Hypothesis corpus
Scored, debated, and tradable. Each hypothesis carries composite, novelty, impact, mechanistic, druggability, and safety scores — plus a live market price when a collider is open.
Showing neurodegeneration hypotheses, sorted by Composite score.
Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration
NLRP3, CASP1, IL1B, PYCARD neurodegeneration 92%Gut microbiota-derived metabolites activate NLRP3 inflammasome in microglia, promoting neuroinflammation in AD mouse models.
h-var-08a4d5c07aAPOE-Dependent Autophagy Restoration
MTOR neurodegeneration 89%APOE4 knock-in neurons show mTORC1 hyperactivation and impaired autophagic flux with p62 accumulation
h-51e7234fHypothesis 4: Metabolic Coupling via Lactate-Shuttling Collapse
SLC16A1, SLC16A7, LDHA, PDHA1 neurodegeneration 89%Astrocyte metabolic reprogramming through SIRT1/PGC1alpha/NAMPT axis reverses cellular senescence (established world model, confidence: 0.79)
h-b2ebc9b2p38α Inhibitor and PRMT1 Activator Combination to Restore Physiological TDP-43 Phosphorylation-Methylation Balance
MAPK14/PRMT1 neurodegeneration 89%P38α phosphorylation and PRMT1 methylation have opposing roles in TDP-43 proteinopathy - PRMT1-mediated methylation opposes p38α phosphorylation in driving TDP-43 pathology
h-ccc05373SIRT1-Mediated Reversal of TREM2-Dependent Microglial Senescence
SIRT1 neurodegeneration 89%Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice.
h-var-b7de826706TREM2-Mediated Astrocyte-Microglia Crosstalk in Neurodegeneration
TREM2 neurodegeneration 89%Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice.
h-var-66156774e7Optimized Temporal Window for Metabolic Boosting Therapy Determines Success of Microglial State Transition Restoration
IFNG neurodegeneration 89%IFNgamma treatment reverses defective glycolytic metabolism and inflammatory functions of microglia mitigating AD pathology
h-f1c67177TREM2-APOE Axis Dissociation for Selective DAM Activation
TREM2-APOE axis neurodegeneration 89%TREM2-APOE pathway drives transcriptional phenotype of dysfunctional microglia
h-5b378bd3Circadian Glymphatic Entrainment via Targeted Orexin Receptor Modulation
HCRTR1/HCRTR2 neurodegeneration 88%Glymphatic clearance increases 10-20 fold during sleep compared to wakefulness in mice
h-9e9fee95Complement Cascade Inhibition Synaptic Protection
neurodegeneration 87%SASP factors drive complement cascade amplification linking senescence to synaptic loss
h-e64a33a8TREM2 R47H Variant-Driven Metabolic Dysfunction as the Primary Trigger for Failed DAM Transition
NAMPT neurodegeneration 86%Single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent responses in AD
h-881bc290H6: Aberrant eIF2α Phosphorylation Creates Stalled Translation State
EIF2S1, EIF2AK3/PERK, PPP1R15B, EIF2B neurodegeneration 86%eIF2α phosphorylation is elevated in Alzheimer's, Parkinson's, and ALS
h-fc1cd0d4bdSenescent Cell ASM-Complement Cascade Intervention
SMPD1 neurodegeneration 85%ASM inhibition with amitriptyline reduces brain ceramide and amyloid pathology by 30% in APP/PS1 mice
h-var-76afa28dfcPrime Editing Precision Correction of APOE4 to APOE3 in Microglia
APOE neurodegeneration 85%Prime editing has been successfully optimized for APOE4 correction with improved efficiency and reduced off-target effects
h-42f50a4aTREM2-Deficient Microglia as Drivers of Amyloid Plaque Toxicity in Alzheimer's Disease
TREM2 neurodegeneration 85%TREM2 R47H and R62H variants confer AD risk in large GWAS; PMID 28165511
h-44b1c9d415Neutral Sphingomyelinase-2 Inhibition for Synaptic Protection in Neurodegeneration
SMPD3 neurodegeneration 84%ASM inhibition with amitriptyline reduces brain ceramide and amyloid pathology by 30% in APP/PS1 mice
h-var-e81fbd3868TYROBP (DAP12) Conditional Antagonism for Early-Stage Neuroprotection
TYROBP neurodegeneration 84%TYROBP knockout cell-autonomously decreases microglial expression of disease-associated genes and mitigates astrogliosis in Huntington's disease models
h-f503b337miR-155/Interferon-gamma Feedback Loop as a Reversible Molecular Switch for Protective Microglial State Transition
MIR155 neurodegeneration 84%miR-155 and interferon-gamma signaling mediate a protective microglial state identified in mouse AD models
h-740803e1Hypothesis 7: SST-SST1R/Gamma Entrainment-Enhanced Astrocyte Secretome
SST, SSTR1, SSTR2 neurodegeneration 84%Gamma entrainment therapy restores hippocampal-cortical synchrony through SST interneuron modulation (established world model, confidence: 0.71)
h-3481330aSequential Iron Chelation (Deferoxamine) and GPX4 Restoration (Sulforaphane) Prevents the Self-Amplifying Iron-Ferroptosis-Edema Cascade Post-Cardiac Arrest
Labile iron pool (deferoxamine target) and GPX4 (sulforaphane target) neurodegeneration 84%Source paper shows marked iron accumulation in hippocampus 24h post-CA
h-5050522dGamma Oscillation Enhancement Synergy
neurodegeneration 84%SST interneurons in EC layer II provide critical gamma frequency gating that blocks tau propagation (established world model, confidence: 0.74)
h-c226f2aaMicroglial Senescence Prevention via TREM2/SASP Axis
TREM2 neurodegeneration 84%TREM2 R47H variant elevates TNF-α levels and disrupts inhibitory neurotransmission in young rats
h-d5dea85fTREM2 Deficiency Drives Microglial Senescence via Lipid Metabolism Dysregulation
TREM2/TYROBP neurodegeneration 84%TREM2 deficiency causes microglial dysfunction and lipid droplet accumulation in 5xFAD mice
h-0ca0f0f8f2AMPK hypersensitivity in astrocytes creates enhanced mitochondrial rescue responses
PRKAA1 neurodegeneration 83%AMPK activation enhances mitochondrial function and promotes metabolic rescue responses
h-43f72e21