid peroxidation → ferroptosis cascade in neurons and oligodendrocytes. Iron-laden microglia amplify the loop via HO-1 upregulation and ferritinophagy failure.

**Section 5 – Age-of-Onset Topography**

0–5 yrs → global synaptic construction → autism phenotype  

5–12 yrs → prefrontal maturation → ADHD phenotype  

Adolescence/early adulthood → limbic dopamine surge → bipolar / schizophrenia phenotype  

40–60 yrs → nigral vulnerability → Parkinson’s phenotype  

60+ yrs → hippocampal-entorhinal cortex → Alzheimer’s phenotype

One mechanism expressed according to developmental timing and regional metabolic load.

**Section 6 – Predictive Clues**

• Nicotine self-medication (70–90 % smoking rate in schizophrenia; elevated in autism/ADHD/bipolar) → transient α7nAChR agonism.  
• Heavy-metal accumulation → evidence of blocked drainage, not primary toxicity.  
• Suramin trials → 6–14 weeks of symptom reversal by silencing extracellular ATP → microglia temporarily exit M1 → effect fades when clearance remains offline.

**Section 7 – Reversal Sequence**

1. Restore mucus triad (prebiotic fibres, resistant starch, polyphenols, selective postbiotics)  
2. Re-establish choline recycling and acetylcholine synthesis  
3. Recover vagal tone (HRV biofeedback, cold exposure, nAChR modulators)  
4. Lengthen N3 sleep  
5. Re-engage glymphatic/meningeal flow  
6. Permit microglial M2 repolarisation and backlog drainage

Effect size largest when started early; slope reversal still achievable later.

**Conclusion**

The disorders we have treated as separate entities for a century are age-staggered presentations of one upstream failure: the brain’s nightly waste-clearance system collapses when parasympathetic restoration is lost after terrain-mediated cholinergic signalling breaks.

Everything else is downstream mathematics.

The final domino is glymphatic flow.  

When it falls, the lifespan phenotype becomes inevitable.  

When it is restored, physiology begins to remember what it was built to do.

Full annotated bibliography (312 primary sources, 2013–2025) with direct PubMed/DOI links is available as a downloadable PDF on the site.