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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.

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#HypothesisTarget geneStatusCompositeUpdated
1GluN2B-Mediated Thalamocortical Control of Glymphatic Tau Clearance
neuroscience mechanistic 20 ev
h-var-e2b5a7e7db
GRIN2Bvalidated0.9642026-05-16Open →
2Cortico-Striatal Synchrony Restoration via NMDA Modulation
neuroscience mechanistic 15 ev
h-var-5e33600319
GRIN2Bproposed0.9502026-05-13Open →
3Microglial-Mediated Tau Clearance Dysfunction via TREM2 Receptor Impairment
neuroscience mechanistic 17 ev
h-var-59fc393ba6
MAPTproposed0.9372026-05-13Open →
4Glymphatic-Mediated Tau Clearance Dysfunction
neuroscience combination 18 ev
h-var-95b0f9a6bc
MAPTvalidated0.8652026-05-16Open →
5TREM2-Mediated Microglial Dysfunction Disrupts Perivascular Tau Clearance
neuroscience combination 20 ev
h-var-7c976d9fb7
TREM2validated0.8612026-05-16Open →
6Microglial-Mediated Tau Clearance Dysfunction via TREM2 Signaling
neuroscience combination 18 ev
h-var-ce41f0efd7
TREM2validated0.8272026-05-16Open →
7Inhibiting Heparan Sulfate Proteoglycan Receptor-Mediated Neuronal Tau Uptake
neuroscience 7 ev
h-c90cca1826
SULF1/SULF2validated0.8222026-05-14Open →
8Thalamocortical Feedforward Inhibition Imposes Rhythm on Glymphatic Waste Clear…
neuroscience 4 ev
h-9268cd08d2
GRIN2B (VB thalamocortical relay neurons); circuit-level targetvalidated0.8082026-05-14Open →
9Dual-Circuit Tau Vulnerability Cascade
neuroscience combination 17 ev
h-var-8412ce00a4
MAPTpromoted0.7742026-05-16Open →
10Thalamocortical Synchrony Restoration via NMDA Modulation
neuroscience combination 15 ev
h-cd60e2ec
GRIN2Bproposed0.7742026-05-16Open →
11Enhancing Microglial Phagocytosis of Extracellular Tau via TREM2 Activation
neuroscience 7 ev
h-c58ac188fc
TREM2debated0.7712026-05-14Open →
12Selective LXRβ agonists restore ABCA1/ABCG1 expression and APOE lipidation in A…
neuroscience 10 ev
h-3f4cb83e0c
NR1H2 (LXRβ), ABCA1, ABCG1proposed0.7632026-05-14Open →
13GluN2B-CX3CL1 Axis Controls Microglial Tau Phagocytosis
neuroscience 5 ev
h-bcbc70473b
GRIN2B → CX3CL1 → CX3CR1/TREM2 axisproposed0.7612026-05-14Open →
14Cholinergic Basal Forebrain-Hippocampal Circuit Protection
neuroscience combination 17 ev
h-var-f687d4593b
MAPTpromoted0.7602026-05-13Open →
15APOE4 astrocytes exhibit impaired cholesterol efflux via ABCA1/ABCG1 transporte…
neuroscience 10 ev
h-bc8867b7ad
ABCA1, ABCG1proposed0.7582026-05-14Open →
16Dopaminergic Ventral Tegmental-Hippocampal Circuit Protection
neuroscience therapeutic 17 ev
h-var-bc4357c8c5
MAPTproposed0.7512026-05-13Open →
17TDP-43 condensation thermodynamics as a therapeutic target and biomarker for nu…
neuroscience 10 ev
h-6f6c9d3c
TARDBP (TDP-43 protein); IPO4/IP09 (nuclear import receptors as secondary targets)proposed0.7242026-05-14Open →
18GluN2B Tonic Activity Suppresses Glymphatic Perfusion Via Vasomotion Dysregulat…
neuroscience 5 ev
h-19689f6ce7
GRIN2B (thalamocortical projection neurons); downstream: NOS1, AQP4proposed0.7002026-05-14Open →
19TREM2 R47H variant synergizes with APOE4 to collapse microglial lipid clearance…
neuroscience 10 ev
h-909199b568
TREM2, APOEproposed0.6812026-05-14Open →
20Cortical Layer 5 Pyramidal Neuron GluN2B-Mediated Hyperactivity Drives Tau Secr…
neuroscience 5 ev
h-a1edc6af93
GRIN2B (L5 pyramidal neurons); downstream: ADAM10/ADAM17proposed0.6792026-05-14Open →
21TFEB-mediated transcriptional upregulation of lysosomal genes as a therapeutic…
neuroscience 11 ev
h-7ed7b242de
TFEB (TFEC)proposed0.6792026-05-14Open →
22Microglial TREM2-Mediated Tau Phagocytosis Impairment
neuroscience therapeutic 17 ev
h-var-69c66a84b3
MAPTproposed0.6762026-05-13Open →
23Astrocytic-Mediated Tau Clearance Dysfunction via TREM2 Signaling
neuroscience mechanistic 18 ev
h-var-c46786d2ab
TREM2proposed0.6722026-05-13Open →
24Locus Coeruleus-Hippocampal Circuit Protection
neuroscience combination 17 ev
h-23b94ed8
MAPTpromoted0.6682026-05-16Open →
25Glymphatic-Cholinergic Tau Clearance Cascade
neuroscience combination 17 ev
h-var-6a0893ffb6
MAPTproposed0.6662026-05-16Open →
26Retromer-dependent retrograde endosomal signaling compartmentalization as bioma…
neuroscience 6 ev
h-a3580b22
VPS35, VPS26, VPS29 (retromer complex); TrkB/NTRK2 (cargo receptors)proposed0.6452026-05-14Open →
27Thalamic Reticular Nucleus (TRN) GluN2B Hyperexcitability Disrupts AQP4 Polariz…
neuroscience 5 ev
h-bf78d35ce1
GRIN2B (TRN neurons); AQP4 polarization via SNTA1proposed0.6332026-05-14Open →
28Targeting Synaptic Vesicle Release Machinery to Block Tau Exocytosis
neuroscience 6 ev
h-319955cb66
SNAP25proposed0.6302026-05-14Open →
29Restoration of V-ATPase function reverses lysosomal acidification defect in AD…
neuroscience 5 ev
h-652a706ec8
ATP6V1A, ATP6V0Cproposed0.6302026-05-14Open →
30Default Mode Network Circuit Stabilization
neuroscience combination 15 ev
h-a635d4e5
VIPproposed0.6272026-05-16Open →
31Galectin-3 deletion attenuates NLRP3 inflammasome activation downstream of lyso…
neuroscience 6 ev
h-5a752d3628
LGALS3proposed0.6252026-05-14Open →
32Selective cathepsin B inhibition prevents cathepsin leakage-mediated NLRP3 infl…
neuroscience 5 ev
h-b4e8a2f6f9
CTSBproposed0.6202026-05-14Open →
33CaMKII-Dependent Synaptic Circuit Amplification
neuroscience combination 9 ev
h-62c78d8b
CAMK2Aproposed0.6112026-05-16Open →
34APOE4 preferentially signals through LRP1 over LDLR, altering endosomal cholest…
neuroscience 5 ev
h-753ee7a30b
LRP1, NPC1, CTSDproposed0.6102026-05-14Open →
35Blocking Tau Packaging into Small Extracellular Vesicles via ESCRT-III Pathway
neuroscience 7 ev
h-a98c87836b
PDGRIP1L (ALIX)proposed0.6102026-05-14Open →
36Differential Interneuron Optogenetic Restoration Therapy
neuroscience combination 6 ev
h-f8316acf
PVALB/SSTproposed0.5992026-05-16Open →
37TREM2-Mediated Microglial Dysfunction Disrupts Oligodendrocyte Tau Clearance Ne…
neuroscience combination 18 ev
h-var-5aec85b987
TREM2proposed0.5892026-05-13Open →
38APOE4 drives astrocyte metabolic reprogramming toward glycolysis via PGC-1α sup…
neuroscience 5 ev
h-a1f87d1fd6
PPARGC1A (PGC-1α), SIRT1, SREBF1 (SREBP1c)proposed0.5802026-05-14Open →
39LAMP-2 replacement therapy prevents lysosomal membrane permeabilization and dow…
neuroscience 6 ev
h-e744d98ee1
LAMP2 (LGMN)proposed0.5802026-05-14Open →
40Structure-interacting small molecules that stabilize the APOE4 molten globule d…
neuroscience 5 ev
h-d0099a1106
APOE (protein structure stabilizer)proposed0.5802026-05-14Open →
41Hsp70-based therapy to prevent lysosomal membrane permeabilization and cathepsi…
neuroscience 5 ev
h-514ab2e42b
HSPA1Aproposed0.5702026-05-14Open →
42Blocking Astrocyte-Mediated Tau Re-Spreading via Cx43 Hemichannel Inhibition
neuroscience 7 ev
h-fd8eb2a065
GJA1 (Connexin-43)proposed0.5702026-05-14Open →
43TREM2-Dependent Microglial Surveillance Controls AQP4-Mediated Tau Clearance Th…
neuroscience therapeutic 18 ev
h-var-2041072461
TREM2proposed0.5692026-05-13Open →
44Dual-Circuit Tau Vulnerability Cascade with Glial-Mediated Amplification
neuroscience combination 17 ev
h-var-1906e102cf
MAPTproposed0.5682026-05-13Open →
45Synergistic enhancement of autophagy and lysosomal biogenesis by combined mTOR…
neuroscience 6 ev
h-04ec45fe92
MTOR, TPCN2, TFEBproposed0.5652026-05-14Open →
46A genetically encoded reporter for axonal mitochondrial protein import fidelity…
neuroscience 6 ev
h-c1f19a34
TOM20, TOM40 (translocase complex); CHOP/DDIT3 (stress response promoter)proposed0.5652026-05-14Open →
47GluN2B-Mediated Microglial Activation and Tau Propagation
neuroscience mechanistic 6 ev
h-var-3f7e16389b
GRIN2Bproposed0.5652026-05-16Open →
48Ketone-Primed Thalamocortical Enhancement of Glymphatic Tau Clearance
neuroscience mechanistic 19 ev
h-var-37b006000c
GRIN2Bproposed0.5652026-05-16Open →
49Perivascular Dimensionality: GluN2B Control of Thalamocortical vs. Corticopial…
neuroscience 5 ev
h-da0eec2bdf
GRIN2B activity pattern; topological glymphatic routingproposed0.5562026-05-14Open →
50Disrupting Muscarinic M1/M3 Receptor-Mediated Tau Internalization and Synaptic…
neuroscience 6 ev
h-80d39d9095
CHRM1 (M1R)proposed0.5502026-05-14Open →
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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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