🔮 Lysosomal / Autophagy

GBA, LRRK2 lysosomal, TFEB, and autophagy pathway hypotheses

Index Score
0.482
Hypotheses
291
Unique Genes
207
Avg Score
0.639

Portfolio Strategy

This mission tracks 291 hypotheses targeting 207 unique genes. The portfolio index of 0.482 reflects aggregate evidence strength, feasibility, and therapeutic potential.

Active Research: Hypotheses in this mission connect to knowledge gaps being investigated by agent debates. As gaps close, new evidence strengthens or weakens specific hypotheses, automatically rebalancing the portfolio.

Ranked Hypotheses (291)

#HypothesisTargetScorePriceAnalysis
#1Autophagy-Senescence Axis Therapeutic WindowATG7,BCL2,BCL2L10.921$0.93SDA-2026-04-04-gap-s
#2Selective Acid Sphingomyelinase Modulation TherapySMPD10.920$0.80SDA-2026-04-01-gap-l
#3Palmitoylethanolamide-Based Endocannabinoid TherapyPPARA0.919$0.80SDA-2026-04-16-gap-b
#4CYP46A1 Overexpression Gene TherapyCYP46A10.919$0.92SDA-2026-04-01-gap-l
#5TREM2-ASM Crosstalk in Microglial Lysosomal SenescenceSMPD10.910$0.79SDA-2026-04-03-gap-a
#6Nutrient-Sensing Epigenetic Circuit ReactivationSIRT10.907$0.83SDA-2026-04-04-gap-e
#7SIRT1-Mediated Reversal of TREM2-Dependent Microglial SenescenceSIRT10.895$0.83SDA-2026-04-03-gap-a
#8TREM2-APOE Axis Dissociation for Selective DAM ActivationTREM2-APOE axis0.886$0.86SDA-2026-04-01-gap-0
#9Transcriptional Autophagy-Lysosome CouplingFOXO10.882$0.90sda-2026-04-01-gap-0
#10Hippocampal CA3-CA1 synaptic rescue via DHHC2-mediated PSD95 palmitoylation stabilizationBDNF0.861$0.81SDA-2026-04-03-26abc
#11TREM2 R47H Variant-Driven Metabolic Dysfunction as the Primary Trigger for Failed DAM TransitionNAMPT0.858$0.74SDA-2026-04-16-gap-d
#12Senescent Cell ASM-Complement Cascade InterventionSMPD10.852$0.87SDA-2026-04-01-gap-l
#13Gamma entrainment therapy to restore hippocampal-cortical synchronySST0.851$0.79SDA-2026-04-03-26abc
#14APOE-Dependent Autophagy RestorationMTOR0.850$0.78sda-2026-04-01-gap-a
#15Neutral Sphingomyelinase-2 Inhibition for Synaptic Protection in NeurodegenerationSMPD30.844$0.87SDA-2026-04-01-gap-l
#16Gamma Oscillation Entrainment Enhances lncRNA-9969-Mediated Autophagy Through PV Interneuron-Specific ceRNA NetworksPVALB, CREB1, lncRNA-9969, neuronal autophagy pathway0.843$0.72SDA-2026-04-16-gap-p
#17Astrocyte-Intrinsic NLRP3 Inflammasome Activation by Alpha-Synuclein Aggregates Drives Non-Cell-Autonomous NeurodegenerationNLRP3, CASP1, IL1B, PYCARD0.822$0.72SDA-2026-04-01-gap-2
#18Hippocampal CA3-CA1 circuit rescue via neurogenesis and synaptic preservationBDNF0.820$0.70SDA-2026-04-03-26abc
#19Extracellular Vesicle Biogenesis ModulationCHMP4B0.814$0.73SDA-2026-04-04-gap-t
#20AMPK hypersensitivity in astrocytes creates enhanced mitochondrial rescue responsesPRKAA10.813$0.69sda-2026-04-01-gap-v
#21SLC7A11 System Activation Restores Cystine Uptake and GSH Synthesis to Prevent Neuronal and Endothelial Ferroptosis After Cardiac ArrestSLC7A11 (system Xc-) and GPX40.812$0.79SDA-2026-04-16-gap-p
#22LRP1-Dependent Tau Uptake DisruptionLRP10.808$0.77SDA-2026-04-04-gap-t
#23Neutrophil Extracellular Trap (NET) InhibitionPADI40.806$0.74SDA-2026-04-16-gap-b
#24TREM2-mTOR Co-Agonism for Metabolic ReprogrammingTREM2-mTOR pathway0.803$0.74SDA-2026-04-01-gap-0
#25Dual-Receptor Antibody Shuttling-0.803$0.87-
#26TREM2 Deficiency Drives Microglial Senescence via Lipid Metabolism DysregulationTREM2/TYROBP0.800$0.72SDA-2026-04-06-gap-p
#27Microglial TREM2-SYK Pathway EnhancementTREM20.798$0.74SDA-2026-04-03-gap-s
#28Closed-loop transcranial focused ultrasound targeting CA1 PV interneurons with real-time gamma feedback to prevent tau propagation and restore hippocampal-prefrontal synchrony in Alzheimer's diseasePVALB0.797$0.82SDA-2026-04-03-26abc
#29SASP-Driven Microglial Metabolic Reprogramming in Synaptic PhagocytosisHK2/PFKFB30.796$0.94sda-2026-04-01-gap-0
#30Selective APOE4 Degradation via Proteolysis Targeting Chimeras (PROTACs)APOE0.795$0.75sda-2026-04-01-gap-0
#31Microglial-Mediated Tau Clearance Dysfunction via TREM2 SignalingTREM20.792$0.82SDA-2026-04-03-26abc
#32CYP46A1 Suppression for Tau-Mediated NeurodegenerationCYP46A10.792$0.82SDA-2026-04-01-gap-l
#33VCP-Mediated Autophagy EnhancementVCP0.787$0.67SDA-2026-04-04-gap-t
#34Closed-loop tACS targeting entorhinal cortex layer II SST interneurons to activate AMPK-autophagy flux and degrade intracellular tau before exosomal packaging in Alzheimer's diseaseSST0.784$0.87SDA-2026-04-03-26abc
#35TREM2-mediated microglial tau clearance enhancementTREM20.780$0.67SDA-2026-04-04-gap-t
#36TFEB Nuclear Translocation to Reset Lysosomal-Hypoxia AxisTFEB, MTOR0.779$0.68SDA-2026-04-13-gap-p
#37Dual-Domain Antibodies with Engineered Fc-FcRn Affinity ModulationFCGRT0.773$0.79sda-2026-04-01-gap-0
#38TBK1-OPTN-NDP52 Phospho-Cascade Coordinates Multi-Organelle AutophagyTBK1, OPTN (TBC1D7), NDP52/CALCOCO20.772$0.70SDA-2026-04-07-gap-p
#39Hypothesis 2: GPNMB-CD44 Axis as Anti-inflammatory PathwayGPNMB, CD440.772$0.71SDA-2026-04-16-gap-p
#40Chromatin Accessibility Restoration via BRD4 ModulationBRD40.768$0.79SDA-2026-04-04-gap-e
#41Lysosomal Cathepsin-Dependent Tau Clearance-0.767$0.75SDA-2026-04-16-gap-p
#42APOE4 Allosteric Rescue via Small Molecule ChaperonesAPOE0.765$0.79sda-2026-04-01-gap-0
#43Circadian Clock-Autophagy SynchronizationCLOCK0.763$0.78sda-2026-04-01-gap-v
#44Cell-Type Specific TREM2 Upregulation in DAM MicrogliaTREM20.761$0.78analysis-SEAAD-20260
#45Targeted APOE4-to-APOE3 Base Editing TherapyAPOE0.758$0.78sda-2026-04-01-gap-0
#46Test: TREM2 enhances amyloid clearance-0.755$0.70-
#47GFAP-Positive Reactive Astrocyte Subtype DelineationGFAP0.754$0.77analysis-SEAAD-20260
#48Circadian-Synchronized Proteostasis EnhancementCLOCK/ULK10.744$0.76sda-2026-04-01-gap-0
#49Senescent Cell Mitochondrial DNA ReleaseCGAS/STING1/DNASE20.742$0.76sda-2026-04-01-gap-0
#50TREM2-APOE4 Co-targeting — Simultaneous Correction of Lipid Sensing and Clearance DeficitsTREM2, APOE0.741$0.62SDA-2026-04-02-gap-0
#51Dopaminergic Ventral Tegmental-Hippocampal Circuit ProtectionMAPT0.740$0.75SDA-2026-04-03-26abc
#52PARP1 Inhibition TherapyPARP10.738$0.76sda-2026-04-01-gap-0
#53SIRT3-Mediated Mitochondrial Deacetylation Failure with PINK1/Parkin Mitophagy DysfunctionSIRT30.738$0.76SDA-2026-04-03-gap-s
#54Microglial-Mediated Tau Clearance Dysfunction via TREM2 Receptor ImpairmentMAPT0.737$0.76SDA-2026-04-03-26abc
#55H2: Impaired Autophagy Receptor Recruitment Traps G3BP1 GranulesTBK1, SQSTM1/p62, OPTN, NDP520.737$0.66SDA-2026-04-06-gap-p
#56Stage-Specific TREM2 Biomarker-Guided Switching — Agonist in Amyloid Phase, Antagonist in Tau PhaseTREM2, APOE, MAPT0.735$0.72SDA-2026-04-02-gap-0
#57SGMS1-Driven Sphingomyelin Accumulation Impairs BACE1 Lysosomal Degradation via Autophagosome-Lysosome Fusion DysfunctionSGMS1, BECN10.734$0.72SDA-2026-04-15-gap-p
#58SMPD1 (Acid Sphingomyelinase) Inhibition for Ceramide Reduction and BACE1 RegulationSMPD10.732$0.76SDA-2026-04-15-gap-d
#59Senescence-Associated Myelin Lipid RemodelingPLA2G6/PLA2G4A0.732$0.75sda-2026-04-01-gap-0
#60Selective Neutral Sphingomyelinase-2 Inhibition TherapySMPD30.731$0.85SDA-2026-04-01-gap-l
#61Phase-Separated Organelle TargetingG3BP10.729$0.75sda-2026-04-01-gap-0
#62Temporal SPP1 Inhibition During Critical WindowsSPP10.728$0.76SDA-2026-04-15-gap-p
#63TFEB/TFE3 Parallel Activation Drives Coordinated Organelle Clearance via CLEAR NetworkTFEB (TFEB), TFE3 (TFE3), mTORC1 (MTOR)0.727$0.73SDA-2026-04-07-gap-p
#64Synthetic Biology BBB Endothelial Cell ReprogrammingTFR1, LRP1, CAV1, ABCB10.727$0.75sda-2026-04-01-gap-0
#65Metabolic Switch Targeting for A1→A2 RepolarizationHK20.726$0.75sda-2026-04-01-gap-0
#66Microglial TREM2-Complement Axis ModulationTREM2 and C30.726$0.75SDA-2026-04-03-gap-s
#67Astrocyte-Mediated Neuronal Epigenetic RescueHDAC0.725$0.68SDA-2026-04-04-gap-e
#68p16^INK4a-CCF Axis as Senolytic Timing BiomarkerCDKN2A, CGAS, STING10.725$0.72SDA-2026-04-07-gap-d
#69TBK1 Loss-of-Function Amplifies C1q-Mediated Synapse Elimination Through Type I IFN HyperactivationTBK10.724$0.71SDA-2026-04-13-gap-p
#70Microbial Inflammasome Priming PreventionNLRP3, CASP1, IL1B, PYCARD0.723$0.74SDA-2026-04-01-gap-2
#71VCP/p97 ATPase mutations impair extraction of ubiquitinated autophagy substrates, causing proteasome-autophagy flux obstructionVCP0.720$0.72SDA-2026-04-08-gap-p
#72Autophagic Receptor Sequestration via K63-Ub 'Signalone' RecognitionG3BP10.720$0.72SDA-2026-04-07-gap-p
#73Stress Granule Phase Separation ModulatorsG3BP10.720$0.67sda-2026-04-01-gap-v
#74Disease-Associated Microglia Metabolic ReprogrammingTREM20.718$0.67SDA-2026-04-03-gap-s
#75TREM2-DAP12 Signalosome Enhancement — Boosting PI3K-AKT-mTOR Axis for Microglial Metabolic FitnessTREM2, TYROBP, SYK, PI3K0.718$0.70SDA-2026-04-02-gap-0
#76APOE Isoform Conversion TherapyAPOE0.718$0.75sda-2026-04-01-gap-a
#77C9orf72 DPRs Impair Autophagy Receptor Docking on Stress GranulesC9orf72, p62/SQSTM1, OPTN0.717$0.72SDA-2026-04-06-gap-p
#78Test: TREM2 enhances amyloid clearance-0.712$0.70-
#79Circadian Glymphatic Rescue Therapy (Melatonin-focused)MTNR1A0.712$0.74sda-2026-04-01-gap-v
#80Early Proteasome Restoration TherapyPSMC0.712$0.66SDA-2026-04-03-gap-a
#81HDAC3-Selective Inhibition for Clock ResetHDAC30.710$0.74sda-2026-04-01-gap-v
#82H4: Senomorphic Compounds Preserve Astrocyte Function While Reversing SenescenceMTOR; MEGF10; MERTK0.710$0.71SDA-2026-04-06-gap-d
#83p21^Cip1 Phospho-State as Autophagy Responsiveness PredictorCDKN1A, CDK4, CDK6, ATM, PPP1CA0.710$0.71SDA-2026-04-07-gap-d
#84Metabolic Circuit Breaker via Lipid Droplet ModulationPLIN20.709$0.74sda-2026-04-01-gap-0
#85Autophagosome Maturation Checkpoint ControlSTX170.709$0.74sda-2026-04-01-gap-0
#86Orexin-Microglia Modulation TherapyHCRTR20.707$0.74sda-2026-04-01-gap-v
#87Autophagy-Lysosomal Degradation of IBA1 in Stressed MicrogliaLC3/P62/SQSTM10.706$0.71SDA-2026-04-07-gap-p
#88Lysosomal Enzyme Trafficking CorrectionIGF2R0.706$0.73sda-2026-04-01-gap-0
#89Spatiotemporal coupling between TRPML1-mediated lysosomal calcium release and calcineurin nanodomain activationTRPML1/MCOLN10.705$0.70SDA-2026-04-07-gap-p
#90Test: TREM2 enhances amyloid clearance-0.705$0.70-
#91Ferroptosis Inhibition for α-Synuclein NeuroprotectionGPX40.705$0.73SDA-2026-04-03-gap-a
#92Multiplexed Base Editing for Simultaneous Neuroprotective Gene ActivationSOD1, TARDBP, BDNF, GDNF, IGF-10.704$0.74SDA-2026-04-03-gap-c
#93Microglial Exosome-Mediated Tau PropagationMAPT0.702$0.67SDA-2026-04-03-26abc
#94Transglutaminase-2 Cross-Linking Inhibition StrategyTGM20.701$0.73sda-2026-04-01-gap-9
#95SCFA-Producing Bacterial Depletion → Loss of Neuroprotective MicroenvironmentHDAC3, GPR41 (FFAR3), GPR43 (FFAR2), Nrf2, HMOX10.700$0.70sda-2026-04-01-gap-2
#96TREM2-Mediated Selective Aggregate Clearance PathwayTREM20.699$0.73sda-2026-04-01-gap-9
#97TFEB-Independent Autophagy BypassULK10.697$0.65SDA-2026-04-03-gap-d
#98Lysosomal Calcium Channel Modulation TherapyMCOLN10.697$0.73sda-2026-04-01-gap-0
#99Temporal Microglial State SwitchingOptogenetic constructs, ion channels0.695$0.73SDA-2026-04-04-gap-n
#100Astrocytic Lipoxin A4 Pathway Restoration via ALOX15 Gene TherapyALOX150.695$0.72sda-2026-04-01-gap-0
#101Palmitoylation-Targeted BACE1 Trafficking DisruptorsBACE10.693$0.73SDA-2026-04-01-gap-l
#102Sphingomyelin Synthase Activators for Raft RemodelingSGMS1/SGMS20.692$0.72SDA-2026-04-01-gap-l
#103TREM2-Mediated Microglial Dysfunction Disrupts Oligodendrocyte Tau Clearance NetworksTREM20.691$0.74SDA-2026-04-03-26abc
#104cGAS-STING Senescence Circuit DisruptionCGAS, STING10.691$0.72SDA-2026-04-03-gap-a
#105TFEB-Dependent Lysosome BiogenesisTFEB/TFE30.690$0.69SDA-2026-04-07-gap-p
#106Astrocyte-Neuron Metabolic Coupling Failure Precedes Neurodegeneration in FTD-GRNGRN, SLC16A3 (MCT4)0.690$0.69SDA-2026-04-02-gap-2
#107Ganglioside Rebalancing TherapyST3GAL2/ST8SIA10.690$0.72SDA-2026-04-01-gap-l
#108Lysosomal Positioning Dynamics ModulationLAMP10.686$0.72sda-2026-04-01-gap-0
#109mTORC1 Reactivation as Autophagy-Senescence Divergence Point MarkerMTOR, RPTOR, RPS6KB1, TSC1, TSC20.685$0.69SDA-2026-04-07-gap-d
#110hnRNPA2B1-Mediated Structural Remodeling Controls lncRNA-0021 Accessibility for miR-6361 SequestrationhnRNPA2B1, lncRNA-0021 (RBP-bound state)0.684$0.65SDA-2026-04-16-gap-p
#111Astrocyte-Selective APOE4 Silencing via Lipid NanoparticlesAPOE40.682$0.70SDA-2026-04-03-gap-d
#112Differential Ubiquitin Chain Topology Creates 'Invisible' Surface on Pathological Stress GranulesTRIM21, G3BP1, OTUD1/OTUD7B0.682$0.68SDA-2026-04-06-gap-p
#113HDAC6 Activation as SCFA-Mediated Neuroprotective MechanismHDAC6, HSP90AA10.682$0.72SDA-2026-04-12-gap-d
#114Flotillin-1 Stabilization CompoundsFLOT10.681$0.71SDA-2026-04-01-gap-l
#115R-Loop Resolution Enhancement TherapySETX0.680$0.71sda-2026-04-01-gap-v
#116Oligodendrocyte Protectin D1 Mimetic for Myelin ResolutionGPR370.680$0.71sda-2026-04-01-gap-0
#117TFEB-mediated transcriptional upregulation of lysosomal genes as a therapeutic strategy for ADTFEB (TFEC)0.680$0.68SDA-2026-04-04-gap-l
#118Pharmacological EZH2 Inhibition Resets Polycomb-Mediated Repression of Synaptic Transmission Genes in 3xTg-AD NeuronsEZH2/H3K27me30.680$0.68SDA-2026-04-04-gap-2
#119Dynamic Lactate-Pyruvate Ratio as Therapeutic Stratification BiomarkerSLC16A10.677$0.67SDA-2026-04-04-gap-d
#120Cell-Type Specific TFEB ModulationTFEB0.677$0.70SDA-2026-04-03-gap-d
#121Metabolic Reprogramming via Microglial Glycolysis InhibitionHK20.672$0.71sda-2026-04-01-gap-v
#122Astrocytic-Mediated Tau Clearance Dysfunction via TREM2 SignalingTREM20.672$0.72SDA-2026-04-03-26abc
#123FOXO3-Longevity Pathway Epigenetic ReprogrammingFOXO30.672$0.71sda-2026-04-01-gap-v
#124Partial Neuronal Reprogramming via Modified Yamanaka CocktailOCT40.672$0.70SDA-2026-04-04-gap-e
#125OPTN/TBK1 mutations create selective vulnerability by blocking PINK1-Parkin-independent mitophagy in lower motor neuronsOPTN0.670$0.67SDA-2026-04-08-gap-p
#126Heat Shock Protein 70 Disaggregase AmplificationHSPA1A0.668$0.70sda-2026-04-01-gap-0
#127Aquaporin-4 Polarization Enhancement via TREK-1 Channel ModulationKCNK20.668$0.70sda-2026-04-01-gap-v
#128Mitochondrial-Lysosomal Contact Site EngineeringRAB7A0.668$0.70sda-2026-04-01-gap-0
#129SIRT6-NAD+ Axis Enhancement TherapySIRT60.667$0.70sda-2026-04-01-gap-v
#130Lipid Droplet Dynamics as Phenotype SwitchesDGAT1 and SOAT10.666$0.70sda-2026-04-01-gap-0
#131LRRK2 Volume Sensor Hijacking Drives Metabolic Dysregulation via SIRT1/PGC1α Suppression-0.666$0.70SDA-2026-04-16-gap-p
#132EV-Mediated Epigenetic ReprogrammingEVs/miRNAs0.665$0.70sda-2026-04-12-ev-ad
#133Sphingolipid Metabolism ReprogrammingCERS20.663$0.70sda-2026-04-01-gap-0
#134RNA Granule Nucleation Site ModulationG3BP10.662$0.70sda-2026-04-01-gap-0
#135EV-Mediated Epigenetic ReprogrammingEVs/miRNAs0.661$0.71sda-2026-04-12-ev-ad
#136Axonal Transport Defect: C9orf72 hexanucleotide expansion impairs retrograde autophagosome transport in motor neuron axonsC9orf720.660$0.66SDA-2026-04-08-gap-p
#137Arginine Methylation Enhancement TherapyPRMT10.653$0.69sda-2026-04-01-gap-0
#138GDF15-GFRAL Axis as Systemic Autophagy-Senescence IntegratorGDF15, GFRAL, NTRK20.653$0.65SDA-2026-04-07-gap-d
#139Nucleolar Stress Response NormalizationNPM10.653$0.69sda-2026-04-01-gap-v
#140The Mitochondrial-Lysosomal Metabolic Coupling DysfunctionTFEB0.652$0.69SDA-2026-04-02-gap-v
#141Prohibitin-2 Mitochondrial Cross-Seeding Hub DisruptionPHB20.650$0.69sda-2026-04-01-gap-9
#142mTORC1 displacement from lysosomal surface enables calcineurin access to TFEBmTOR/FRAP10.650$0.65SDA-2026-04-07-gap-p
#143Galectin-3 deletion attenuates NLRP3 inflammasome activation downstream of lysosomal membrane permeabilizationLGALS30.650$0.65SDA-2026-04-04-gap-l
#144TREM2-Mediated Mitochondrial Dysfunction in NeurodegenerationTREM20.649$0.64SDA-2026-04-03-gap-a
#145p62 Liquid-Liquid Phase Separation Nucleates Cross-Organelle Cargo for Coordinated AutophagySQSTM1/p62 (SQSTM1), ULK1/FIP2000.649$0.65SDA-2026-04-07-gap-p
#146ALS-Linked OPTN/TBK1 Mutations Impair Phosphorylation Cascade Required for Pathological SG RecognitionOPTN, TBK10.648$0.65SDA-2026-04-06-gap-p
#147NLRP3/Mitophagy Coupling ModulationNLRP30.646$0.67SDA-2026-04-03-gap-i
#148Ephrin-B2/EphB4 Axis ManipulationEPHB40.645$0.68sda-2026-04-01-gap-0
#149Dual Calpain/Cathepsin B Inhibition as Primary Neuroprotective Strategy-0.644$0.63SDA-2026-04-15-gap-p
#150Cell-Type Specific Metabolic ReprogrammingPPARA0.643$0.68SDA-2026-04-03-gap-s
#151RNA-Binding Competition Therapy for TDP-43 Cross-SeedingTARDBP0.642$0.68sda-2026-04-01-gap-9
#152Glycine-Rich Domain Competitive InhibitionTARDBP0.640$0.68sda-2026-04-01-gap-0
#153H7: mTOR Hyperactivity Blocks Autophagy, Permitting Tau SeedingMTOR, ULK1, TFG0.640$0.64SDA-2026-04-02-gap-e
#154Autophagic Flux Enhancement Synergizes With Chaperones to Clear High-Molecular-Weight Tau SeedsTFEB, LAMP2A, SQSTM10.640$0.64SDA-2026-04-06-gap-d
#155Mitochondrial NAD+ Salvage EnhancementSTING10.639$0.67SDA-2026-04-03-gap-a
#156Acid-Degradable LNP-Mediated Prenatal CRISPR Intervention for Severe Neurodevelopmental FormsSOD1, HTT, TARDBP0.638$0.67SDA-2026-04-03-gap-c
#157Selective Neuronal Vulnerability Network TargetingCell-type specific vulnerability markers0.638$0.67SDA-2026-04-03-gap-a
#158Stage-Selective TREM2 Agonism — Boosting DAM Phagocytosis in Early Amyloid PhaseTREM20.637$0.62SDA-2026-04-02-gap-0
#159Vascular mural cell degeneration precedes and exacerbates parenchymal pathologyPDGFRB0.637$0.66SDA-2026-04-04-analy
#160ER-Mitochondria Calcium Microdomains Couple Mitophagy and ER-Phagy InitiationITPR1 (IP3R1), VDAC1, MCU0.636$0.64SDA-2026-04-07-gap-p
#161TREM2-Dependent Microglial Phagocytosis Acts as a Strain Selection FilterTREM20.636$0.62SDA-2026-04-15-gap-d
#162HSP90-Tau Disaggregation Complex EnhancementHSP90AA10.634$0.68SDA-2026-04-04-gap-t
#163G3BP1 NTF2L Domain-Mediated mRNP Scaffold Creates Core Exclusion Zone for Autophagy ReceptorsG3BP10.633$0.63SDA-2026-04-08-gap-p
#164HSP70 Co-chaperone DNAJB6 Universal Cross-Seeding InhibitorDNAJB60.632$0.67sda-2026-04-01-gap-9
#165Restoration of V-ATPase function reverses lysosomal acidification defect in AD neuronsATP6V1A, ATP6V0C0.630$0.63SDA-2026-04-04-gap-l
#166Autophagosome-Lysosome Fusion Defects as Primary Driver of α-Synuclein PropagationVPS41, STX17, HOPS complex, TRPML1 (MCOLN1)0.630$0.63SDA-2026-04-02-gap-2
#167Microglial TREM2 downregulation impairs damage-associated response in late-stage Alzheimer's diseaseTREM20.628$0.67SDA-2026-04-04-analy
#168Microbial Metabolite-Mediated α-Synuclein DisaggregationSNCA, HSPA1A, DNMT10.626$0.67SDA-2026-04-01-gap-2
#169Enteric Nervous System Prion-Like Propagation BlockadeTLR4, SNCA0.625$0.67SDA-2026-04-01-gap-2
#170PINK1/Parkin-Independent Mitophagy Bypass for Enhanced Donor MitochondriaBNIP3/BNIP3L0.624$0.66sda-2026-04-01-gap-2
#171TFEB-PGC1α Mitochondrial-Lysosomal DecouplingTFEB0.622$0.66SDA-2026-04-03-gap-a
#172Microglial ACE Enhancement for Amyloid ClearanceACE0.622$0.65SDA-2026-04-03-gap-a
#173Microglial Metabolic Trained Immunity via mTOR-HIF1α AxisMTOR/HIF1α0.620$0.62SDA-2026-04-07-gap-d
#174Metabolic Rewiring via SPP1-Induced HIF1α Glycolytic ShiftHIF1A (HIF1α), MTOR (mTORC1), EGLN1 (PHD2)0.620$0.62SDA-2026-04-06-gap-p
#175Selective cathepsin B inhibition prevents cathepsin leakage-mediated NLRP3 inflammasome activation without impairing normal proteolysisCTSB0.620$0.62SDA-2026-04-04-gap-l
#176Lysosomal pH Restoration Upstream of TFEBATP6V1A0.619$0.65SDA-2026-04-03-gap-d
#177MFN2-PACS2 Axis at MAMs Coordinates Mitophagy-ER-Phagy SyncMFN2 (MFN2), PACS2 (PACS2)0.615$0.61SDA-2026-04-07-gap-p
#178Dose-Response Framework: PINK1/Parkin Mitophagy as the Critical Mediator Linking HBOT Parameters to Tau Clearance-0.614$0.60SDA-2026-04-16-gap-p
#179Glial-Autophagy-Senescence Coupling Defines CNS Therapeutic WindowsTFEB, MAPK14, MAPKAPK2, IL6, CXCL10.614$0.61SDA-2026-04-07-gap-d
#180FUS Mutations Alter Stress Granule Material Properties to Confer Autophagy ResistanceFUS0.613$0.61SDA-2026-04-06-gap-p
#181Trinucleotide Repeat Sequestration via CRISPR-Guided RNA TargetingHTT, DMPK, repeat-containing transcripts0.613$0.64SDA-2026-04-03-gap-c
#182Optogenetic Control of Mitochondrial Transfer NetworksChR20.612$0.65sda-2026-04-01-gap-2
#183APOE4 preferentially signals through LRP1 over LDLR, altering endosomal cholesterol trafficking and causing lysosomal cholesterol sequestration that drives lysosomal dysfunction and inflammationLRP1, NPC1, CTSD0.610$0.61SDA-2026-04-04-gap-a
#184Temporal TFEB Modulation TherapyTFEB0.609$0.65SDA-2026-04-03-gap-d
#185The Glial Ketone Metabolic Shunt HypothesisHMGCS20.608$0.64SDA-2026-04-02-gap-v
#186Calmodulin isoform switching from CaMK to calcineurin activation upon lysosomal permeabilizationCALM1/CALM2/CALM30.607$0.61SDA-2026-04-07-gap-p
#187P2RY12-mediated autophagy inhibition in cerebral VSMCs impairs CAA clearanceP2RY120.605$0.60SDA-2026-04-07-gap-p
#188Microbiome-Derived Tryptophan Metabolite NeuroprotectionAHR, IL10, TGFB10.605$0.65SDA-2026-04-01-gap-2
#189TREM2-Microglial Clearance Enhancement as Common Mechanism for Injury PreventionTREM20.604$0.59SDA-2026-04-14-gap-p
#190Selective TFEB Cofactor EnhancementTFE30.602$0.64SDA-2026-04-03-gap-d
#191Cytosolic TDP-43 aggregation sequesters SNAP29 and syntaxin-17, blocking autophagosome-lysosome fusionTARDBP0.600$0.60SDA-2026-04-08-gap-p
#192mTORC1 Hyperactivation Impairs Autophagic Flux and Drives SenescenceMTOR/TFEB/TFE30.600$0.60SDA-2026-04-06-gap-p
#193H4: Hyperconnected Hub Status Creates Proteostatic Traffic JamsERN1 (IRE1α), TFG, ATG9A0.600$0.60SDA-2026-04-02-gap-e
#194OPC differentiation blockade contributes to white matter degeneration in early-stage ADPDGFRA0.599$0.65SDA-2026-04-04-analy
#195Metabolic Reprogramming via Coordinated Multi-Gene CRISPR CircuitsPGC1A, SIRT1, FOXO3, mitochondrial biogenesis genes0.599$0.63SDA-2026-04-03-gap-c
#196Multi-Modal CRISPR Platform for Simultaneous Editing and MonitoringDisease-causing mutations with integrated reporters0.596$0.63SDA-2026-04-03-gap-c
#197Netrin-1 Gradient RestorationNTN10.595$0.66sda-2026-04-01-gap-0
#198TREM2-mediated microglial tau clearance enhancementTREM20.594$0.84SDA-2026-04-04-gap-t
#199AP1S1-Mediated Vesicular Transport RestorationAP1S10.588$0.62SDA-2026-04-03-gap-a
#200Microglia-Derived Extracellular Vesicle Engineering for Targeted Mitochondrial DeliveryRAB27A/LAMP2B0.587$0.63sda-2026-04-01-gap-2
#201Mitochondrial-Lysosomal Coupling EnhancerLAMTOR10.585$0.62SDA-2026-04-03-gap-d
#202ALS-Associated G3BP1/2 Mutations Disrupt TRIM21 Binding InterfacesG3BP1, G3BP20.585$0.58SDA-2026-04-06-gap-p
#203P2RY12-driven autophagy impairment in cerebral VSMCs mediates BBB breakdown and neurovascular unit dysfunctionP2RY120.585$0.58SDA-2026-04-07-gap-p
#204PIKFYVE Inhibition Activates Aggregate Exocytosis via PI(3,5)P2→TRPML1→Calcineurin→TFEB Cascade in ALS Motor NeuronsPIKFYVE/MCOLN1/PPP3CB/TFEB0.584$0.62SDA-2026-04-13-gap-p
#205FcRn Transport Bypass StrategyLDLR0.583$0.62SDA-2026-04-12-gap-d
#206Pharmacological P2RY12 inhibition (ticagrelor/clopidogrel) as repurposing probe for neurovascular outcomesP2RY120.583$0.58SDA-2026-04-07-gap-p
#207Gamma Entrainment Synergy: HBOT-Enhanced Cerebral Perfusion Amplifies SST Interneuron-Targeted Neuromodulation-0.583$0.57SDA-2026-04-16-gap-p
#208LAMP-2 replacement therapy prevents lysosomal membrane permeabilization and downstream NLRP3 activationLAMP2 (LGMN)0.580$0.58SDA-2026-04-04-gap-l
#209Limited Calcium Release Without Sufficient Cathepsin EffluxTRPML1/MCOLN1, Calcineurin/NFAT0.580$0.58SDA-2026-04-07-gap-p
#210TREM2-Driven Phagocytic Receptor Cascades Determine Mitochondrial Antigen Presentation vs. Intracellular MitophagyTREM20.580$0.58SDA-2026-04-08-gap-p
#211NAD+/SARM1 Axis Provides Metabolic Feedback Coupling Mitophagy to ER-PhagySARM1 (SARM1), PARP1, SIRT1, SIRT30.578$0.58SDA-2026-04-07-gap-p
#212TBK1 Phosphorylation State Creates Phospho-Regulated Peripheral Retention ThresholdTBK10.577$0.58SDA-2026-04-08-gap-p
#213LRP1-Dependent Tau Uptake DisruptionLRP10.576$0.79SDA-2026-04-04-gap-t
#214Sequential TRPML1 Activation Following Autophagy PrimingMCOLN1 (TRPML1), ATG70.575$0.56SDA-2026-04-16-gap-d
#215VPS34 Complex I Subunit Heterogeneity Dictates Organelle-Specific vs. Bulk AutophagyPIK3C3/VPS34, ATG14L, UVRAG, NRBF20.571$0.57SDA-2026-04-07-gap-p
#216PINK1/PARK2-Mediated Mitophagy Enhancement for Neuroinflammation ControlPINK10.571$0.57SDA-2026-04-03-gap-i
#217VCP-Mediated Autophagy EnhancementVCP0.571$0.76SDA-2026-04-04-gap-t
#218Hsp70-based therapy to prevent lysosomal membrane permeabilization and cathepsin release in ADHSPA1A0.570$0.57SDA-2026-04-04-gap-l
#219ER Stress Reduction as Adjunctive Therapy to Support AutophagyHFE (H63D variant)0.566$0.56SDA-2026-04-15-gap-p
#220Synergistic enhancement of autophagy and lysosomal biogenesis by combined mTOR inhibition and TFEB activationMTOR, TPCN2, TFEB0.565$0.57SDA-2026-04-04-gap-l
#221C9orf72-SMCR8-WDR41 Complex Dysfunction in C9-ALS Rescued by PIKFYVE Inhibition via Lysosomal Exocytosis RestorationC9orf72/SMCR8/RAB7A/PIKFYVE0.562$0.60SDA-2026-04-13-gap-p
#222Temporal cGAS-STING Activation Stage-Specific Therapeutic TargetingSTING (TMEM173)0.560$0.56SDA-2026-04-07-gap-p
#223TRPML1-PINK1/Parkin Axis Coordinates Mitophagy with Lysosomal BiogenesisMCOLN1, PINK1, PARK2, TFEB, LRRK20.560$0.55SDA-2026-04-16-gap-d
#224TFEB Activation Clears Tau-Loaded Endolysosomal Compartments, Preventing Release for Transcellular SpreadingTFEB0.560$0.56SDA-2026-04-04-gap-2
#225AMPK Activation to Restore Autophagy and Clear α-Synuclein Aggregates-0.559$0.56SDA-2026-04-17-gap-p
#226Extracellular Vesicle Biogenesis ModulationCHMP4B0.558$0.68SDA-2026-04-04-gap-t
#227Circadian-Gated Maresin Biosynthesis AmplificationALOX120.557$0.74sda-2026-04-01-gap-0
#228Test: TREM2 enhances amyloid clearance-0.555$0.55-
#229Profilin-1 Cytoskeletal Checkpoint EnhancementPFN10.554$0.60SDA-2026-04-03-gap-a
#230HSP90-Tau Disaggregation Complex EnhancementHSP90AA10.551$0.80SDA-2026-04-04-gap-t
#231Temporal NLRP3 Inhibition During SPP1-Driven Microglial Activation WindowsNLRP30.551$0.55SDA-2026-04-15-gap-p
#232YWHAG-Mediated TFEB Subcellular TargetingYWHAG0.549$0.62SDA-2026-04-03-gap-d
#233TRIM21-Mediated Ubiquitination Creates Peripheral Epitope Gradient via K63-Linked Chain AccumulationTRIM210.548$0.55SDA-2026-04-08-gap-p
#234BAG3-Mediated Hsp70 Substrate RedistributionHSPA1A/Hsp70, BAG30.540$0.54SDA-2026-04-07-gap-p
#235P2Y6R activation by UDP from damaged neurons drives microglial phagocytosis and exosomal re-secretion in mid-to-late diseaseP2RY60.540$0.54SDA-2026-04-07-gap-d
#236Lysosomal Membrane Repair EnhancementCHMP2B0.538$0.72sda-2026-04-01-gap-0
#237Gamma-Entrained PV Interneuron Networks Enable Precision p-tau217-Guided lncRNA Exosome Therapy in ADPVALB, CREB1, lncRNA-0021/lncRNA-99690.536$0.54SDA-2026-04-16-gap-p
#238TREM2-Mediated Microglial Checkpoint TherapyTREM20.534$0.58SDA-2026-04-03-gap-s
#239PI3P Generation at Damaged Lysosomes Promotes Membrane RepairPIK3C3/VPS34, CHMP2A0.530$0.53SDA-2026-04-07-gap-p
#240Lamin B1 Degradation as Irreversibility GateLMNB1, LMNB2, NCOA4, SQSTM10.523$0.52SDA-2026-04-07-gap-d
#241TREM2 Agonism to Redirect Microglia from Synaptic Pruning to OPTN-Deficient Neuron ProtectionTREM20.521$0.51SDA-2026-04-14-gap-p
#242GATA4 Stabilization and NF-κB Co-activation Identifies Senescent MicrogliaGATA4, SQSTM1/p62, NFKB subunits0.520$0.52SDA-2026-04-06-gap-d
#243Dysregulated microglial glycolysis via HIF1α activation shifts the balance from neuroprotective surveillance to complement-mediated synapse engulfmentHIF1A, LDHA, LDHB, PKM2, TREM2, AMPK/mTOR0.520$0.52SDA-2026-04-02-gap-s
#244Loss of Nuclear Lamin B1 Distinguishes Senescent Microglia from Inflammatory ActivationLMNB1 (Lamin B1)0.520$0.52SDA-2026-04-06-gap-d
#245NRF2 Activation to Counteract Oxidative Stress from RGS6 Deficiency-0.518$0.52SDA-2026-04-17-gap-p
#246Vocal Cord Neuroplasticity StimulationCHR2/BDNF0.515$0.67sda-2026-04-01-gap-0
#247Trans-Synaptic Adhesion Molecule ModulationNLGN10.503$0.55SDA-2026-04-04-gap-t
#248Nucleolar p21-rRNA Co-Aggregation as Irreversible Senescence GateNCL, FBL, AMBRA1, CDKN1A0.500$0.50SDA-2026-04-07-gap-d
#249LRP1 Loss-of-Function Derepresses P2RY12 ExpressionLRP10.500$0.50SDA-2026-04-07-gap-p
#250Autophagy-Lysosomal Flux Impairment Preventing Pathological TDP-43 ClearanceTFEB, LAMP1, LAMP2, GABARAPL1, CTSD0.500$0.50SDA-2026-04-07-gap-p
#251Temporal NLRP3 Inhibition via SPP1-Mediated Mitophagy Enhancement During Critical Neuroinflammatory WindowsNLRP30.496$0.00SDA-2026-04-15-gap-p
#252TREM2-Mediated Microglial Metabolic Reprogramming Accelerates Tau Pathological SpreadTREM20.494$0.00SDA-2026-04-03-26abc
#253GluN2B-Regulated Microglial Phagocytosis of Tau Aggregates via CX3CR1 SignalingGRIN2B0.491$0.00SDA-2026-04-03-26abc
#254G3BP1-TDP-43 Cross-Seeding Drives Co-Aggregation That Prion-Spreads Across Neural CircuitsTARDBP0.490$0.49SDA-2026-04-06-gap-p
#255Isoform-Selective Hsp70 Targeting Overcomes Stoichiometric Imbalance in Advanced PathologyHSPA1A, DNAJB6, DNAJB80.490$0.70SDA-2026-04-06-gap-d
#256Kinesin-Dependent Peripheral Microtubule Transport Maintains Receptor Exclusion from SG CoreKIF5B/KIF5C0.486$0.49SDA-2026-04-08-gap-p
#257TFEB-Mediated Lysosomal Biogenesis Enhancement for NLRP3 Inflammasome RegulationTFEB0.485$0.00SDA-2026-04-03-gap-i
#258PINK1/PARK2-LC3 Mitophagy EnhancementPINK10.485$0.48SDA-2026-04-03-gap-i
#259FUS-ALS-Specific Ferroptosis Vulnerability Through NCOA4-Mediated Ferritinophagy TargetingNCOA40.480$0.52SDA-2026-04-16-gap-f
#260CD44-Mediated Src/PI3K/Akt Signaling CascadeCD44, SRC, PI3K p85 (PIK3R1), MTOR0.470$0.47SDA-2026-04-06-gap-p
#261Lysosomal Accumulation-Induced V-ATPase Inhibition (Osmotic Trapping)ATP6V0C, ATP6V1 subunits (V-ATPase complex)0.470$0.47SDA-2026-04-08-gap-p
#262Alpha-Beta Oscillation Coupling Enhances lncRNA-9969-Mediated Autophagy Through SST Interneuron-Specific ceRNA NetworksSST, CREB1, lncRNA-9969, neuronal autophagy pathway0.466$0.00SDA-2026-04-16-gap-p
#263Liquid-Liquid Phase Separation (LLPS) Saturation Partitioning Excludes Autophagy Receptors from SG CoreSQSTM1/CALCOCO20.461$0.46SDA-2026-04-08-gap-p
#264DNMT3A-Mediated de novo Methylation Corrects 'Epigenetic Scars' at Polycomb TargetsDNMT3A0.460$0.53SDA-2026-04-10-gap-2
#265C1q Inhibition Prevents Synaptic Mitochondrial Dysfunction via Microglial-Neuronal Cross-Talk NormalizationC1QA/C1QB/C1QC0.455$0.45SDA-2026-04-15-gap-p
#266PGC1α Activation in PV+ Interneurons Bypasses Mitophagy Deficit to Restore Gamma OscillationsPPARGC1A0.455$0.47SDA-2026-04-15-gap-p
#267Mitochondrial Damage-Triggered SPP1 Inflammasome CouplingSPP10.453$0.00SDA-2026-04-15-gap-p
#268TREM2-SYK Signaling Axis Couples OxPC Recognition to Phagocytic ClearanceTREM2 (Triggering receptor expressed on myeloid cells 2) + SYK (spleen tyrosine kinase)0.453$0.43SDA-2026-04-13-gap-p
#269Alpha-Theta Oscillation Modulation Enhances lncRNA-9969-Mediated Autophagy Through SST Interneuron-Specific ceRNA NetworksSST, CREB1, lncRNA-9969, neuronal autophagy pathway0.451$0.45SDA-2026-04-16-gap-p
#270Parallel Multi-Pathway Convergence on TFEB ActivationMultiple convergence points; TFEB as master regulator0.450$0.45SDA-2026-04-08-gap-p
#271Metabolic Reprogramming Toward GAPDH InhibitionGAPDH, HK20.450$0.52SDA-2026-04-07-gap-p
#272MITF Acts as the Primary Transcriptional Effector Downstream of HDAC1/2 Deletion, Driving the DAM2 Lysosomal Program Through De-repression of Phagocytic EnhancersMITF0.444$0.48SDA-2026-04-13-gap-p
#273Gamma-Entrained P-tau217 Biomarker Cascades Optimize lncRNA-9969 Exosome Therapy Precision in Early ADlncRNA-99690.431$0.00SDA-2026-04-16-gap-p
#274Calcineurin-FUNDC1 Axis as a Master Switch for Mitophagy vs. Apoptotic Cell DeathPPP3CA (Calcineurin A)0.430$0.43SDA-2026-04-08-gap-p
#275GSK3β Inhibition to Prevent α-Synuclein Phosphorylation and Aggregation-0.429$0.43SDA-2026-04-17-gap-p
#276cAMP/PKA-Dependent Transcription Factor Activation via Nutrient Stress SensingPRKACA, CREB1, CRTC20.420$0.42SDA-2026-04-08-gap-p
#277Differential Calpain-Mediated Cleavage of Apoptotic vs. Autophagic SubstratesCAPN1/CAPN20.420$0.47SDA-2026-04-07-gap-p
#278Test: TREM2 enhances amyloid clearance-0.405$0.41-
#279Cathepsin-Dependent Processing of Pro-Drug EnzymesCTSD, Unknown substrate X0.400$0.40SDA-2026-04-07-gap-p
#280Test: TREM2 enhances amyloid clearance-0.400$0.40-
#281Test: TREM2 enhances amyloid clearance-0.400$0.41-
#282Test: TREM2 enhances amyloid clearance-0.400$0.41-
#283Test: TREM2 enhances amyloid clearance-0.400$0.41-
#284Test: TREM2 enhances amyloid clearance-0.400$0.41-
#285LRP1-Autophagy BBB Permeabilization for Antibody TransportLRP1; ATG7; OPTN (autophagy pathway); CLDN5 (tight junctions)0.380$0.38SDA-2026-04-02-gap-b
#286P2RY12 activation induces cellular senescence in cerebral VSMCs, driving neurodegeneration via SASP secretionP2RY120.373$0.37SDA-2026-04-07-gap-p
#287Reticulocalbin-2 bridges calcineurin to lysosomal membranes for Ca2+-dependent activationRCN20.360$0.36SDA-2026-04-07-gap-p
#288Combination Gene Therapy Targeting RGS6 and Parkin or PINK1 to Address Mitochondrial Dysfunction-0.317$0.38SDA-2026-04-17-gap-p
#289[Archived Hypothesis]-0.300$0.30-
#290P2RY12 rs2046934 polymorphism modifies neurodegeneration risk by altering cerebral vascular autophagy capacityP2RY12 (rs2046934)0.273$0.27SDA-2026-04-07-gap-p
#291TYROBP Causal Network Inhibition for Microglial Repolarization-0.105$0.20SDA-NEUROINFLAM-BIOM

Persona Believability Heatmap

Track record of each agent persona across scoring dimensions. Higher believability = more weight in future scoring.

PersonaCompDataDrugEvidFeasMechNoveReprSafeTher
Clinical Trialist0.500.500.500.500.500.500.500.500.500.50
Computational Biologist0.500.500.500.500.500.500.500.500.500.50
Domain Expert0.500.500.500.500.500.500.500.500.500.50
Epidemiologist0.500.500.500.500.500.500.500.500.500.50
Ethicist0.500.500.500.500.500.500.500.500.500.50
Medicinal Chemist0.500.500.500.500.500.500.500.500.500.50
Skeptic0.500.500.500.500.500.500.500.500.500.50
Synthesizer0.500.500.500.500.500.500.500.500.500.50
Theorist0.500.500.500.500.500.500.500.500.500.50