The corpus's own open questions

Moderate (inference) — Disrupting the amyloid-ABAD interaction is a therapeutically meaningful intervention rather than only a useful experimental manipulation.

in AG18051 and the Aβ–ABAD Complex

Would be settled by. A brain-penetrant analogue with acceptable selectivity tested against a disease endpoint.

Moderate (inference, the programme's own claim) — The disease is best read as a stereotyped process in time — a fifty-year front crossing the brain — rather than as a contest between primary molecules.

in Alzheimer's disease — a process in time

Would be settled by. A longitudinal cohort staged across brainstem, hippocampal and cortical markers showing the stated order in the same individuals.

Moderate (inference, the paper's own claim) — Astrocytes are the hidden drivers of clearance — a principal determinant rather than a supporting one.

in Astrocytes: The Hidden Drivers of Brain Waste Clearance

Would be settled by. Selective impairment of astrocytic clearance with neuronal and microglial capacity intact, and measurement of the resulting burden.

Moderate (inference, the paper's own claim) — Astrocytes are the hidden drivers of clearance — a principal determinant rather than a supporting one.

in ASTROCYTES: THE HIDDEN DRIVERS OF BRAIN WASTE CLEARANCE

Would be settled by. Selective impairment of astrocytic clearance with neuronal and microglial capacity intact, and measurement of the resulting burden.

Moderate (inference, the paper's own claim) — Mitochondrial and autophagy-lysosomal quality control is the machinery that the earlier theses invoked loosely as 'metabolic fitness'.

in BIOENERGETIC COLLAPSE (Revised)

Would be settled by. Manipulating quality-control capacity alone and showing the metabolic-fitness phenotype follows.

Moderate (inference, the paper's own claim) — The effect runs through two mechanisms at once — removal of a specific neurotropic pathogen, and non-specific trained immunity with epigenetic reprogramming of myeloid cells.

in Can Vaccines Protect Against Dementia?

Would be settled by. Comparing dementia incidence after a vaccine that induces trained immunity without targeting a neurotropic virus, against one that does both.

Moderate (inference, the paper's own claim) — The effect runs through two mechanisms at once — removal of a specific neurotropic pathogen, and non-specific trained immunity with epigenetic reprogramming of myeloid cells.

in CAN VACCINES PROTECT AGAINST DEMENTIA?

Would be settled by. Comparing dementia incidence after a vaccine that induces trained immunity without targeting a neurotropic virus, against one that does both.

Moderate (inference, the paper's own claim) — The competing viral hypotheses can be compared on a common mechanistic footing rather than treated as rival camps.

in Comparing Different Viral Triggers

Moderate (inference, the paper's own claim) — The competing viral hypotheses can be compared on a common mechanistic footing rather than treated as rival camps.

in COMPARING DIFFERENT VIRAL TRIGGERS

Moderate (inference, the corpus's own frame) — Alzheimer's disease is a disease of network failure in which multiple independent mechanisms converge on shared nodes, and no single mechanism is sufficient alone.

in Convergent Synaptic Collapse (CSC) — Grading Reference

Would be settled by. Blocking two convergent mechanisms separately and together, testing for synergy rather than addition.

Moderate (inference) — Strain identity is what distinguishes the human tauopathies from one another.

in Different Tau Strains Cause Different Diseases

Would be settled by. Strain typing of human cases against clinical phenotype in a series large enough to test whether strain predicts syndrome independently of the other differences.

Moderate (inference) — Strain identity is what distinguishes the human tauopathies from one another.

in DIFFERENT TAU STRAINS CAUSE DIFFERENT DISEASES

Would be settled by. Strain typing of human cases against clinical phenotype in a series large enough to test whether strain predicts syndrome independently of the other differences.

Moderate (inference, the paper's own claim) — Disciplinary siloing, rather than absence of evidence, is why assembly took seventy years.

in Disciplinary Silos in Alzheimer's Disease Research, 1950–2020

Would be settled by. Comparison against a matched field in which components were assembled faster, holding funding concentration constant.

Moderate (judgement, not evidence) — That absence is a defect in the account rather than an appropriate division of labour between mechanism and experience.

in Ecce Homo: City Air

Moderate (inference) — That combination renders oligodendrocytes the most ferroptosis-primed cells in the brain.

in Ferroptosis and the Phase II Oligodendrocyte Crisis

Would be settled by. Comparative ferroptosis-sensitivity measurement across CNS cell types under matched insult.

Moderate (inference, the corpus's own claim) — Matrix integrity constitutes a seventh convergence axis, distinct from the six the earlier framework named.

in FISCHER'S MATRIX

Moderate (inference) — Fischer's marginalisation was substantially a product of institutional power and circumstance rather than of the quality of his work.

in Fischer's Sidelining: A Biographical–Intellectual History

Moderate (inference, the paper's own claim) — Cumulative synaptic subtraction is what carries a neuron to death, rather than death arriving by a separate mechanism.

in FROM SYNAPSE LOSS TO NEURONAL DEATH IN ALZHEIMER'S DISEASE

Would be settled by. Preventing synapse removal alone and showing the neuron survives an otherwise lethal course.

Would be refuted by. Neuronal death proceeding on schedule with synapse removal blocked, which would make subtraction a parallel process rather than the route.

Moderate (inference) — The plaque is therefore a consequence of intraneuronal accumulation and neuronal death rather than an independent extracellular process.

in Gouras: Intraneuronal Aβ and the Inside-Out Paradigm

Would be settled by. Lineage or high-resolution longitudinal pathology tying individual deposits to individual dead neurons.

Moderate (inference) — The plaque is therefore a consequence of intraneuronal accumulation and neuronal death rather than an independent extracellular process.

in GOURAS: INTRANEURONAL AΒ AND THE INSIDE-OUT PARADIGM

Would be settled by. Lineage or high-resolution longitudinal pathology tying individual deposits to individual dead neurons.

Moderate (inference, the paper's own claim) — The attack and failure models are not rivals but sequential states of one trajectory, so the apparent incompatibility dissolves once time is added.

in Homeostatic Microglial Collapse

Would be settled by. Longitudinal or pseudotemporal single-cell trajectories in human tissue showing the attacking state as a precursor of the exhausted one rather than a parallel lineage.

Would be refuted by. Attacking and exhausted populations shown to arise from separate precursors, which would make them genuinely different cells rather than different moments.

Moderate (inference, the paper's own claim) — The attack and failure models are not rivals but sequential states of one trajectory, so the apparent incompatibility dissolves once time is added.

in HOMEOSTATIC MICROGLIAL COLLAPSE

Would be settled by. Longitudinal or pseudotemporal single-cell trajectories in human tissue showing the attacking state as a precursor of the exhausted one rather than a parallel lineage.

Would be refuted by. Attacking and exhausted populations shown to arise from separate precursors, which would make them genuinely different cells rather than different moments.

Moderate (inference, the paper's own claim) — Fischer's 1907 observations anticipate modern findings that the field arrived at independently a century later.

in How 1907 Observations Predict Modern Findings

Would be settled by. Systematic comparison of all Fischer's stated claims against modern findings, counting the failures alongside the anticipations.

Moderate (inference, the paper's own claim) — Fischer's 1907 observations anticipate modern findings that the field arrived at independently a century later.

in HOW 1907 OBSERVATIONS PREDICT MODERN FINDINGS

Would be settled by. Systematic comparison of all Fischer's stated claims against modern findings, counting the failures alongside the anticipations.

Moderate (inference, the paper's own claim) — Oxidative inhibition of the proton pump phenocopies the genetic defects of familial disease, producing the autophagy failure Nixon describes.

in How Free Radicals Disable the Recycling System

Would be settled by. Measurement of pump adduction against lysosomal pH in sporadic human tissue, with familial cases as the comparison.

Moderate (inference, the paper's own claim) — Oxidative inhibition of the proton pump phenocopies the genetic defects of familial disease, producing the autophagy failure Nixon describes.

in HOW FREE RADICALS DISABLE THE RECYCLING SYSTEM

Would be settled by. Measurement of pump adduction against lysosomal pH in sporadic human tissue, with familial cases as the comparison.

Moderate (inference, the paper's own claim) — Those two facts together indicate the extracellular deposit is not the driver, and a timeline of plaque formation must start inside the cell.

in How Plaques Actually Form: A Timeline

Would be settled by. Anti-amyloid therapy given presymptomatically with a cognitive endpoint, which separates wrong-target from wrong-time.

Moderate (inference, the paper's own claim) — Those two facts together indicate the extracellular deposit is not the driver, and a timeline of plaque formation must start inside the cell.

in HOW PLAQUES ACTUALLY FORM: A TIMELINE

Would be settled by. Anti-amyloid therapy given presymptomatically with a cognitive endpoint, which separates wrong-target from wrong-time.

Moderate (inference, the programme's own claim) — The same receptor that clears pathology also carries it — LRP1 mediates uptake and spread of tau, turning a clearance route into a highway.

in How the Brain's Clearance System Becomes the Disease's Highway

Would be settled by. Selective LRP1 blockade in a spreading model, measuring propagation rather than uptake.

Moderate (inference, the programme's own claim) — The same receptor that clears pathology also carries it — LRP1 mediates uptake and spread of tau, turning a clearance route into a highway.

in HOW THE BRAIN'S CLEARANCE SYSTEM BECOMES THE DISEASE'S HIGHWAY

Would be settled by. Selective LRP1 blockade in a spreading model, measuring propagation rather than uptake.

Moderate (inference, the paper's own claim) — A therapeutic convergence approach — addressing the shared autophagic collapse across dementia subtypes at once — would shift treatment paradigms.

in How to Fix the Broken Recycling System

Moderate (inference, the paper's own claim) — A therapeutic convergence approach — addressing the shared autophagic collapse across dementia subtypes at once — would shift treatment paradigms.

in HOW TO FIX THE BROKEN RECYCLING SYSTEM

Moderate (inference) — That persistence contributes causally to chronic neurodegenerative conditions rather than being an incidental accompaniment.

in How Viruses Enter and Hide in the Brain

Would be settled by. Antiviral intervention against a specific organism with a neurodegenerative endpoint.

Moderate (inference) — That persistence contributes causally to chronic neurodegenerative conditions rather than being an incidental accompaniment.

in HOW VIRUSES ENTER AND HIDE IN THE BRAIN

Would be settled by. Antiviral intervention against a specific organism with a neurodegenerative endpoint.

Moderate (inference, the paper's own claim) — That subversion is a plausible etiological trigger for chronic proteinopathy, not only for acute encephalitis.

in How Viruses Sabotage Brain Cleanup

Would be settled by. Longitudinal cohorts with documented CNS infection and later proteinopathy incidence, with the autophagy readout measured in between.

Moderate (inference, the paper's own claim) — That subversion is a plausible etiological trigger for chronic proteinopathy, not only for acute encephalitis.

in HOW VIRUSES SABOTAGE BRAIN CLEANUP

Would be settled by. Longitudinal cohorts with documented CNS infection and later proteinopathy incidence, with the autophagy readout measured in between.

Moderate (inference) — The anatomical route of spread in human Parkinson's disease follows connectivity as the model predicts.

in How α-Synuclein Spreads Through the Brain

Would be settled by. Longitudinal human imaging of spread along tracts, rather than inference from cross-sectional staging.

Moderate (inference) — The anatomical route of spread in human Parkinson's disease follows connectivity as the model predicts.

in HOW Α-SYNUCLEIN SPREADS THROUGH THE BRAIN

Would be settled by. Longitudinal human imaging of spread along tracts, rather than inference from cross-sectional staging.

Moderate (inference) — Those failures are explained by amyloid's physiological role — removing it removes something the brain needs as well as something it does not.

in Huang: Aβ as a Two-Faced Molecule

Would be settled by. A trial in which amyloid is reduced to a defined intermediate rather than a minimum, testing for a U-shaped rather than monotonic response.

Moderate (inference) — Those failures are explained by amyloid's physiological role — removing it removes something the brain needs as well as something it does not.

in HUANG: AΒ AS A TWO-FACED MOLECULE

Would be settled by. A trial in which amyloid is reduced to a defined intermediate rather than a minimum, testing for a U-shaped rather than monotonic response.

Moderate (inference, the paper's own claim) — The ER-mitochondria contact site is the real driver — upstream of amyloid rather than downstream of it.

in Is the ER–Mitochondria Contact Site the Real Driver?

Would be settled by. Contact-site correction alone preventing amyloid pathology downstream, in a system where the reverse manipulation does not prevent contact-site abnormality.

Moderate (inference, the paper's own claim) — The ER-mitochondria contact site is the real driver — upstream of amyloid rather than downstream of it.

in IS THE ER–MITOCHONDRIA CONTACT SITE THE REAL DRIVER?

Would be settled by. Contact-site correction alone preventing amyloid pathology downstream, in a system where the reverse manipulation does not prevent contact-site abnormality.

Moderate (inference, the paper's own claim) — The calcium hypothesis and the acidification account are the same account seen from two sides — calcium dysregulation and acidification failure are mechanistically coupled.

in Khachaturian: Calcium × Autolysosomal Acidification

Would be settled by. Correcting acidification alone and measuring whether calcium handling normalises, or the reverse.

Moderate (inference, the paper's own claim) — The calcium hypothesis and the acidification account are the same account seen from two sides — calcium dysregulation and acidification failure are mechanistically coupled.

in KHACHATURIAN: CALCIUM × AUTOLYSOSOMAL ACIDIFICATION

Would be settled by. Correcting acidification alone and measuring whether calcium handling normalises, or the reverse.

Moderate (inference) — Calcium dysregulation is a systems failure that sits upstream of the proteinopathies rather than beside them.

in Khachaturian: The Calcium Hypothesis & Systems Failure

Would be settled by. Correcting calcium handling alone in a model and showing proteinopathy is prevented rather than merely reduced.

Moderate (inference) — Calcium dysregulation is a systems failure that sits upstream of the proteinopathies rather than beside them.

in KHACHATURIAN: THE CALCIUM HYPOTHESIS & SYSTEMS FAILURE

Would be settled by. Correcting calcium handling alone in a model and showing proteinopathy is prevented rather than merely reduced.

Moderate (inference) — The corpus's own model is weaker than it has admitted in three places, including that its perineuronal-net arm is largely animal and post-mortem.

in LOW SIGNAL, HIGH NOISE

Moderate (inference, the paper's own claim) — Diverse upstream insults — familial mutations, viral infection, environmental toxins — are mechanistically unified by converging on the autophagy-lysosomal system.

in Many Causes, One Bottleneck

Would be settled by. Blocking the bottleneck downstream of two unrelated upstream insults and showing both are arrested to the same degree.

Moderate (inference, the paper's own claim) — Diverse upstream insults — familial mutations, viral infection, environmental toxins — are mechanistically unified by converging on the autophagy-lysosomal system.

in MANY CAUSES, ONE BOTTLENECK

Would be settled by. Blocking the bottleneck downstream of two unrelated upstream insults and showing both are arrested to the same degree.

Moderate (inference) — Fischer's terms map onto modern molecular categories closely enough for the mapping to be informative rather than merely suggestive.

in Mapping 1907 Terms to Modern Science

Moderate (inference) — Fischer's terms map onto modern molecular categories closely enough for the mapping to be informative rather than merely suggestive.

in MAPPING 1907 TERMS TO MODERN SCIENCE

Moderate (inference, the paper's own claim) — A vascular Phase 0 precedes bioenergetic ignition, so the Phase I-III architecture is incomplete without it.

in MAPPING THE VASCULAR DIMENSION ONTO THE GENETIC DIMENSION

Would be settled by. A cohort with both vascular integrity measures and brainstem tau imaging, showing which becomes abnormal first in the same individuals.

Would be refuted by. Vascular measures found normal in subjects already carrying locus-coeruleus pathology, which would place the vascular layer downstream rather than prior.

Moderate (inference) — The Phase 0 genome is largely orthogonal to the Phase I-III genome, converging on it through three integrative nodes — APOE, TREM2 and the matrix.

in MAPPING THE VASCULAR DIMENSION ONTO THE GENETIC DIMENSION

Moderate (inference, the programme's own claim) — Synapses are dismantled from within by a regulated proteostatic programme rather than destroyed from without.

in Margolis: How Synapses Are Dismantled from Within

Would be settled by. Blocking the internal programme and showing synapses survive an otherwise sufficient external insult.

Moderate (inference, the programme's own claim) — Synapses are dismantled from within by a regulated proteostatic programme rather than destroyed from without.

in MARGOLIS: HOW SYNAPSES ARE DISMANTLED FROM WITHIN

Would be settled by. Blocking the internal programme and showing synapses survive an otherwise sufficient external insult.

Moderate (inference, the paper's own claim) — The proximate cause of symptomatic decline in late disease is structural digestion of perineuronal nets rather than protein aggregation.

in MMP-9 Inhibitors and the Phase III Therapeutic Window

Would be settled by. Preventing net digestion in a model that continues to accumulate protein, and showing cognition is preserved.

Would be refuted by. Net digestion blocked without preservation of function, which would make the matrix a marker rather than the mechanism.

Moderate (inference, the programme's own claim) — Chronic excitatory insufficiency is the root cause — the network is tipped toward inhibition and amyloid and tau are compensatory sensitisers rather than toxins.

in Moosmann & Sohre: NMDA Failure as the Root Cause

Would be settled by. Direct measurement of net excitatory-inhibitory balance in early human disease, rather than inference from downstream phenomena.

Moderate (inference, the programme's own claim) — Chronic excitatory insufficiency is the root cause — the network is tipped toward inhibition and amyloid and tau are compensatory sensitisers rather than toxins.

in MOOSMANN & SOHRE: NMDA FAILURE AS THE ROOT CAUSE

Would be settled by. Direct measurement of net excitatory-inhibitory balance in early human disease, rather than inference from downstream phenomena.

Moderate (inference, the paper's own claim) — One clearance mechanism underlies Alzheimer's, Parkinson's, ALS and Huntington's — the diseases differ in which cells fail rather than in how.

in One Mechanism, Many Diseases (AD, PD, ALS, HD)

Would be settled by. A clearance lesion introduced into different vulnerable populations, reproducing each disease's phenotype in turn.

Moderate (inference, the paper's own claim) — One clearance mechanism underlies Alzheimer's, Parkinson's, ALS and Huntington's — the diseases differ in which cells fail rather than in how.

in ONE MECHANISM, MANY DISEASES (AD, PD, ALS, HD)

Would be settled by. A clearance lesion introduced into different vulnerable populations, reproducing each disease's phenotype in turn.

Moderate (inference, the paper's own claim) — One sensor drives two distinct collapses — the proteinopathy road and the matrix road — rather than one collapse with two descriptions.

in ONE SENSOR, TWO COLLAPSES: THE AGGREGATIVE AND PROTEOLYTIC ARMS OF THE MICROGLIAL NLRP3 INFLAMMASOME IN ALZHEIMER'S DISEASE

Would be settled by. Inflammasome manipulation with proteinopathy and matrix readouts taken together, showing they can be dissociated.

Moderate (inference, the corpus's own claim) — PARP-driven NAD+ erosion is the specific mechanism of slow cell-autonomous attrition in coerulean neurons.

in PARP Inhibitors and the Locus Coeruleus

Would be settled by. PARP activity and NAD+ measured in human locus coeruleus across early Braak stages.

Moderate (inference, the paper's own claim) — Perineuronal net degradation is a mechanistic contributor to Alzheimer pathogenesis rather than a downstream marker of it.

in Perineuronal Nets, Microglial Neuroinflammation, and Alzheimer's

Would be settled by. Protecting the net in a model that otherwise proceeds, and showing the cognitive phenotype is delayed.

Moderate (inference, the paper's own claim) — Perineuronal net degradation is a mechanistic contributor to Alzheimer pathogenesis rather than a downstream marker of it.

in PERINEURONAL NETS, MICROGLIAL NEUROINFLAMMATION, AND ALZHEIMER'S

Would be settled by. Protecting the net in a model that otherwise proceeds, and showing the cognitive phenotype is delayed.

Moderate (inference, the paper's own claim) — The plaque is the residue of a dead neuron rather than the agent of its death.

in Plaques Are Tombstones, Not Killers

Would be settled by. High-resolution longitudinal pathology establishing whether dense-core plaques form at sites of neuronal death or seed independently.

Moderate (inference, the paper's own claim) — The plaque is the residue of a dead neuron rather than the agent of its death.

in PLAQUES ARE TOMBSTONES, NOT KILLERS

Would be settled by. High-resolution longitudinal pathology establishing whether dense-core plaques form at sites of neuronal death or seed independently.

Moderate (inference) — The seeded-inoculation paradigm reflects the natural initiating mechanism of sporadic disease rather than only demonstrating that propagation is possible.

in Proving That Misfolded Proteins Spread Like Prions

Would be settled by. Identification of a naturally occurring seeding event in sporadic human disease, rather than inference from experimental inoculation.

Moderate (inference) — The seeded-inoculation paradigm reflects the natural initiating mechanism of sporadic disease rather than only demonstrating that propagation is possible.

in PROVING THAT MISFOLDED PROTEINS SPREAD LIKE PRIONS

Would be settled by. Identification of a naturally occurring seeding event in sporadic human disease, rather than inference from experimental inoculation.

Moderate (inference, the programme's own claim) — Lipid peroxidation, not amyloid, is the primary driver — with amyloid and tau appearing downstream of ApoER2 crosslinking and signalling failure.

in Ramsden: When Oxidative Damage Reaches the Synapse

Would be settled by. An intervention that blocks peroxidation-driven crosslinking specifically, showing amyloid and tau pathology are prevented downstream.

Moderate (inference, the programme's own claim) — Lipid peroxidation, not amyloid, is the primary driver — with amyloid and tau appearing downstream of ApoER2 crosslinking and signalling failure.

in RAMSDEN: WHEN OXIDATIVE DAMAGE REACHES THE SYNAPSE

Would be settled by. An intervention that blocks peroxidation-driven crosslinking specifically, showing amyloid and tau pathology are prevented downstream.

Moderate (inference, the programme's own claim) — Alzheimer's disease is a failure of adaptive response plasticity at that membrane gate rather than a proteinopathy.

in Rappoport: The Lipid-Raft Hypothesis and Adaptive Response Plasticity

Would be settled by. A manipulation of domain assembly that reproduces or prevents the disease phenotype independently of protein burden.

Moderate (inference, the programme's own claim) — Alzheimer's disease is a failure of adaptive response plasticity at that membrane gate rather than a proteinopathy.

in RAPPOPORT: THE LIPID-RAFT HYPOTHESIS AND ADAPTIVE RESPONSE PLASTICITY

Would be settled by. A manipulation of domain assembly that reproduces or prevents the disease phenotype independently of protein burden.

Moderate (inference) — Synapse elimination therefore has a neuron-intrinsic arm requiring no microglion.

in Shatz & Brott: Complement-Mediated Synaptic Pruning

Would be settled by. Demonstration in human tissue, or in a microglia-depleted preparation, that spine loss proceeds on the C4d-LilrB2 route alone.

Moderate (inference) — Synapse elimination therefore has a neuron-intrinsic arm requiring no microglion.

in SHATZ & BROTT: COMPLEMENT-MEDIATED SYNAPTIC PRUNING

Would be settled by. Demonstration in human tissue, or in a microglia-depleted preparation, that spine loss proceeds on the C4d-LilrB2 route alone.

Moderate (inference) — Retromer dysfunction is upstream of amyloid rather than a parallel abnormality.

in Small: The Endosomal Traffic Jam

Would be settled by. Restoring retromer function alone in a model and showing deposition is prevented rather than merely reduced.

Moderate (inference) — Retromer dysfunction is upstream of amyloid rather than a parallel abnormality.

in SMALL: THE ENDOSOMAL TRAFFIC JAM

Would be settled by. Restoring retromer function alone in a model and showing deposition is prevented rather than merely reduced.

Moderate (inference) — The panel measures the disease rather than one lane of it.

in Standard Diagnostic Biomarkers Explained

Would be settled by. A biomarker sensitive to brainstem involvement, which would test whether the current panel is missing an earlier phase.

Moderate (inference) — The panel measures the disease rather than one lane of it.

in STANDARD DIAGNOSTIC BIOMARKERS EXPLAINED

Would be settled by. A biomarker sensitive to brainstem involvement, which would test whether the current panel is missing an earlier phase.

Moderate (inference) — A mechanistic rather than syndromic nosology would classify these conditions better.

in Telling Different Dementias Apart

Would be settled by. A mechanistic classification shown to predict course or treatment response better than the syndromic one.

Moderate (inference) — A mechanistic rather than syndromic nosology would classify these conditions better.

in TELLING DIFFERENT DEMENTIAS APART

Would be settled by. A mechanistic classification shown to predict course or treatment response better than the syndromic one.

Moderate (inference, the corpus's own claim) — These components form a single coherent cascade in the stated order.

in TERMINAL COLLAPSE

Moderate (inference, the paper's own claim) — Overlaying the protocol on the autophagy-lysosomal failure account identifies which of its components could plausibly act and which could not.

in Testing a Popular Treatment Protocol

Moderate (inference, the paper's own claim) — Overlaying the protocol on the autophagy-lysosomal failure account identifies which of its components could plausibly act and which could not.

in TESTING A POPULAR TREATMENT PROTOCOL

Moderate (inference, the paper's own claim) — The trilogy's treatment of the neuronal substrate as a fixed population is an oversimplification that the adult-born neuron corrects.

in THE ADULT-BORN NEURON

Moderate — in Alzheimer's disease the sulfation code drifts from reelin-staging (N-) toward tau-serving (3-O-/6-O-), with HS3ST2 upregulated in the diseased hippocampus

in THE ARCHITECT'S HANDSHAKE

Moderate — reelin-bearing entorhinal neurons are selectively depleted early, subtracting interfaces from the vulnerable circuit

in THE ARCHITECT'S HANDSHAKE

Moderate — reelin-expressing entorhinal neurons are selectively depleted early in the disease

in THE ARCHITECT'S REPRIEVE

Moderate — the reelin-immunoreactive neurons of entorhinal layer II are the population in which the earliest intracellular amyloid appears

in THE ARCHITECT'S REPRIEVE

Moderate — reducing reelin accelerates amyloid and tau pathology in vivo

in THE ARCHITECT'S REPRIEVE

Moderate — restoring or supplementing reelin signalling rescues cognition and synapses in disease models

in THE ARCHITECT'S REPRIEVE

Moderate — perineuronal-net-ensheathed neurons are relatively protected from tau pathology

in THE ARCHITECT'S SCAFFOLD

Moderate — perineuronal nets are degraded by activated microglia in Alzheimer's disease

in THE ARCHITECT'S SCAFFOLD

Moderate — the perineuronal matrix functions as a sulfation-addressed reservoir for surface-signalling proteins

in THE ARCHITECT'S SCAFFOLD

Moderate (inference) — The reelin variant is the cause of that protection rather than a coincident finding.

in THE ARCHITECT'S UNDERSTUDY

Would be settled by. A second independent carrier of the same variant with a comparable delay, or a model reproducing the protection.

Moderate (inference, the paper's own claim) — A defence is as informative as a lesion: every protective allele names a step the disease must pass through.

in THE ARCHITECTURE OF RESISTANCE

Moderate (inference, the corpus's own claim) — The biomarker cascade maps onto the corpus's three phases rather than describing a different partition.

in THE BIOMARKER CASCADE

Would be settled by. A brainstem-sensitive biomarker that detects Phase I, which would let the two staging schemes be compared directly rather than aligned by argument.

Moderate (inference, the programme's own claim) — The cysteine difference matters through lipid peroxidation chemistry — a bond that ApoE4 cannot make.

in THE BOND NOT MADE

Would be settled by. A human measurement tying peroxidation adduct burden to genotype and to outcome in the same subjects.

Moderate (inference) — Amyloid deposition in human disease is, at least in part, an antimicrobial response rather than a purely pathological accumulation.

in The Brain's Own Antimicrobial Defense

Would be settled by. Demonstration that deposition in human brain tracks microbial burden rather than the other risk structure of the disease.

Moderate (inference) — Amyloid deposition in human disease is, at least in part, an antimicrobial response rather than a purely pathological accumulation.

in THE BRAIN'S OWN ANTIMICROBIAL DEFENSE

Would be settled by. Demonstration that deposition in human brain tracks microbial burden rather than the other risk structure of the disease.

Moderate (inference) — Synapse elimination in this disease has a neuron-intrinsic arm requiring no microglion.

in THE BRAKE AND THE BLADE

Moderate (inference) — Those facts are better explained by amyloid being the initiating cause than by amyloid being one validated node in a multi-lane architecture.

in THE CASE FOR THE CASCADE

Would be settled by. Presymptomatic anti-amyloid intervention in autosomal dominant carriers with a cognitive endpoint, which separates initiating-cause from downstream-node more cleanly than any trial run so far.

Moderate (inference, the paper's own claim) — The decline of autophagic flux with age is a causative driver of senescence rather than a passive correlate of it.

in The Cell's Garbage System Controls Aging

Would be settled by. Restoring flux alone in an otherwise ageing system and showing the senescent phenotype is delayed rather than merely accompanied.

Moderate (inference, the paper's own claim) — The decline of autophagic flux with age is a causative driver of senescence rather than a passive correlate of it.

in THE CELL'S GARBAGE SYSTEM CONTROLS AGING

Would be settled by. Restoring flux alone in an otherwise ageing system and showing the senescent phenotype is delayed rather than merely accompanied.

Moderate (inference, the paper's own claim) — The census — which cells and how many, cell type by cell type and synapse class by synapse class — resolves the disease in cellular space as its companion resolves it in time.

in THE CELLULAR ARCHITECTURE OF COLLAPSE

Would be settled by. A single cohort counted across all the populations in the census with one method, testing whether the relative ordering survives.

Moderate (inference) — The three failures are one machinery, not three that converge.

in THE CLEARANCE COLLAPSE

Would be settled by. A cell or animal carrying a single acidification lesion showing mitochondrial, lipid and endosomal cargo accumulating together and in proportion, without three separate insults.

Would be refuted by. A cell carrying both a closure lesion and an acidification lesion accumulating cargo faster than one carrying the more severe single lesion — which would mean the pipeline is not a single directional pipeline.

Moderate (imported, contested in scope) — Microglial metabolic failure is autophagy-dependent.

in THE CLEARANCE COLLAPSE

Moderate (inference, the paper's own claim) — Reciting the two together has produced a consequential error — they describe two processes, not one continuous one from beginning to end.

in THE COERULEAN CLOCK

Would be settled by. Stage-resolved counts in the same nucleus across Braak stages, showing whether depopulation tracks the early tau or begins separately.

Would be refuted by. A continuous monotonic relation between pretangle burden and cell loss across stages, which would restore the single-process reading.

Moderate (inference, the paper's own claim) — The vagal-coerulean interface is a route by which peripheral inflammation initiates or accelerates the earliest phase.

in THE COERULEAN INTERFACE: VAGAL INFLAMMATORY LOAD, NORADRENERGIC RESTRAINT, AND THE MICROGLIAL FATE OF THE LOCUS COERULEUS IN ALZHEIMER'S DISEASE

Would be settled by. Vagotomy or vagal modulation in a model, measuring coerulean tau rather than a general inflammatory readout.

Moderate — chronic norepinephrine excess over-activates glycogen-synthase-kinase-3β and drives tau, constituting the second arm

in THE COERULEAN PINCER

Moderate — matrix metalloproteinase-9 degrades the lectican perineuronal net in the brain

in THE COERULEAN PINCER

Moderate — to-plausible — norepinephrine induces matrix metalloproteinase-9 in the brain through β-adrenergic receptors on microglia and astrocytes (the first arm's receptor joint)

in THE COERULEAN PINCER

Moderate — the noradrenergic output rises, not falls, during the pathogenic window (the excess the pincer requires)

in THE COERULEAN PINCER

Moderate — MMP-9 degrades the lectican core proteins of the perineuronal net in the brain

in THE COERULEAN SHEARS

Moderate — the apolipoprotein-E ε4 allele raises the MMP-9 tone that unstages reelin

in THE COERULEAN SHEARS

Moderate — to-plausible — norepinephrine induces MMP-9 in the brain through β-adrenergic receptors on microglia and astrocytes

in THE COERULEAN SHEARS

Moderate (inference, the corpus's own frame) — Complement pruning is the principal destructive output of post-homeostatic microglia rather than one of several.

in THE COMPLEMENT-PRUNING SUBSTRATE

Would be settled by. Blocking each output arm separately in the same model and comparing the synaptic loss prevented.

Moderate (inference, the paper's own claim) — The single-sentence account — extra APP, more amyloid, earlier disease — is a profound under-reading of what trisomy 21 does.

in THE COMPRESSED ARCHITECTURE

Would be settled by. Isolating APP dosage from the rest of trisomy 21 — as partial trisomies and APP-normalised models allow — and asking how much of the phenotype survives.

Moderate (inference) — The contested residue is nonetheless the right place to look — the conflict is substantive rather than technical.

in The Contested Serine

Moderate (inference, the corpus's own frame) — Failure of noradrenergic governance is a principal cause of that turn, though not the only one.

in THE CORRUPTION OF THE GARDENER

Would be settled by. Restoring noradrenergic tone alone in a model with established matrix degradation, and measuring how much of the turn reverses.

Moderate (inference, the corpus's own frame) — These states are post-homeostatic trajectories from a Butovsky-defined baseline rather than independent populations.

in THE DAM TRAJECTORY AND THE MATRIX-DEGRADING ARM

Would be settled by. Lineage tracing or live longitudinal imaging showing the transition occurring in individual cells.

Moderate (inference, the paper's own claim) — Depression and Alzheimer's disease lie on one continuum, differing in the reversibility of the same axis failures rather than in their identity.

in THE DEPRESSION CONTINUUM

Would be settled by. Longitudinal measurement of the five axes across subjects moving from depressive to neurodegenerative phenotype, testing whether the axes are shared and the difference is in reversibility.

Would be refuted by. An axis found engaged in one condition and demonstrably absent in the other.

Moderate (inference, the paper's own claim) — Everything previously described as microglial activation is better read as the successive lapse of a braking system on a cell that is dangerous by constitution.

in THE DOUBLE RELEASE

Would be settled by. Identification of a brake whose restoration alone reverses a phenotype previously attributed to activation.

Moderate (inference) — Fischer's staging is a developmental sequence of one lesion rather than a taxonomy of several.

in The Eight Stages

Moderate (inference, the corpus's own claim) — This is the mechanism by which a bioenergetic deficit becomes tau-specific pathology in Alzheimer's disease.

in THE ENERGY-GATED TAUOPATHY

Would be settled by. Complex I activity measured against tau burden in human brainstem across early stages.

Moderate (inference, the paper's own claim) — The epigenetic layer lies upstream of the senescent state and is what the corpus's use of the word ageing ultimately refers to.

in THE FADING SCORE

Would be settled by. Manipulating the epigenetic layer alone and showing the senescent state follows rather than accompanies.

Moderate (inference, the programme's own claim) — The microbial ecosystem is the most upstream and most modifiable variable in the chain ending at the disease.

in THE FERMENTED PRODROME: THE GUT MICROBIOME AS THE ECOLOGICAL ORIGIN OF DEPRESSION, AND DEPRESSION AS THE FIRST REVERSIBLE READING OF THE COLLAPSE CONTINUUM

Would be settled by. A microbiome intervention with a downstream neurodegenerative endpoint, rather than a composition-outcome association.

Moderate (inference, the corpus's own claim) — The four substrates are co-extensive and held by a TGF-beta/SMAD loop gated by an APOE/LRP1 lipid-availability axis, so resilience lies in their joint preservation.

in The Fifth Surface

Would be settled by. Preserving three substrates while ablating the fourth and testing whether resilience is lost, which the joint-preservation claim requires.

Moderate (inference, the paper's own claim) — The opposite effects are explained by when the drug is given — the same agent acting on a different phase of the disease.

in THE FIFTY-YEAR PRESCRIPTION

Would be settled by. An SSRI trial stratified by disease stage with both amyloid-kinetic and cognitive endpoints.

Would be refuted by. Cognitive worsening found in presymptomatic subjects too, which would make the effect stage-independent and the prescription unsafe rather than mistimed.

Moderate (mechanistic, partly inferred) — norepinephrine reaches the cytosol through activity-dependent over-reuptake as autoreceptors internalise

in THE FIRST EMBER

Moderate (inference, the corpus's own reading) — Entrainment works, where it works, by restoring interneuron function and the metabolic support of the circuit rather than by clearing amyloid directly.

in THE GAMMA INTERVENTION

Moderate (inference, the paper's own claim) — Resilience is an active state maintained by microglial restraint, not merely the absence of a second insult.

in THE GARDENER'S RESTRAINT

Would be settled by. Removing the proposed restraint in an otherwise resilient brain or model and showing the cognitive phenotype appears.

Moderate (inference, the paper's own claim) — The genes implicated in neurodegeneration are a temporally structured architecture, different genes being load-bearing at different biological moments, rather than a flat list of risk modifiers.

in THE GENETIC ARCHITECTURE OF NEURODEGENERATION

Would be settled by. A longitudinal cohort with staged biomarkers in which the genes carrying risk at conversion differ from those carrying risk at symptom onset.

Moderate (inference) — APOE acts through three mechanistically distinct routes, one in each phase, rather than through a single lipid-transport mechanism.

in THE GENETIC ARCHITECTURE OF NEURODEGENERATION

Moderate (inference, the paper's own claim) — A causal grading matrix can rank each cellular element's contribution by its chronological appearance in the cascade.

in The Glial Consortium and the Timeline of Collapse

Would be settled by. Intervention at each element in turn, measuring effect size rather than inferring it from timing.

Moderate (inference, the paper's own claim) — A causal grading matrix can rank each cellular element's contribution by its chronological appearance in the cascade.

in THE GLIAL CONSORTIUM AND THE TIMELINE OF COLLAPSE

Would be settled by. Intervention at each element in turn, measuring effect size rather than inferring it from timing.

Moderate (inference, the paper's own claim) — Extracellular clearance failure completes the intracellular account of the companion volume — one clearance failure at two scales.

in THE GLYMPHATIC COLLAPSE

Moderate (inference, the paper's own claim) — Sporadic Alzheimer's disease emerges from the simultaneous, parallel failure of these substrates rather than from a linear cascade among them.

in The Homeostatic–Matrix–Synaptic (HMS) Collapse Model

Would be settled by. Time-resolved measurement of two or more of the eight substrates in the same tissue, testing whether they fail together or in order.

Would be refuted by. A reproducible ordering among the substrates, which would make the model a cascade after all.

Moderate (inference, the paper's own claim) — Sporadic Alzheimer's disease emerges from the simultaneous, parallel failure of these substrates rather than from a linear cascade among them.

in THE HOMEOSTATIC–MATRIX–SYNAPTIC (HMS) COLLAPSE MODEL

Would be settled by. Time-resolved measurement of two or more of the eight substrates in the same tissue, testing whether they fail together or in order.

Would be refuted by. A reproducible ordering among the substrates, which would make the model a cascade after all.

Moderate — the reset is implemented by the alternation the somatostatin cell schedules

in THE HOMEWARD VECTOR

Moderate — the deficit in getting lost is in the reset rather than the metric

in THE HOMEWARD VECTOR

Moderate — cholinergic denervation degrades both the metric and the switch

in THE HOMEWARD VECTOR

Moderate — sundowning reflects circadian phase delay

in THE HOMEWARD VECTOR

Moderate (inference, the corpus's own claim) — The immunometabolic checkpoint is where NAD+ availability converts into microglial state — the link the bioenergetic thesis left unspecified.

in THE IMMUNOMETABOLIC CHECKPOINT

Would be settled by. CD38 manipulation with microglial state as the readout in the same preparation.

Moderate (inference, the corpus's own claim) — The inflammasome, complement and TREM2 axes intersect at a definable nexus rather than acting in parallel.

in THE INFLAMMASOME-COMPLEMENT-TREM2 NEXUS

Would be settled by. Manipulating one axis and reading the other two in the same preparation.

Moderate (inference, the paper's own claim) — Ceramide is read in two opposite directions by the clinic because it genuinely has two faces, and a therapeutic strategy must respect both.

in The Janus Lipid

Would be settled by. Dose-ranging ceramide modulation showing a window rather than a monotonic response.

Moderate (inference, the paper's own claim) — Ketamine's effects present a paradox for the corpus's account — an NMDA antagonist helping where the account predicts excitatory insufficiency should be worsened.

in THE KETAMINE PARADOX

Would be settled by. Cell-type-resolved measurement of ketamine's effect on parvalbumin versus pyramidal populations in an Alzheimer model.

Moderate (inference, the paper's own claim) — A specific tyrosine phosphorylation licenses the switch between those activities, and its dysregulation is where the disease acts on the spine.

in The Licensing Tyrosine

Would be settled by. Blocking the phosphorylation alone and showing spine loss is prevented under an otherwise disease-competent insult.

Moderate (inference, the paper's own claim) — The therapeutic inference that ceramide should therefore be lowered is wrong, because ceramide is load-bearing as well as damaging.

in The Load-Bearing Lipid

Would be settled by. A dose-ranging intervention showing a therapeutic window with harm at the low end, rather than monotonic benefit.

Would be refuted by. Monotonic benefit from ceramide reduction across the achievable range, which would vindicate the simple inference.

Moderate (inference) — There is a noradrenergic prodrome — a clinically detectable period of coerulean dysfunction preceding cognitive symptoms.

in The Locus Coeruleus & the Noradrenergic Prodrome

Would be settled by. Coerulean integrity imaging against prodromal symptom measures in the same subjects, longitudinally.

Moderate (inference) — There is a noradrenergic prodrome — a clinically detectable period of coerulean dysfunction preceding cognitive symptoms.

in THE LOCUS COERULEUS & THE NORADRENERGIC PRODROME

Would be settled by. Coerulean integrity imaging against prodromal symptom measures in the same subjects, longitudinally.

Moderate (inference, the corpus's own claim) — Loss of that projection is the bridge from the bioenergetic phase to the microglial phase — the mechanism by which one phase hands over to the next.

in THE LOCUS COERULEUS BRIDGE

Would be settled by. Ablating the projection in an otherwise healthy animal and showing the microglial phenotype follows on the predicted timescale.

Would be refuted by. Microglial collapse proceeding normally with noradrenergic tone preserved.

Moderate (inference, the programme's own claim) — Amyloid-beta is a competition signal — secreted by an axon to protect itself and mark its rivals — rather than primarily a toxin.

in THE LOSING AXON

Would be settled by. Demonstration that manipulating amyloid secretion by one axon changes the survival of a competing axon specifically, rather than through a general toxic effect.

Moderate (inference, the paper's own claim) — All roads lead to the same failure — the diverse etiologies of dementia converge on clearance breakdown.

in The Master Theory: Why All Roads Lead to the Same Failure

Would be settled by. An etiology shown to produce the disease phenotype without passing through clearance failure, which would bound the convergence.

Would be refuted by. That same result, if found, refutes the master framing rather than merely bounding it.

Moderate (inference, the paper's own claim) — All roads lead to the same failure — the diverse etiologies of dementia converge on clearance breakdown.

in THE MASTER THEORY: WHY ALL ROADS LEAD TO THE SAME FAILURE

Would be settled by. An etiology shown to produce the disease phenotype without passing through clearance failure, which would bound the convergence.

Would be refuted by. That same result, if found, refutes the master framing rather than merely bounding it.

Moderate (inference, the paper's own claim) — The extracellular matrix is the missing node that the eight frameworks converge on without naming.

in THE MATRIX OF COLLAPSE

Would be settled by. A prediction the matrix node makes that the eight frameworks do not, tested and confirmed.

Moderate (inference, the paper's own claim) — The microbial ecosystem is the prologue — the most upstream modifiable variable in the chain.

in THE MICROBIAL PROLOGUE: THE GUT ECOSYSTEM AS THE UPSTREAM ORIGIN OF THE VAGAL–COERULEAN CASCADE IN NEURODEGENERATION

Would be settled by. A microbiome intervention with a brainstem or neurodegenerative endpoint rather than a compositional one.

Moderate (inference, the paper's own claim) — The attack and failure models are not rivals but sequential states of one trajectory, so the apparent incompatibility dissolves once time is added.

in The Microglial Thesis (Downloadable PDF)

Would be settled by. Longitudinal or pseudotemporal single-cell trajectories in human tissue showing the attacking state as a precursor of the exhausted one rather than a parallel lineage.

Would be refuted by. Attacking and exhausted populations shown to arise from separate precursors, which would make them genuinely different cells rather than different moments.

Moderate (inference, the paper's own claim) — The attack and failure models are not rivals but sequential states of one trajectory, so the apparent incompatibility dissolves once time is added.

in THE MICROGLIAL THESIS (DOWNLOADABLE PDF)

Would be settled by. Longitudinal or pseudotemporal single-cell trajectories in human tissue showing the attacking state as a precursor of the exhausted one rather than a parallel lineage.

Would be refuted by. Attacking and exhausted populations shown to arise from separate precursors, which would make them genuinely different cells rather than different moments.

Moderate (inference, the paper's own claim) — Mitochondrial quality-control failure is a shared upstream substrate whose cell-type-specific manifestation determines which clinical phenotype appears.

in THE MITOCHONDRION AS NEXUS: FUNCTION, DYSFUNCTION, AND THE BIOENERGETIC ARCHITECTURE OF NEURODEGENERATION

Would be settled by. A single quality-control lesion introduced into different neuronal populations, producing the phenotype characteristic of each population's disease.

Moderate — physical activity attenuates the coupling of amyloid burden to cognitive decline in the preclinical brain

in THE MUSCLE'S ERRAND

Moderate — a multidomain lifestyle intervention including exercise slows cognitive decline in at-risk, non-demented elders

in THE MUSCLE'S ERRAND

Moderate (inference) — The mitochondrial import channel is a plausible mechanistic route by which the locus could act, independent of lipid transport.

in The Narrow Gate

Moderate (inference, the paper's own claim) — The inflammasome axis and the matrix axis are coupled — the speck and the net act on one another rather than in parallel.

in THE NET AND THE SPECK: THE NLRP INFLAMMASOME AND THE PERINEURONAL NET IN ALZHEIMER'S DISEASE

Would be settled by. Inflammasome blockade with matrix integrity as the readout, or matrix protection with inflammasome activity as the readout.

Moderate (inference, the paper's own claim) — Not every vagal afferent signal is equivalent — a noxious subset specifically drives the locus coeruleus beyond its bioenergetic means.

in THE NOXIOUS AFFERENT: THE PERIPHERAL STIMULI BY WHICH THE VAGUS NERVE HARMS THE LOCUS COERULEUS

Would be settled by. Selective stimulation of the noxious subset with a coerulean metabolic readout.

Moderate — to-strong — regulatory T cell amplification (low-dose interleukin-2) is protective in animal models

in THE PEACEKEEPER'S PARADOX

Moderate — regulatory T cell function is impaired in established human Alzheimer's disease

in THE PEACEKEEPER'S PARADOX

Moderate (inference, the paper's own claim) — The transition between microglial failure and synaptic collapse — not either state — is where the disease becomes irreversible.

in THE PERINEURONAL TURN

Would be settled by. An intervention effective before the turn and ineffective after it, in the same model, which would locate the threshold rather than assume it.

Moderate (inference, the paper's own claim) — Effective therapeutics will have to act on the parenchymal TGF-beta niche and the peripheral gate simultaneously.

in The Peripheral Arm of Homeostatic Collapse

Would be settled by. A single-compartment intervention shown to be insufficient where a dual intervention succeeds.

Moderate (inference, the paper's own claim) — Effective therapeutics will have to act on the parenchymal TGF-beta niche and the peripheral gate simultaneously.

in THE PERIPHERAL ARM OF HOMEOSTATIC COLLAPSE

Would be settled by. A single-compartment intervention shown to be insufficient where a dual intervention succeeds.

Moderate (inference, the paper's own claim) — Declining melatonergic support is a mechanism of coerulean vulnerability rather than a parallel feature of ageing.

in THE PINEAL INTERFACE: MELATONERGIC WITHDRAWAL, CIRCADIAN DISINTEGRATION, AND THE UNDEFENDED LOCUS COERULEUS IN ALZHEIMER'S DISEASE

Would be settled by. Melatonergic support maintained in an ageing model, with coerulean tau as the readout.

Moderate (inference, the paper's own claim) — Apathy and weight loss in the prodrome are consequences of mesolimbic dopamine loss — the price of effort rising.

in The Price and the Permission

Would be settled by. Dopaminergic imaging of the VTA against prodromal apathy measures in the same subjects.

Moderate (inference, the corpus's own frame) — The three-phase partition — bioenergetic ignition in the brainstem, microglial inflection in the hippocampus, structural disintegration of the cortical matrix — is the right partition of the natural history.

in THE PROTEOLYTIC TURN

Would be settled by. A longitudinal cohort staged on brainstem, hippocampal and cortical markers, entering the phases in the stated order.

Moderate (inference, the paper's own claim) — There is a proteolytic turn — a definable transition at which the microglial phase gives way to matrix digestion.

in THE PROTEOLYTIC TURN

Would be settled by. Time-resolved measurement of matrix-degrading activity against microglial state in the same tissue, showing a turn rather than a ramp.

Moderate (inference, the corpus's own correction) — Classifying Tsai's programme as therapeutic-rescue is correct for GENUS but wrong for the wider programme, which is causal in position.

in THE PV+/GAMMA AXIS

Moderate (inference, the paper's own claim) — Sleep is the shared off-line state that every axis of collapse depends on, and its withdrawal from the locus coeruleus is a mechanism rather than an accompaniment.

in THE RESTORATIVE INTERVAL: SLEEP AS THE SHARED OFF-LINE STATE OF THE COLLAPSING BRAIN, AND ITS WITHDRAWAL FROM THE LOCUS COERULEUS IN ALZHEIMER'S DISEASE

Would be settled by. A sleep intervention in the preclinical window with an amyloid-accumulation endpoint.

Moderate (inference, the paper's own claim) — The nine accounts are descriptions of one failure seen from nine positions, not nine competing mechanisms.

in THE RETURN LEG

Would be settled by. An intervention against one programme's mechanism producing the phenotype another programme predicts, which would show the mechanisms are coupled rather than parallel.

Would be refuted by. Two of the nine mechanisms shown to be independently sufficient for synapse loss in the same preparation, which would make them alternatives rather than aspects.

Moderate (inference, the paper's own claim) — Because it is the same machine, amyloid production and synaptic maintenance cannot be separated — anything that loads the machine degrades the synapse.

in THE SAME MACHINE

Would be settled by. Increasing amyloid production without loading the recycling compartments, and asking whether synaptic function is spared.

Moderate (inference, the paper's own method) — A second reading against the convergence framework grades the submissions more informatively than the original tiering did.

in The Second Reading

Moderate (inference, the corpus's own frame) — The tripartite temporal architecture — brainstem bioenergetic, hippocampal microglial, cortical matrix — is the right partition of the disease's natural history.

in THE SENESCENT FRONT

Would be settled by. A longitudinal cohort staged on all three substrates, entering them in the stated order.

Moderate (inference, the paper's own claim) — Senescence is the front that unifies the three phases beneath the sequence — the age-dependent process the whole architecture rests on.

in THE SENESCENT FRONT

Would be settled by. Senolytic intervention at a defined phase producing the phase-specific change the architecture predicts, rather than a general improvement.

Moderate (inference, the paper's own claim) — The inflammasome is machinery rather than scenery — a driver of the disease rather than a marker of it.

in THE SENSOR AND THE SPECK: NLRP INFLAMMASOMES, PYROPTOTIC AMPLIFICATION, AND THE INNATE-IMMUNE CONVERSION OF ALZHEIMER'S DISEASE

Would be settled by. Inflammasome ablation in a model with established proteinopathy, showing the phenotype is arrested rather than merely dampened.

Would be refuted by. Ablation leaving the disease course substantially unchanged, which would return the inflammasome to the status of amplifier.

Moderate — to-strong — the NLRP3 inflammasome drives tau pathology by deranging the neuronal balance of tau kinases and phosphatases, and its reach includes the phosphatase

in THE SILENCED ERASER

Moderate — the microglial inflammatory milieu is the driver that mislocalises and cleaves SET, silencing PP2A in the neuron

in THE SILENCED ERASER

Moderate — TGF-β/SMAD signalling is impaired in the Alzheimer brain, contributing to the microglial turn

in THE SILENCED ERASER

Moderate — IL-1β degrades the perineuronal net / sulfated matrix in the Alzheimer brain via the microglial aggrecanase secretome

in THE SPECK AND THE ARCHITECT

Moderate — IL-18 raises GSK-3β in neurons, converging with reelin-unstaging on one kinase

in THE SPECK AND THE ARCHITECT

Moderate (inference, the paper's own claim) — Neuronal death in this disease runs on a spectrum between an intrinsic pole — quality-control failure — and an extrinsic pole — assault after loss of protection — rather than by one mode.

in THE SPECTRUM OF COLLAPSE

Would be settled by. Assigning individual dying neurons in human tissue to positions on the spectrum, rather than inferring the spectrum from the two poles.

Moderate (inference) — Fischer's continuum is a genuine developmental sequence rather than an artefact of sampling different lesions at one moment.

in The Staged Deposit

Would be settled by. Longitudinal imaging or serial models showing individual deposits passing through the stages in the stated order.

Moderate (inference, the entry's own claim) — The shared structure indicates a systematic error — subtraction of an excess that is compensatory rather than causal.

in The Subtraction Error

Would be settled by. A fourth subtraction trial, prospectively predicted by the account to fail, doing so with target engagement demonstrated.

Would be refuted by. A subtraction trial succeeding, which the account holds should not happen for a compensatory excess.

Moderate (inference) — Two distinct routes exist by which a neuron loses synapses and acquires tangles without amyloid acting directly on it.

in The Switch and the Sieve

Would be settled by. Blocking each route separately in the same preparation and measuring how much of the phenotype each accounts for.

Moderate (inference, the entry's own claim) — Applying that instinct one level down — reading a chemical state as a process with a history rather than a static fact — is the right move for the synapse.

in The synapse that could not switch off

Moderate (inference, the paper's own claim) — The deepest structure of the disease is temporal: a stereotyped three-phase progression with two mechanistically specified transitions between the phases.

in THE TEMPORAL ARCHITECTURE OF COLLAPSE

Would be settled by. A longitudinal cohort staged on brainstem, hippocampal and cortical markers, showing the three phases entered in the stated order in the same individuals.

Would be refuted by. Cortical matrix failure found in subjects without antecedent brainstem or microglial involvement, which would break the ordering the architecture asserts.

Moderate (inference, the paper's own claim) — Therapeutics should be matched to disease phase, because an intervention correct for one phase can be inert or harmful in another.

in The Therapeutic Landscape of Collapse

Moderate (inference, the paper's own claim) — Therapeutics should be matched to disease phase, because an intervention correct for one phase can be inert or harmful in another.

in THE THERAPEUTIC LANDSCAPE OF COLLAPSE

Moderate — cerebrospinal fluid production and turnover decline

in THE TIDE-GATE

Moderate — blood–CSF barrier leak and transporter decline

in THE TIDE-GATE

Moderate — to-strong (description) / speculative (therapy) — the immune gateway

in THE TIDE-GATE

Moderate (inference) — The theory's spatial topography claim — that pathology should radiate from the neurogenic niches — is testable against existing staging data.

in THE TROJAN NEUROBLAST

Moderate (inference, the paper's own claim) — The partition of tryptophan between branches is a shared metabolic node at which several axes of the disease meet.

in THE TRYPTOPHAN PARTITION: A SHARED METABOLIC SUBSTRATE IN THE BIOENERGETIC ARCHITECTURE OF NEURODEGENERATION

Would be settled by. Shifting the partition experimentally and measuring the downstream axes together, testing whether they move in concert.

Moderate (inference, the paper's own claim) — A framework can be stated so that it cannot confirm itself, by anchoring it to two independent points that were not chosen to fit it.

in THE TWO ANCHORS

Would be settled by. An anchor that fails — a case where the framework predicts one thing and an anchor says another, recorded rather than absorbed.

Moderate (inference, the programme's own claim) — Failure to clear that signal — leaving the platform assembled — is a mechanism of disease rather than a consequence of it.

in THE UNCLEARED SIGNAL

Would be settled by. Restoring signal clearance alone in a disease model and showing the downstream phenotype resolves.

Moderate (inference, the paper's own claim) — A temporal, cellular and ecological architecture explains those three features together, where single-molecule cascades explain them separately or not at all.

in THE UNIFIED ARCHITECTURE OF COLLAPSE

Moderate (inference) — Amyloid occupies a bounded place in the architecture rather than a primary one, with the boundary conditions stated.

in THE UNIFIED ARCHITECTURE OF COLLAPSE

Moderate — the somatostatin cell's calcium exposure is unusually high and its buffering unusually low

in THE UNNETTED GOVERNOR

Moderate — the somatostatin interneuron is predominantly unnetted while its parvalbumin sibling is predominantly netted, and this explains the order of inhibitory loss

in THE UNNETTED GOVERNOR

Moderate — the somatostatin lesion contributes to Alzheimer network hyperexcitability

in THE UNNETTED GOVERNOR

Moderate (inference, the paper's own claim) — The raphe belongs beside the locus coeruleus as a co-equal early station rather than as a secondary one.

in THE UNPICKED SEAM

Would be settled by. Stage-resolved comparison of the two nuclei in the same brains across early Braak stages.

Moderate (inference, the programme's own claim) — Memory formation runs as a two-stage process — candidate generation, then selection — and the gate between the stages is that membrane domain.

in THE UNTHROWN SWITCH

Would be settled by. Manipulating domain assembly and showing candidate generation and selection dissociate as the two-stage account requires.

Moderate (inference, the corpus's own claim) — That afferent traffic couples the peripheral immunometabolic state to the earliest phase of the disease.

in THE VAGAL INTERFACE: THE TENTH CRANIAL NERVE AS THE PERIPHERAL–CENTRAL CONDUIT OF NEURODEGENERATIVE COLLAPSE

Would be settled by. Vagal manipulation in a model with a brainstem-specific readout rather than a general inflammatory one.

Moderate (inference, the paper's own claim) — The vagus-to-coeruleus connection is a multi-synaptic relay with specifiable anatomy rather than the single arrow the companion volumes drew.

in THE VAGO-COERULEAN RELAY: THE ANATOMICAL AND NEUROCHEMICAL MECHANISMS BY WHICH THE VAGUS NERVE MODULATES THE LOCUS COERULEUS

Would be settled by. Tract-specific manipulation at each relay in turn, measuring coerulean response.

Moderate (inference, the paper's own claim) — The trilogy's parenchymal account is incomplete without the vascular dimension, which contributes actively rather than consequentially.

in THE VASCULAR DIMENSION

Would be settled by. Vascular and parenchymal measures taken together longitudinally, establishing which moves first in the same subjects.

Moderate (inference, the corpus's own frame) — The tripartite temporal architecture — brainstem bioenergetic, hippocampal microglial, cortical matrix — is the right partition of the disease's natural history.

in THE VASCULAR PHASING: CEREBROVASCULAR PATHOLOGY ACROSS THE THREE TEMPORAL PHASES OF THE COLLAPSE TRILOGY

Would be settled by. A longitudinal cohort staged on all three substrates, entering them in the stated order.

Moderate (inference, the paper's own claim) — Vascular pathology phases with the parenchymal sequence rather than accumulating independently alongside it.

in THE VASCULAR PHASING: CEREBROVASCULAR PATHOLOGY ACROSS THE THREE TEMPORAL PHASES OF THE COLLAPSE TRILOGY

Would be settled by. Vascular and parenchymal markers measured together longitudinally, testing for coupling rather than co-occurrence.

Moderate (inference, the corpus's own frame) — The three-phase partition — bioenergetic ignition in the brainstem, microglial inflection in the hippocampus, structural disintegration of the cortical matrix — is the right partition of the natural history.

in THE VIRAL TRAJECTORY: PATHOGEN REACTIVATION ACROSS THE THREE TEMPORAL PHASES OF ALZHEIMER'S DISEASE

Would be settled by. A longitudinal cohort staged on brainstem, hippocampal and cortical markers, entering the phases in the stated order.

Moderate (inference, the paper's own claim) — Pathogen reactivation maps onto the three phases, contributing differently in each rather than acting as a single insult.

in THE VIRAL TRAJECTORY: PATHOGEN REACTIVATION ACROSS THE THREE TEMPORAL PHASES OF ALZHEIMER'S DISEASE

Would be settled by. Reactivation measured longitudinally against phase-specific markers, showing the contribution changes with phase.

Moderate (inference, the programme's own claim) — MAM dysfunction is upstream in Alzheimer's disease rather than a consequence of it.

in The Wax and the Weld

Would be settled by. Selective disruption of the tether in an otherwise healthy system, and whether the disease phenotype follows.

Moderate (inference, the paper's own claim) — Withdrawal of that subsidy is a cause of synapse loss rather than a consequence of having fewer synapses to support.

in THE WITHDRAWN SUBSIDY

Would be settled by. Restoring BDNF signalling alone in a model with established pathology and measuring whether synapse loss halts.

Moderate (inference, the paper's own claim) — The failures reflect the wrong half of the molecule being delivered rather than choline being irrelevant.

in THE WRONG HALF OF THE MOLECULE

Would be settled by. A trial delivering the species the account specifies, with a target-engagement readout showing it reached brain.

Would be refuted by. That trial failing with engagement demonstrated, which would indict choline itself rather than its delivery.

Moderate (inference, the paper's own claim) — The consistency across different vaccines points to a shared non-specific mechanism — trained immunity — rather than to any one pathogen.

in Vaccines That May Prevent Dementia

Moderate (inference, the paper's own claim) — The consistency across different vaccines points to a shared non-specific mechanism — trained immunity — rather than to any one pathogen.

in VACCINES THAT MAY PREVENT DEMENTIA

Moderate (inference, the paper's own claim) — Failure of oligodendrocyte maintenance is an upstream contributor rather than a consequence of neuronal loss.

in When Myelin's Caretakers Fail

Would be settled by. Selective disruption of oligodendrocyte maintenance in an otherwise intact system, and whether neuronal loss follows.

Moderate (inference, the paper's own claim) — Failure of oligodendrocyte maintenance is an upstream contributor rather than a consequence of neuronal loss.

in WHEN MYELIN'S CARETAKERS FAIL

Would be settled by. Selective disruption of oligodendrocyte maintenance in an otherwise intact system, and whether neuronal loss follows.

Moderate (inference, the paper's own claim) — That diagnostic blind spot causes systematic misattribution between vascular and degenerative dementia.

in When Poor Blood Flow Causes Dementia

Would be settled by. Autopsy-confirmed comparison of clinical diagnosis against pathology in a consecutive series, quantifying the misattribution rather than inferring it.

Moderate (inference, the paper's own claim) — That diagnostic blind spot causes systematic misattribution between vascular and degenerative dementia.

in WHEN POOR BLOOD FLOW CAUSES DEMENTIA

Would be settled by. Autopsy-confirmed comparison of clinical diagnosis against pathology in a consecutive series, quantifying the misattribution rather than inferring it.

Moderate (inference) — Microglial autophagic failure is what turns a protective immune cell into a damaging one.

in When the Brain's Immune Cells Turn Toxic

Would be settled by. Restoring autophagic capacity in microglia alone and showing the damaging phenotype reverses.

Moderate (inference) — Microglial autophagic failure is what turns a protective immune cell into a damaging one.

in WHEN THE BRAIN'S IMMUNE CELLS TURN TOXIC

Would be settled by. Restoring autophagic capacity in microglia alone and showing the damaging phenotype reverses.

Moderate (inference, the paper's own claim) — The major neurodegenerative diseases are therefore one disease, differing in which protein templates and which cells are vulnerable.

in Why All Major Neurodegenerative Diseases Are the Same Disease

Would be settled by. A shared intervention against templating that alters the course of more than one of these diseases.

Moderate (inference, the paper's own claim) — The major neurodegenerative diseases are therefore one disease, differing in which protein templates and which cells are vulnerable.

in WHY ALL MAJOR NEURODEGENERATIVE DISEASES ARE THE SAME DISEASE

Would be settled by. A shared intervention against templating that alters the course of more than one of these diseases.

Moderate (inference, the programme's own claim) — The neuron dies from the inside out — internal proteostatic failure — rather than from external assault by aggregates.

in Why Damaged Mitochondria Can't Be Cleared

Would be settled by. Preventing intraneuronal accumulation while leaving extracellular deposition intact, and asking whether the neuron survives.

Moderate (inference, the programme's own claim) — The neuron dies from the inside out — internal proteostatic failure — rather than from external assault by aggregates.

in WHY DAMAGED MITOCHONDRIA CAN'T BE CLEARED

Would be settled by. Preventing intraneuronal accumulation while leaving extracellular deposition intact, and asking whether the neuron survives.

Moderate (inference, the paper's own claim) — Decline is threshold-like rather than gradual — a system that compensates until it cannot, then fails quickly.

in Why Decline Happens Suddenly, Not Gradually

Would be settled by. Longitudinal measurement of clearance capacity alongside function in the same subjects, testing for a knee in the curve rather than a slope.

Would be refuted by. Clearance capacity and function found to decline proportionally, which would make the process gradual after all.

Moderate (inference, the paper's own claim) — Decline is threshold-like rather than gradual — a system that compensates until it cannot, then fails quickly.

in WHY DECLINE HAPPENS SUDDENLY, NOT GRADUALLY

Would be settled by. Longitudinal measurement of clearance capacity alongside function in the same subjects, testing for a knee in the curve rather than a slope.

Would be refuted by. Clearance capacity and function found to decline proportionally, which would make the process gradual after all.

Moderate (inference, the paper's own claim) — The HMS model as currently drawn is incomplete and requires a fourth layer.

in Why HMS Becomes HMS+P

Would be settled by. A case in which the three-layer model makes a wrong prediction that the four-layer model makes correctly.

Moderate (inference, the paper's own claim) — The HMS model as currently drawn is incomplete and requires a fourth layer.

in WHY HMS BECOMES HMS+P

Would be settled by. A case in which the three-layer model makes a wrong prediction that the four-layer model makes correctly.

Moderate (inference, the paper's own claim) — Structural, assembly and chaperone defects of the V-ATPase are a principal route by which neuronal clearance fails in disease.

in Why the Cell's Recycling System Breaks

Would be settled by. Measuring assembly state and chaperone availability in affected human neurons alongside lysosomal pH.

Moderate (inference, the paper's own claim) — Structural, assembly and chaperone defects of the V-ATPase are a principal route by which neuronal clearance fails in disease.

in WHY THE CELL'S RECYCLING SYSTEM BREAKS

Would be settled by. Measuring assembly state and chaperone availability in affected human neurons alongside lysosomal pH.