Top 50 hypotheses ranked by tournament Elo, market confidence, debate depth, and citation provenance
| # | Hypothesis | Elo | Market | Debates | Citations | Updated | Score |
|---|---|---|---|---|---|---|---|
| 🥇 |
TREM2-Mediated Microglial Dysfunction Disrupts Perivascular Tau Clearanc
combination
• TREM2
• neuroscience
|
228812 matches | 0.840 Market | 5 Transcript | 28 | 2026-04-27 | 0.861 |
| 🥈 |
[Archived Hypothesis]
—
• —
• —
|
22124 matches | 0.115 Market hub | 1 No transcript | 10 | 2026-04-17 | 0.256 |
| 🥉 |
Glymphatic-Mediated Tau Clearance Dysfunction
combination
• MAPT
• neuroscience
|
218935 matches | 0.599 Market hub | 3 Transcript | 31 | 2026-04-26 | 0.865 |
| 4 |
Closed-loop transcranial focused ultrasound to restore hippocampal gamma
therapeutic
• PVALB
• alzheimers
|
211211 matches | 0.840 Market | 18 Transcript | 68 | 2026-04-27 | 0.865 |
| 5 |
CYP46A1 Overexpression Gene Therapy
therapeutic
• CYP46A1
• neurodegeneration
|
210570 matches | 0.919 Market | 5 Transcript | 85 | 2026-04-28 | 0.768 |
| 6 |
H6: Aberrant eIF2α Phosphorylation Creates Stalled Translation State
—
• EIF2S1, EIF2AK3/PERK, PPP1R15B, EIF2B
• neurodegeneration
|
20968 matches | 0.800 Market hub | 1 Transcript | 50 | 2026-04-28 | 0.856 |
| 7 |
TREM2-Dependent Microglial Senescence Transition
mechanistic
• TREM2
• neurodegeneration
|
208871 matches | 0.541 Market | 5 Transcript | 72 | 2026-04-26 | 0.618 |
| 8 |
SASP-Mediated Complement Cascade Amplification
mechanistic
• C1Q/C3
• neurodegeneration
|
208071 matches | 0.910 Market | 3 Transcript | 66 | 2026-04-28 | 0.822 |
| 9 |
TREM2-Dependent Astrocyte-Microglia Cross-talk in Neurodegeneration
mechanistic
• TREM2
• neurodegeneration
|
207334 matches | 0.990 Market hub | 5 Transcript | 54 | 2026-04-27 | 0.716 |
| 10 |
NLRP3/Mitophagy Coupling Modulation
combination
• NLRP3
• neuroinflammation
|
206110 matches | 0.563 Market hub | 1 Transcript | 15 | 2026-04-12 | 0.681 |
| 11 |
Microglial-Mediated Tau Clearance Dysfunction via TREM2 Signaling
combination
• TREM2
• neuroscience
|
205824 matches | 0.601 Market hub | 18 Transcript | 7 | 2026-04-27 | 0.827 |
| 12 |
miR-33 Antisense Oligonucleotide Hyper-Lipidation Strategy
therapeutic
• miR-33/ABCA1
• molecular-biology
|
20338 matches | 0.741 Market | 1 Transcript | 8 | 2026-04-26 | 0.824 |
| 13 |
Inhibiting Heparan Sulfate Proteoglycan Receptor-Mediated Neuronal Tau U
—
• SULF1/SULF2
• neuroscience
|
20154 matches | 0.612 Market hub | 2 Transcript | 0 | 2026-04-27 | 0.822 |
| 14 |
TFEB Activation to Restore Lysosomal Biogenesis in Aged Synapses
—
• TFEB (TFE3, TFE4 family)
• proteomics
|
20068 matches | 0.553 Market hub | 1 Transcript | 0 | 2026-04-25 | 0.591 |
| 15 |
Selective Acid Sphingomyelinase Modulation Therapy
therapeutic
• SMPD1
• neurodegeneration
|
200571 matches | 0.920 Market | 5 Transcript | 83 | 2026-04-27 | 0.782 |
| 16 |
STING Antagonists as ALS Therapeutics: Drug Repurposing
—
• STING (TMEM173)
• neuroinflammation
|
19994 matches | 0.611 Market hub | 1 Transcript | 13 | 2026-04-22 | 0.821 |
| 17 |
eIF2α Phosphorylation Imbalance Creates Integrated Stress Response Overf
mechanistic
• EIF2S1,eIF2α,PERK,GCN2,ATF4,ATF5,CHOP,DDIT3,integrated stress response,protein synthesis
• als
|
19854 matches | 0.693 Market hub | 1 No transcript | 15 | 2026-04-27 | 0.896 |
| 18 |
Seed match plus local RNA structure jointly determine lncRNA-0021 bindin
—
• lncRNA-0021
• molecular-neurobiology
|
19854 matches | 0.583 Market hub | 1 Transcript | 0 | 2026-04-25 | 0.670 |
| 19 |
p16^INK4a-CCF Axis as Senolytic Timing Biomarker
—
• CDKN2A, CGAS, STING1
• molecular-biology
|
19854 matches | 0.565 Market hub | 1 Transcript | 6 | 2026-04-22 | 0.805 |
| 20 |
Nutrient-Sensing Epigenetic Circuit Reactivation
mechanistic
• SIRT1
• neurodegeneration
|
198470 matches | 0.907 Market | 4 Transcript | 90 | 2026-04-28 | 0.700 |
| 21 |
FcRn Transport Bypass Strategy
combination
• LDLR
• neuropharmacology
|
19786 matches | 0.514 Market hub | 1 Transcript | 15 | 2026-04-12 | 0.585 |
| 22 |
Exposed amyloidogenic segments (β-sheet propensity residues) serve as HS
—
• HSPA8, HSPA1A, DNAJB6, DNAJB2
• protein-biochemistry
|
19597 matches | 0.624 Market hub | 1 Transcript | 40 | 2026-04-21 | 0.840 |
| 23 |
Epigenetic Priming Ketone Protocol
—
• HDAC2/HDAC3
• metabolic-neuroscience
|
19408 matches | 0.598 Market hub | 2 Transcript | 8 | 2026-04-26 | 0.661 |
| 24 |
Integrated Multi-Analyte CSF Panel Combining YKL-40, sTREM2, and Neurogr
—
• CHI3L1/TREM2/NRGN
• biomarkers
|
19254 matches | 0.613 Market hub | 1 Transcript | 8 | 2026-04-22 | 0.807 |
| 25 |
ω-3 Docosahexaenoic Acid (DHA) Epoxide Generation via CYP2J2 to Protect
—
• CYP2J2/ω-3 DHA epoxides (sEH inhibition)
• lipidomics
|
19244 matches | 0.561 Market hub | 2 Transcript | 4 | 2026-04-28 | 0.802 |
| 26 |
NAD+ Precursor Supplementation to Reverse Poly(ADP-ribose) Polymerase-Dr
—
• PARP1, SIRT1/3, NAD+
• metabolomics
|
19244 matches | 0.533 Market hub | 1 Transcript | 0 | 2026-04-25 | 0.547 |
| 27 |
Kinetic Modeling Predicts Threshold-Dependent Efficacy—Early Interventio
—
• Seed amplification threshold (RT-QuIC diagnostic)
• protein-folding
|
19044 matches | 0.617 Market hub | 1 Transcript | 8 | 2026-04-22 | 0.815 |
| 28 |
IL-6 Trans-Signaling Blockade at the Oligodendrocyte-Microglia Interface
mechanistic
• IL6R, IL6
• neuroinflammation
|
189610 matches | 0.806 Market | 1 Transcript | 29 | 2026-04-26 | 0.831 |
| 29 |
Circulating hs-CRP as Disease-Modifying Target via Microglial IL-1β Ampl
—
• CRP → IL-1β → TLR4/MyD88 axis
• immunomics
|
18944 matches | 0.543 Market hub | 1 Transcript | 0 | 2026-04-25 | 0.565 |
| 30 |
Microglial TREM2 Activation to Enhance Synaptic Pruning Regulation
—
• Microglial TREM2
• connectomics
|
18944 matches | 0.531 Market hub | 1 Transcript | 0 | 2026-04-25 | 0.535 |
| 31 |
Temporal SPP1 Inhibition During Critical Windows
combination
• SPP1
• neuroinflammation
|
188510 matches | 0.665 Market hub | 1 Transcript | 8 | 2026-04-15 | 0.752 |
| 32 |
Focused Ultrasound with Microbubble Contrast Agents
—
• IGFBPL1
• drug-delivery
|
18822 matches | 0.589 Market hub | 1 Transcript | 8 | 2026-04-22 | 0.684 |
| 33 |
Microglial Metabolic Trained Immunity via mTOR-HIF1α Axis
—
• MTOR/HIF1α
• developmental-neurobiology
|
18813 matches | 0.579 Market hub | 1 Transcript | 0 | 2026-04-21 | 0.644 |
| 34 |
Prime Editing Precision Correction of APOE4 to APOE3 in Microglia
mechanistic
• APOE
• neurodegeneration
|
187739 matches | 0.612 Market hub | 3 Transcript | 38 | 2026-04-11 | 0.850 |
| 35 |
TFEB Activation to Restore Lysosomal Biogenesis in Alzheimer's Disease N
—
• TFEB
• proteomics
|
18743 matches | 0.531 Market hub | 1 Transcript | 0 | 2026-04-26 | 0.523 |
| 36 |
Circadian Glymphatic Entrainment via Targeted Orexin Receptor Modulation
therapeutic
• HCRTR1/HCRTR2
• neurodegeneration
|
185667 matches | 0.841 Market | 2 Transcript | 50 | 2026-04-26 | 0.882 |
| 37 |
Activity-Dependent Synaptic Tagging via CREB-BDNF-TrkB Signaling
—
• CREB1, BDNF, NTRK2 (TrkB)
• synaptic-biology
|
18557 matches | 0.575 Market hub | 1 Transcript | 0 | 2026-04-21 | 0.646 |
| 38 |
Gamma Oscillation Entrainment Enhances lncRNA-9969-Mediated Autophagy Th
—
• PVALB, CREB1, lncRNA-9969, neuronal autophagy pathway
• molecular-neurobiology
|
185311 matches | 0.682 Market hub | 1 Transcript | 38 | 2026-04-28 | 0.865 |
| 39 |
Closed-loop focused ultrasound targeting EC-II SST interneurons to resto
therapeutic
• SST
• alzheimers
|
185010 matches | 0.900 Market | 18 Transcript | 50 | 2026-04-28 | 0.748 |
| 40 |
Transcriptional Autophagy-Lysosome Coupling
mechanistic
• FOXO1
• neurodegeneration
|
182659 matches | 0.882 Market | 2 Transcript | 97 | 2026-04-28 | 0.777 |
| 41 |
TREM2-Dependent Switch Hypothesis: TREM2 Agonism Redirects SPP1 Signalin
—
• TREM2
• synaptic-biology
|
18246 matches | 0.614 Market hub | 1 Transcript | 8 | 2026-04-21 | 0.813 |
| 42 |
Multi-Biomarker Composite Index Surpassing Amyloid PET for Treatment Res
—
• COMPOSITE_BIOMARKER
• neurodegeneration
|
182431 matches | 0.581 Market | 3 Transcript | 9 | 2026-04-28 | 0.579 |
| 43 |
Dual-Circuit Tau Vulnerability Cascade
combination
• MAPT
• neuroscience
|
181936 matches | 0.567 Market hub | 18 Transcript | 17 | 2026-04-27 | 0.774 |
| 44 |
TREM2-Deficient Microglia as Drivers of Amyloid Plaque Toxicity in Alzhe
—
• TREM2
• neurodegeneration
|
18128 matches | 0.880 Market | 3 Transcript | 39 | 2026-04-27 | 0.847 |
| 45 |
p21^Cip1 Phospho-State as Autophagy Responsiveness Predictor
—
• CDKN1A, CDK4, CDK6, ATM, PPP1CA
• molecular-biology
|
18104 matches | 0.608 Market hub | 1 Transcript | 8 | 2026-04-21 | 0.768 |
| 46 |
STMN2 Cryptic Exon Inclusion is the Earliest Loss-of-Function Marker of
mechanistic
• TARDBP
• als
|
18104 matches | 0.596 Market hub | 1 Transcript | 5 | 2026-04-28 | 0.760 |
| 47 |
Transcriptome-wide competition determines functional selectivity after d
—
• mmu-miR-6361
• molecular-neurobiology
|
18104 matches | 0.529 Market hub | 1 Transcript | 0 | 2026-04-25 | 0.509 |
| 48 |
Beta-frequency entrainment therapy targeting PV interneuron-astrocyte co
therapeutic
• SST
• alzheimers
|
180756 matches | 0.827 Market | 18 Transcript | 57 | 2026-04-27 | 0.884 |
| 49 |
CD33-Dependent Switch Hypothesis: CD33 Antagonism Redirects SPP1 Signali
—
• CD33
• synaptic-biology
|
17982 matches | 0.529 Market hub | 1 Transcript | 0 | 2026-04-26 | 0.519 |
| 50 |
Cholinergic Basal Forebrain-Hippocampal Circuit Protection
combination
• MAPT
• neuroscience
|
179740 matches | 0.567 Market hub | 18 Transcript | 17 | 2026-04-27 | 0.760 |