Adult Cognitive Disease

Start Here 5

One Mechanism, Many Diseases (AD, PD, ALS, HD) One Mechanism, Many Diseases (AD, PD, ALS, HD) 0 words Standard Diagnostic Biomarkers Explained Standard Diagnostic Biomarkers Explained 0 words Telling Different Dementias Apart Telling Different Dementias Apart 0 words The Master Theory The Master Theory: Why All Roads Lead to the Same Failure 0 words The Temporal Architecture of Collapse The 50-Year Front — The Temporal Architecture of Alzheimer's 9,580 words

The Record 10

Fischer, 1907 — and how the field went wrong

Disciplinary Silos in Alzheimer's Disease Research, 1950–2020 Disciplinary Silos in AD Research, 1950–2020 9,076 words Fischer's Matrix Fischer's Matrix: The Founder Axis Rediscovered 10,065 words Fischer's Sidelining Fischer's Sidelining: A Biographical–Intellectual History 12,542 words How 1907 Observations Predict Modern Findings How 1907 Observations Predict Modern Findings 0 words Mapping 1907 Terms to Modern Science Mapping 1907 Terms to Modern Science 0 words The Eight Stages The Eight Stages 19,849 words The Geode and the Flower The Geode and the Flower 27,173 words The Second Reading The Second Reading 15,039 words The Staged Deposit The Plaque Was Staged Before It Was Counted 15,812 words What If We'd Listened to Fischer? What If We'd Listened to Fischer? 0 words

Groundwork 32

The substrate beneath every phase

Astrocytes Astrocytes: The Hidden Drivers of Brain Waste Clearance 0 words Huang Huang: Aβ as a Two-Faced Molecule 0 words Is the ER–Mitochondria Contact Site the Real Driver? Is the ER–Mitochondria Contact Site the Real Driver? 0 words Khachaturian Khachaturian: Calcium × Autolysosomal Acidification 0 words Khachaturian Khachaturian: The Calcium Hypothesis & Systems Failure 0 words Mapping the Vascular Dimension Onto the Genetic Dimension Mapping the Vascular onto the Genetic Dimension (PhD) 16,318 words The Architecture of Resistance The Genes That Protect — Phenocopy the Fortunate 12,580 words The Bond not Made The Bond Not Made 17,272 words The Cellular Architecture of Collapse Collapse, Traced Cell Type by Cell Type 17,509 words The Compressed Architecture Down Syndrome as the Disease Run in Fast-Forward 13,312 words The Crowded Cleft The Crowded Cleft 26,173 words The Fading Score The Reversible Layer — Erosion of the Cell's Memory 7,646 words The Fifth Surface The Fifth Surface 14,384 words The Fifty-year Prescription The Fifty-Year Prescription 35,696 words The Genetic Architecture of Neurodegeneration The Genetic Architecture of Neurodegeneration (PhD) 17,941 words The Glial Consortium and the Timeline of Collapse The Glial Consortium and the Timeline of Collapse 0 words The Janus Lipid The Lipid That Kills Neurons and Spares Tumours 8,510 words The Load-Bearing Lipid The Load-Bearing Lipid 18,943 words The Mitochondrion as Nexus The Mitochondrion as Nexus 15,180 words The Muscle's Errand Why Exercise Prevents but Does Not Cure 8,758 words The Narrow Gate The Narrow Gate Every Mitochondrial Protein Must Pass 12,797 words The Scheduled Withdrawal The Scheduled Withdrawal 25,062 words The Senescent Front The Cell Biology of the Word 'Ageing' 8,044 words The Uncleared Signal The Uncleared Signal 14,593 words The Unthrown Switch The Unthrown Switch 16,527 words The Vascular Dimension Vascular Pathology as a Substrate Across Phases 12,123 words The Vascular Phasing The Vascular Phasing (PhD Thesis) 14,585 words The Wax and the Weld Where the Lipid Disorder and the Energy Disorder Are One 10,176 words The Withdrawn Subsidy When the Brain's Trophic Subsidy Is Withdrawn 8,597 words The Wrong Half of the Molecule The Wrong Half of the Molecule 16,905 words When Myelin's Caretakers Fail When Myelin's Caretakers Fail 0 words When the Brain's Immune Cells Turn Toxic When the Brain's Immune Cells Turn Toxic 0 words

Phase I — The Silent Brainstem Erosion 21

Age 20–50 · the locus coeruleus, decades before symptoms

AG18051 and the Aβ–ABAD Complex Blocking the Aβ–ABAD Complex — A Pharmacology 7,298 words BIOENERGETIC COLLAPSE (Revised) The Bioenergetic Thesis (Downloadable PDF) 4,609 words NAD⁺ Restoration and CD38 Inhibition NAD⁺ Restoration and CD38 Inhibition 8,705 words PARP Inhibitors and the Locus Coeruleus Phase I: PARP Inhibitors and the Locus Coeruleus 10,818 words The Coerulean Interface The Coerulean Interface — The Brainstem Origin of Alzheimer's 9,216 words The Coerulean Pincer Norepinephrine as a Two-Armed Pincer on Tau 15,806 words The Coerulean Shears The Enzyme That Cuts the Protective Lattice 12,133 words The Energy-gated Tauopathy Re-evaluating Höglinger's Complex I → Tau Program 2,486 words The Fermented Prodrome When the Gut Writes the First Depression 12,046 words The First Ember Where the First Tangle Is Lit 12,286 words The Locus Coeruleus & the Noradrenergic Prodrome The Locus Coeruleus & the Noradrenergic Prodrome 0 words The Microbial Prologue The Gut Ecosystem as the Upstream Origin 9,814 words The Noxious Afferent What the Vagus Carries That Does Harm 3,114 words The Pineal Interface The Failing Clock That Stops Defending the Brainstem 13,622 words The Price and the Permission The Price and the Permission 15,946 words The Restorative Interval Sleep as the Shared Off-Line State of Every Collapse Axis 13,877 words The Standing Relay The Standing Relay 14,936 words The Tryptophan Partition The Tryptophan Partition (PhD Thesis) 14,281 words The Unpicked Seam The Unpicked Seam 16,696 words The Vagal Interface Anatomy of a Neurodegenerative Conduit — The Vagal Interface 12,363 words The Vago-coerulean Relay How the Gut Nerve Reaches the Brainstem 7,802 words

Phase II — The Hippocampal Bridgehead 23

Age 50–70 · microglia, the inflammasome, and the matrix

Ferroptosis and the Phase II Oligodendrocyte Crisis Phase II: Ferroptosis and the Oligodendrocyte Crisis 7,920 words Homeostatic Microglial Collapse Homeostatic Microglial Collapse 0 words Iron Chelation and GPX4 Stabilization Iron Chelation and GPX4 Stabilization 8,345 words One Sensor, Two Collapses One Sensor, Two Collapses — Which Arm Matters More? 7,715 words Perineuronal Nets, Microglial Neuroinflammation, and Alzheimer's Perineuronal Nets, Microglial Neuroinflammation, and Alzheimer's 0 words The Corruption of the Gardener Everything That Corrupts the Brain's Gardener, Ranked 5,742 words The DAM Trajectory and the Matrix-degrading Arm Re-evaluating Deczkowska's DAM Trajectory 2,727 words The Gardener's Restraint The Gardener's Restraint 9,638 words The Immunometabolic Checkpoint Re-evaluating Chini's CD38–NAD Program 2,524 words The INFLAMMASOME-COMPLEMENT-TREM2 Nexus Re-evaluating Gate's NLRP3 / TREM2 Program 2,307 words The Locus Coeruleus Bridge The Locus Coeruleus as Phase Bridge 5,501 words The Matrix of Collapse The Matrix as the Seventh Axis of Collapse 4,891 words The Microglial Thesis (Downloadable PDF) The Microglial Thesis (Downloadable PDF) 0 words The Net and the Speck When the Inflammasome Turns on the Matrix 7,552 words The Peacekeeper's Paradox The Immune Cells That Keep the Peace — Until They Don't 10,808 words The Perineuronal Turn When the Attack Turns Proteolytic 5,980 words The Peripheral Arm of Homeostatic Collapse The Peripheral Arm of Homeostatic Collapse 0 words The Proteolytic Turn The Phase II → III Transition: Iron, Lipid, PNN 9,707 words The Sensor and the Speck The Innate-Immune Sensor That Converts the Disease 12,494 words The Silenced Eraser The Microglion That Silences Tau's Phosphatase 14,691 words The Speck and the Architect The Inflammasome Versus the Reelin Brake 11,858 words The Tide-gate The Brain's Border Gate: Source, Sieve, and Sentinel 8,580 words The Unnetted Governor The Unnetted Governor 16,270 words

Phase III — The Synaptic Disintegration 25

Age 70+ · where the disease finally becomes visible

Convergent Synaptic Collapse (CSC) — Grading Reference Convergent Synaptic Collapse 629 words From Synapse Loss to Neuronal Death in Alzheimer's Disease The Quiet Death 9,126 words Gouras Gouras: Intraneuronal Aβ and the Inside-Out Paradigm 0 words Margolis Margolis: How Synapses Are Dismantled from Within 0 words MMP-9 Inhibitors and the Phase III Therapeutic Window Phase III: MMP-9 Inhibitors and the Therapeutic Window 9,141 words Moosmann & Sohre Moosmann & Sohre: NMDA Failure as the Root Cause 0 words Ramsden Ramsden: When Oxidative Damage Reaches the Synapse 0 words Rappoport Rappoport: The Lipid-Raft Hypothesis and Adaptive Response Plasticity 0 words Shatz & Brott Shatz & Brott: Complement-Mediated Synaptic Pruning 0 words Small Small: The Endosomal Traffic Jam 0 words The Adult-born Neuron How Adult Neurogenesis Carries Cognitive Reserve 8,562 words The Architect's Handshake The Three-Body Clasp at the Membrane 8,767 words The Architect's Reprieve The Brain's Architect and the Brake It Puts on Tau 9,471 words The Architect's Scaffold One Sugar Lattice, Three Jobs 7,026 words The Architect's Understudy Can a Drug Copy the Luckiest Mutation? 14,298 words The Brake and the Blade The Brake and the Blade 15,005 words The Complement-pruning Substrate Re-evaluating Stevens's Complement-Pruning Program 2,756 words The Homeward Vector The Homeward Vector 15,912 words The Indifferent Neuron The Indifferent Neuron 19,020 words The Load-Bearing Neuron The Load-Bearing Neuron 38,816 words The Losing Axon The Losing Axon 21,259 words The Pv+/gamma Axis Re-evaluating Tsai's 40 Hz Gamma Program 2,659 words The Same Machine The Same Machine 11,450 words The Switch and the Sieve The Switch and the Sieve 13,380 words The Trojan Neuroblast Re-evaluating Abbate's Neurogenic Hypothesis 20,039 words

The Spread 6

Templated misfolding across the network

Different Tau Strains Cause Different Diseases Different Tau Strains Cause Different Diseases 0 words How the Brain's Clearance System Becomes the Disease's Highway How the Brain's Clearance System Becomes the Disease's Highway 0 words How α-Synuclein Spreads Through the Brain How α-Synuclein Spreads Through the Brain 0 words Proving That Misfolded Proteins Spread Like Prions Proving That Misfolded Proteins Spread Like Prions 0 words Why All Major Neurodegenerative Diseases Are the Same Disease Why All Major Neurodegenerative Diseases Are the Same Disease 0 words Why HMS Becomes HMS+P Why HMS Becomes HMS+P 0 words

The Convergence 18

Autophagic collapse, and the upstream triggers that feed it

Can Vaccines Protect Against Dementia? Can Vaccines Protect Against Dementia? 0 words Causal and Common Causal and Common 12,039 words Comparing Different Viral Triggers Comparing Different Viral Triggers 0 words How Free Radicals Disable the Recycling System How Free Radicals Disable the Recycling System 0 words How Plaques Actually Form How Plaques Actually Form: A Timeline 0 words How to Fix the Broken Recycling System How to Fix the Broken Recycling System 0 words How Viruses Enter and Hide in the Brain How Viruses Enter and Hide in the Brain 0 words How Viruses Sabotage Brain Cleanup How Viruses Sabotage Brain Cleanup 0 words Many Causes, One Bottleneck Many Causes, One Bottleneck 0 words Plaques Are Tombstones, Not Killers Plaques Are Tombstones, Not Killers 0 words The Acid Test The Acid Test 21,385 words The Cell's Garbage System Controls Aging The Cell's Garbage System Controls Aging 0 words The Clearance Collapse The Clearance Collapse — One Machinery, Three Failures 6,519 words The Glymphatic Collapse How the Brain Washes Itself — and Why That Fails 9,019 words The Viral Trajectory Viral Reactivation Across Three Phases (PhD) 24,171 words When Poor Blood Flow Causes Dementia When Poor Blood Flow Causes Dementia 0 words Why Damaged Mitochondria Can't Be Cleared Why Damaged Mitochondria Can't Be Cleared 0 words Why the Cell's Recycling System Breaks Why the Cell's Recycling System Breaks 0 words

The Synthesis 13

The cross-axis architecture

Alzheimer's disease — a process in time Alzheimer's Disease — A Process in Time 6,117 words Terminal Collapse Terminal Collapse: Naming the Death 0 words The Biomarker Cascade The Biomarker Cascade (PhD Thesis) 16,565 words The Case for the Cascade The Strongest Case FOR the Amyloid Cascade 3,227 words The Depression Continuum Depression as Reversible Collapse 14,171 words The Expected Event The Expected Event 20,288 words The Homeostatic–Matrix–Synaptic (HMS) Collapse Model The Homeostatic–Matrix–Synaptic (HMS) Collapse Model 0 words The Honest Cascade The Honest Cascade 17,914 words The Ketamine Paradox The Ketamine Paradox 6,147 words The Return Leg The Return Leg 48,702 words The Spectrum of Collapse The Spectrum of Collapse 7,195 words The Two Anchors The Two Anchors 5,950 words The Unified Architecture of Collapse The Whole Architecture, Graded by Evidence 10,974 words

The Frontier 6

Therapeutics, experiments, and open questions

Documents