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Hypotheses

Top-ranked hypotheses by composite score. Filter by lifecycle status, disease, or target gene; sort by score or recency. Click a row to open evidence, scoring detail, and any live prediction markets referencing it.

365
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#HypothesisTarget geneStatusCompositeUpdated
1eIF2α Phosphorylation Imbalance Disrupts Mitochondrial Protein Import and Bioen…
als mechanistic 6 ev
h-var-501d347dbb
EIF2S1,eIF2α,PERK,GCN2,ATF4,TOMM20,TIMM23,NDUFS1,NDUFS3,COX4I1,COX5A,mitochondrial protein importopen—2026-05-13Open →
2GluN2B-Mediated Thalamocortical Control of Glymphatic Tau Clearance
neuroscience mechanistic 20 ev
h-var-e2b5a7e7db
GRIN2Bvalidated0.9642026-05-16Open →
3Cortico-Striatal Synchrony Restoration via NMDA Modulation
neuroscience mechanistic 15 ev
h-var-5e33600319
GRIN2Bproposed0.9502026-05-13Open →
4Microglial-Mediated Tau Clearance Dysfunction via TREM2 Receptor Impairment
neuroscience mechanistic 17 ev
h-var-59fc393ba6
MAPTproposed0.9372026-05-13Open →
5Gut Microbiome Remodeling to Prevent Systemic NLRP3 Priming in Neurodegeneration
neurodegeneration mechanistic 37 ev
h-var-08a4d5c07a
NLRP3, CASP1, IL1B, PYCARDvalidated0.9242026-05-13Open →
6eIF2α Phosphorylation Imbalance Creates Integrated Stress Response Overflow Tha…
als mechanistic 6 ev
h-alsmnd-870c6115d68c
EIF2S1,eIF2α,PERK,GCN2,ATF4,ATF5,CHOP,DDIT3,integrated stress response,protein synthesisvalidated0.8962026-05-13Open →
7SIRT1-Mediated Reversal of TREM2-Dependent Microglial Senescence
neurodegeneration mechanistic 55 ev
h-var-b7de826706
SIRT1validated0.8932026-05-16Open →
8TREM2-Mediated Astrocyte-Microglia Crosstalk in Neurodegeneration
neurodegeneration mechanistic 53 ev
h-var-66156774e7
TREM2validated0.8922026-05-16Open →
9ACSL4-Driven Ferroptotic Priming in Disease-Associated Microglia
Alzheimer's Disease mechanistic 45 ev
h-seaad-v4-26ba859b
ACSL4validated0.8912026-05-16Open →
10RBM45 Liquid-Liquid Phase Separation Dominance Hijacks RNA Processing Condensat…
als mechanistic 7 ev
h-alsmnd-9d62ae58bdc1
RBM45,GSK3B,TDP-43,TARDBP,hnRNP A1,HNRNPA1,phase separation,Liquid dropletvalidated0.8682026-05-13Open →
11SFPQ Paralog Displacement Triggers Cryptic Polyadenylation and Global RNA Stabi…
als mechanistic 5 ev
h-alsmnd-c5d2e9c2edeb
SFPQ,NONO,PSP1,TARDBP,poly(A) machinery,CPSF,PABPN1validated0.8642026-05-13Open →
12hnRNP A2/B1 Staufen2-Mediated Axonal RNA Granule Transport Failure Drives Dista…
als mechanistic 6 ev
h-alsmnd-006d646506ab
HNRNPA2B1,STAU2,PRMT1,GSK3B,MAP1B,β-actin,axonal transport machineryvalidated0.8512026-05-13Open →
13Prime Editing Precision Correction of APOE4 to APOE3 in Microglia
neurodegeneration mechanistic 30 ev
h-42f50a4a
APOEvalidated0.8502026-05-16Open →
14ATM Kinase Hyperactivation Triggers DNA Damage Response Overflow and p53-Depend…
als mechanistic 5 ev
h-alsmnd-9d07702213f0
ATM,CHEK2,TP53,BAX,PUMA,BCL2,DNA damage response,oxidative stressvalidated0.8372026-05-13Open →
15IL-6 Trans-Signaling Blockade at the Oligodendrocyte-Microglia Interface
neuroinflammation mechanistic 13 ev
h-2dbf5f1f
IL6R, IL6validated0.8312026-05-14Open →
16Microglial AIM2 Inflammasome as the Primary Driver of TDP-43 Proteinopathy Neur…
neurodegeneration mechanistic 31 ev
h-var-a0933e666d
AIM2, CASP1, IL1B, PYCARD, TARDBPvalidated0.8242026-05-16Open →
17GLE1-Mediated mRNA Export Defect Creates Translation-Competent mRNA Starvation…
als mechanistic 6 ev
h-alsmnd-e448328ae294
GLE1,DBP10,EXPORTIN-1,XPO1,mRNA export machinery,NPCvalidated0.8232026-05-13Open →
18SASP-Mediated Complement Cascade Amplification
neurodegeneration mechanistic 30 ev
h-58e4635a
C1Q/C3validated0.8222026-05-16Open →
19Astrocyte-Intrinsic NLRP3 Inflammasome Activation by Alpha-Synuclein Aggregates…
neurodegeneration mechanistic 31 ev
h-var-adfecef68a
NLRP3, CASP1, IL1B, PYCARDvalidated0.8222026-05-13Open →
20TIA1 Low-Complexity Domain Oxidation Drives Aberrant Stress Granule Assembly an…
als mechanistic 6 ev
h-alsmnd-54f981ca6a25
TIA1,TDP-43,TARDBP,G3BP1,MAPK1,Oxidative stress responsevalidated0.8102026-05-13Open →
21Mitochondrial DAMPs-Driven AIM2 Inflammasome Activation in Neurodegeneration
neurodegeneration mechanistic 31 ev
h-var-6957745fea
AIM2, CASP1, IL1B, PYCARDvalidated0.8052026-05-13Open →
22Calcium-Dysregulated mPTP Opening as an Alternative mtDNA Release Mechanism for…
neurodegeneration mechanistic 31 ev
h-var-af9eb8e59b
AIM2, CASP1, IL1B, PYCARD, PPIFvalidated0.8042026-05-13Open →
23Mitochondrial DNA-Driven AIM2 Inflammasome Activation in Neurodegeneration
neurodegeneration mechanistic 31 ev
h-var-d04a952932
AIM2, CASP1, IL1B, PYCARDvalidated0.8032026-05-13Open →
24MATR3 Nuclear Body Disruption Impairs RNA Processing Hubs and Triggers Splicing…
als mechanistic 7 ev
h-alsmnd-01446b71d93f
MATR3,U1 snRNP,SNRPB,SNRNP70, splicing machinery,spliceosomevalidated0.8012026-05-13Open →
25ACSL4-Ferroptotic Priming in Stressed Oligodendrocytes Drives White Matter Dege…
alzheimers mechanistic 48 ev
h-var-22c38d11cd
ACSL4validated0.8012026-05-13Open →
2640 Hz Gamma Entrainment Gates ACSL4-Mediated Ferroptotic Priming to Selectively…
alzheimers mechanistic 45 ev
h-var-261452bfb4
ACSL4validated0.8012026-05-13Open →
27Selective APOE4 Degradation via Proteolysis Targeting Chimeras (PROTACs)
neurodegeneration mechanistic 77 ev
h-11795af0
APOEpromoted0.7952026-05-13Open →
28Targeting SASP-Complement Amplification Through HIF-1α Downstream Effectors
neurodegeneration mechanistic 10 ev
h-a9f2570b
C1QA, C1QB, C3, IL1Bpromoted0.7932026-05-14Open →
29Competitive APOE4 Domain Stabilization Peptides
neurodegeneration mechanistic 73 ev
h-d0a564e8
APOEpromoted0.7842026-05-13Open →
30LAMP2A Liquid-Liquid Phase Separation Defects in Dopaminergic Neurons Create Se…
neurodegeneration mechanistic 7 ev
hyp-lyso-snca-1d58cf205e1f
LAMP2active0.7832026-05-13Open →
31SASP-Driven Aquaporin-4 Dysregulation
neurodegeneration mechanistic 30 ev
h-807d7a82
AQP4promoted0.7822026-05-13Open →
32TFEB Nuclear Translocation to Reset Lysosomal-Hypoxia Axis
neurodegeneration mechanistic 21 ev
h-810ec0eb
TFEB, MTORpromoted0.7792026-05-14Open →
33ACSL4-Driven Ferroptotic Priming in Disease-Associated Oligodendrocytes Underli…
alzheimers mechanistic 44 ev
h-var-f96e38ec20
ACSL4superseded0.7792026-05-13Open →
34PDE4 Inhibition as Inflammatory Reset for PD Oligodendrocytes
neuroinflammation mechanistic 13 ev
h-67914e81
PDE4A, PDE4B, PDE4Dpromoted0.7792026-05-14Open →
35Transcriptional Autophagy-Lysosome Coupling
neurodegeneration mechanistic 50 ev
h-ae1b2beb
FOXO1promoted0.7772026-05-16Open →
36LPCAT3-Mediated Lands Cycle Remodeling as the Primary Ferroptotic Priming Engin…
Alzheimer's Disease mechanistic 44 ev
h-var-e4cae9d286
LPCAT3debated0.7772026-05-16Open →
37Exosomal SNCA Propagation from Lysosome-Compromised Neurons Contains a Distinct…
neurodegeneration mechanistic 7 ev
hyp-lyso-snca-3429d8065d63
SNCAactive0.7772026-05-13Open →
38LPCAT3-Mediated Lands Cycle Amplification of Ferroptotic Substrate Pools in Dis…
Alzheimer's Disease mechanistic 43 ev
h-var-c56b26facf
LPCAT3debated0.7762026-05-16Open →
39ALOX15-Driven Enzymatic Ferroptosis in AD Oligodendrocytes via PUFA-PE Peroxida…
Alzheimer's Disease mechanistic 44 ev
h-var-97b18b880d
ALOX15debated0.7722026-05-16Open →
40APOE4 Allosteric Rescue via Small Molecule Chaperones
neurodegeneration mechanistic 55 ev
h-44195347
APOEdebated0.7652026-05-13Open →
41Chromatin Remodeling-Mediated Nutrient Sensing Restoration
neurodegeneration mechanistic 43 ev
h-var-a09491064e
SMARCA4promoted0.7642026-05-16Open →
42LPCAT3-Mediated Lands Cycle Amplification of Ferroptotic Vulnerability in Disea…
Alzheimer's Disease mechanistic 43 ev
h-var-70a95f9d57
LPCAT3debated0.7642026-05-16Open →
43SASP-Mediated Cholinergic Synapse Disruption
neurodegeneration mechanistic 32 ev
h-1acdd55e
MMP2/MMP9promoted0.7632026-05-13Open →
44Circadian Clock-Autophagy Synchronization
neurodegeneration mechanistic 32 ev
h-b7898b79
CLOCKdebated0.7632026-05-13Open →
45Cell-Type Specific TREM2 Upregulation in DAM Microglia
Alzheimer's Disease mechanistic 37 ev
h-seaad-51323624
TREM2promoted0.7612026-05-16Open →
46STMN2 Cryptic Exon Inclusion is the Earliest Loss-of-Function Marker of TDP-43…
als mechanistic 7 ev
ec8b839c-6440-45dc-aff6-5edea1fd2d6d
TARDBPopen0.7602026-05-13Open →
47Multi-Modal Stress Response Harmonization
neurodegeneration mechanistic 17 ev
h-1e564178
NR3C1/CRH/TNFApromoted0.7562026-05-13Open →
48GFAP-Positive Reactive Astrocyte Subtype Delineation
alzheimers mechanistic 42 ev
h-seaad-56fa6428
GFAPpromoted0.7542026-05-13Open →
49GBA1 Loss Triggers a TFEB-to-TFE3 Compensatory Switch in A9 Dopaminergic Neuron…
neurodegeneration mechanistic 6 ev
hyp-lyso-snca-3a610efd001e
TFEBactive0.7502026-05-13Open →
50Astrocyte C3aR Signaling as Bifurcation Point for A1/A2 Fate
Alzheimer's disease, Parkinson's disease mechanistic 9 ev
h-immunity-6e54942b
C3, C3aR, NFKB1, PPARGC1Aopen0.7492026-05-16Open →
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Hypothesis index sorted by composite score. Each hypothesis is a scientific claim produced by multi-agent analysis, scored on 10 dimensions. Filter by hypothesis_type, target_gene, disease, or status. Links to /hypotheses/[id] for the full scoring breakdown.

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