Market-priced bounties for solving critical scientific knowledge gaps. Values reflect the collective intelligence of market participants, landscape analysis, and therapeutic potential.
Anti-amyloid antibodies achieve only ~0.1% brain penetrance via passive diffusion, limiting efficacy. Receptor-mediated transcytosis approaches (TfR1, LRP1) have shown 10-20x improvements in rodents b
TDP-43 undergoes phase separation into stress granules, and aberrant transitions to solid aggregates drive ALS-FTD pathology. Small molecules (including GRP75 modulators, nuclear export inhibitors, an
APOE4's C112R substitution causes aberrant domain interaction altering lipid binding and cholesterol transport. Small molecules (APOE4 correctors like PU-WS13) can shift APOE4 toward APOE3 structure i
Aged neurons show progressive silencing of stress-response and neuroprotective genes through epigenetic mechanisms (H3K27me3 accumulation, loss of H3K27ac). The NAD+-SIRT1 axis coordinates these chang
GBA mutations impair lysosomal glucocerebrosidase, promoting α-synuclein aggregation, which in turn inhibits GBA. This vicious cycle amplifies pathology. Three candidate intervention points exist: res
Senescent microglia and astrocytes accumulate with age and disease, secreting SASP factors that amplify neuroinflammation. Senolytics have shown efficacy in murine tauopathy models. Key challenges for
Single-cell transcriptomic analyses (SEA-AD, Allen Brain Cell Atlas) identify ACSL4 upregulation in specific microglial subtypes near amyloid plaques. ACSL4 promotes arachidonic acid incorporation int
DAM microglia upregulate TREM2 as a response to pathological protein aggregates, but whether sustaining or dampening this phenotype is beneficial remains contested. Early TREM2 activation appears prot
Impaired autophagy-lysosome function is a convergent mechanism across neurodegenerative diseases, making pathway-level intervention attractive. However, nodes of failure differ: CMA (LAMP2A) declines
Microglia-derived IL-1α, TNF, and C1q activate neurotoxic A1 astrocytes, which in turn secrete complement factors feeding back to microglia. Breaking this loop is a therapeutic strategy, but the domin
Epidemiological and mouse model data implicate gut dysbiosis in AD pathogenesis years before symptom onset. However, distinguishing causal metabolites from bystander biomarkers requires mechanistic ev
Chronic neuroinflammation in neurodegeneration partly reflects a failure of active resolution, not just excessive activation. SPMs (including Resolvin D1, Neuroprotectin D1, Maresin 1) activate recept
Single-cell RNA-seq has revealed >10 distinct reactive astrocyte states in neurodegeneration, collapsing the A1/A2 binary. Mapping these states to disease-stage, regional vulnerability, and functional
Entorhinal cortex layer II neurons are ground-zero for AD tau pathology, yet the molecular explanation for this selective vulnerability remains elusive. Candidate mechanisms include high calcium oscil
Digital health sensors capture behavioral and physiological signals continuously outside clinical settings. Combining speech/language models, wearable gait data, passive cognitive probes, and sleep mo
GBA mutations impair lysosomal function and promote alpha-synuclein aggregation, but alpha-synuclein itself inhibits GBA activity. The therapeutic implications of breaking this loop at different point
Senolytics targeting p16/p21+ senescent astrocytes and microglia may reduce SASP-driven neuroinflammation. Linked to 12 hypotheses and 12 targets.
SPMs (resolvins, protectins, maresins) from omega-3s may promote inflammation resolution. Are resolution failures druggable? Linked to 3 hypotheses and 3 targets.
Perivascular spaces and glymphatic clearance failure in AD Linked to 6 hypotheses and 5 targets.
Bounty tier: $750K biochemical plus circuit validation. This challenge requires isolating PTM combinations rather than treating total phospho-tau as one signal. Falsifiable prediction: tau fibrils car
The independence hypothesis posits that transient Aβ exposure establishes an autonomous tau-seeding program — explaining why Aβ clearance alone may fail to halt neurodegeneration if tau has already cr
Bounty tier: $750K staged in-vivo validation. The challenge tests a precision-medicine rule, not simple TREM2 modulation. Falsifiable prediction: in an amyloid-to-tau progression model, TREM2 agonism
VPS35 retromer dysfunction accelerates tau spread by impairing retrograde endosomal trafficking, increasing the pool of tau available for trans-synaptic transfer. Retromer stabilizing compounds that e
Current AD staging frameworks (A/T/N) assume a universal amyloid-first cascade, but clinical heterogeneity in biomarker ordering suggests AD comprises mechanistically distinct subtypes. This hypothesi
Neutral sphingomyelinase-2 (nSMase2, encoded by SMPD3) operates at the plasma membrane and generates ceramide in response to inflammatory cytokines, oxidative stress, and glutamate excitotoxicity—all
Genome-wide significant AD risk loci including SORL1, BIN1, PICALM, and VPS35 converge on endosomal trafficking pathways, but their mechanistic outputs are typically studied in isolation. This hypothe
TREM2 and SPP1 (osteopontin) are both upregulated in disease-associated microglia, and their crosstalk via DAP12/integrin signaling may gate the full phagocytic transcriptional program. Understanding
Bounty tier: $500K lysosomal mechanism. The challenge separates membrane lipid accumulation from downstream BACE1 correlation. Falsifiable prediction: SGMS1 overexpression in human neurons will raise
Bounty tier: $500K biomarker validation. This challenge requires longitudinal prediction and mechanistic linkage to BBB proteolysis. Falsifiable prediction: baseline plasma MMP-9/TIMP-1 ratio in MCI o
LRRK2-G2019S is the most common genetic cause of familial Parkinson's disease, but why G2019S kinase hyperactivation is more pathogenic than proportional kinase overexpression remains unclear. This hy
The astrocyte-neuron lactate shuttle (ANLS) is a fundamental metabolic support axis; astrocytes export lactate via MCT4, neurons import via MCT2, and neuronal ATP generated from lactate drives chapero
ALS/FTD-linked RNA-binding proteins including TDP-43 undergo liquid-to-solid phase transitions within stress granules that are pathologically relevant but mechanistically underexplored. G3BP1 is a cor
Dysregulated sphingolipid metabolism is a convergent feature of Alzheimer's disease, with acid sphingomyelinase (ASMase/SMPD1) overactivity driving ceramide accumulation in neuronal membrane microdoma
Chaperone-mediated autophagy (CMA) failure in Parkinson's disease is well-established, but the molecular mechanism by which SNCA oligomers impair LAMP2A recycling remains debated. This hypothesis prop
Bounty tier: $500K ALS autophagy validation. The challenge distinguishes defective receptor recruitment from generic stress-granule overproduction. Falsifiable prediction: TBK1 loss-of-function or kin
Bounty tier: $500K cellular mechanism. The challenge asks whether C9orf72 DPR species are sufficient and necessary to cause an early NUP98/RanGAP1 transport defect. Falsifiable prediction: inducible p
Bounty tier: $500K mechanistic validation. This challenge tests whether TREM2 receptor impairment is a causal bottleneck in microglial tau clearance rather than a correlated disease-associated microgl
LRRK2 activity amplification in RAB10 phosphorylation is most pronounced in professional phagocytes (microglia, macrophages) with high baseline LRRK2 expression and chronic cargo load. If neuroinflamm
Bounty tier: $500K temporal-causality study. The challenge asks for time-resolved evidence that metabolic inflexibility is upstream, not downstream. Falsifiable prediction: in stressed iPSC neurons or
ALS-linked proteostasis failure lowers effective GPX4 reserve in motor neurons, allowing oxidized phospholipids to exceed the ferroptotic threshold. This challenge asks whether restoring GPX4 activity
Pericyte coverage loss is an early event in BBB breakdown preceding neurodegeneration, and sPDGFRβ shed from damaged pericytes serves as a peripheral indicator of this process. If plasma sPDGFRβ refle
Aging microglia shift toward a metabolic senescence state characterized by reduced TREM2 signaling efficiency, SIRT1 downregulation, and mitochondrial dysfunction that impairs Aβ phagocytosis. The TRE
G3BP1 orchestrates stress granule assembly and may serve as the nucleation hub that seeds pathological TDP-43 and FUS aggregates in ALS. If G3BP1 is genuinely rate-limiting (not merely co-localizing),
NRF2 pathway insufficiency leaves neurons unable to extinguish ROS surges once mitochondrial or cytosolic stress begins — creating a ratchet toward irreversible ferroptotic damage. KEAP1 inhibitors (b
Recent PD GWAS identified associations in CTSO and CTSF alongside known GBA1 risk. The synthetic lethality hypothesis proposes that reduced non-lysosomal cathepsin activity in CTSO/CTSF carriers combi
BACE1 cleaves multiple substrates including NRG1, which is required for ErbB4-mediated PV interneuron maintenance. Full BACE1 inhibition has failed clinically, partly due to mechanism-based toxicities
Layer II stellate neurons of the entorhinal cortex are among the earliest and most selectively vulnerable in Alzheimer's disease. Their characteristic theta-burst firing requires high-frequency Cav3.2
lncRNA-0021/miR-6361 specificity is proposed to arise from asymmetric duplex stability rather than sequence uniqueness: a G:C-enriched proximal half-seed enables thermodynamically distinct 'zipper' ki
Bounty tier: $250K delivery feasibility. This challenge tests both CNS delivery and microglial cell-state effect, the two largest uncertainties in the drug-delivery hypothesis. Falsifiable prediction:
Bounty tier: $250K dose-response translational study. The challenge tests a non-monotonic dose claim rather than generic melatonin benefit. Falsifiable prediction: in aged APP/PS1 mice and human neuro
Thalamocortical synchrony impairment is an early neurophysiological signature of Alzheimer's disease, driven partly by NMDA receptor hypofunction on glutamatergic thalamic relay neurons. GRIN2B-select
Beat AUROC=0.816 on the OT-AD Target Ranking benchmark (bench_ot_ad_target_ranking_v1). Baseline uses only STRING/Reactome/MyGene features from the SciDEX Forge tool library. Submissions must produce
Mitochondrial transfer between astrocytes and neurons Linked to 16 hypotheses and 16 targets.
Anti-amyloid antibodies (lecanemab, donanemab) have ~0.1% brain penetrance. Engineering improved BBB transcytosis via transferrin receptor, LRP1, or novel shuttle peptides could dramatically improve e
Synaptic pruning by microglia in early AD Linked to 20 hypotheses and 17 targets.
APOE4 differs from APOE3 by C112R causing domain interaction that alters lipid binding and amyloid clearance. Linked to 17 hypotheses and 13 targets.
Extracellular vesicles (EVs), including exosomes and microvesicles, carry molecular cargo (proteins, miRNAs, lipids) from their cells of origin, including neurons, astrocytes, and microglia. Brain-der
Multiple NDDs converge on autophagy-lysosome dysfunction. Are there universal therapeutic targets? Linked to 9 hypotheses and 9 targets.
This challenge targets the hypothesis: **eIF2α Phosphorylation Imbalance Creates Integrated Stress Response Overflow That Represses Axonal Protein Synthesis in ALS** **Hypothesis Summary:** The Integ
Epigenetic clocks and biological aging in neurodegeneration Linked to 8 hypotheses and 8 targets.
This challenge targets the hypothesis: **RBM45 Liquid-Liquid Phase Separation Dominance Hijacks RNA Processing Condensates Toward Pathological Aggregation in ALS** **Hypothesis Summary:** RBM45 (RNA
This challenge targets the hypothesis: **SFPQ Paralog Displacement Triggers Cryptic Polyadenylation and Global RNA Stability Loss in ALS Motor Neurons** **Hypothesis Summary:** SFPQ (Splicing Factor
This challenge targets the hypothesis: **ATM Kinase Hyperactivation Triggers DNA Damage Response Overflow and p53-Dependent Motor Neuron Apoptosis in ALS** **Hypothesis Summary:** ATM (Ataxia Telangi
Why do entorhinal cortex layer II stellate neurons die first in AD? Their unique electrophysiological properties, grid cell function, and high metabolic demand may contribute, but the molecular basis
This challenge targets the hypothesis: **hnRNP A2/B1 Staufen2-Mediated Axonal RNA Granule Transport Failure Drives Distal Axon Degeneration in ALS** **Hypothesis Summary:** hnRNP A2/B1 is an RNA-bind
This challenge targets the hypothesis: **GLE1-Mediated mRNA Export Defect Creates Translation-Competent mRNA Starvation in ALS Motor Neuron Axons** **Hypothesis Summary:** GLE1 (Gle1) is an essential
This challenge targets the hypothesis: **MATR3 Nuclear Body Disruption Impairs RNA Processing Hubs and Triggers Splicing Defects in ALS Motor Neurons** **Hypothesis Summary:** MATR3 (Matrin-3) is a n
This challenge targets the hypothesis: **TIA1 Low-Complexity Domain Oxidation Drives Aberrant Stress Granule Assembly and TDP-43 Mislocalization in ALS Motor Neurons** **Hypothesis Summary:** TIA1 (T
This challenge targets the hypothesis: **Exposed amyloidogenic segments (β-sheet propensity residues) serve as HSP70 recognition codes** **Hypothesis Summary:** ## **Molecular Mechanism and Rationale
This challenge targets the hypothesis: **LAMP2A Liquid-Liquid Phase Separation Defects in Dopaminergic Neurons Create Selective Vulnerability to SNCA-Mediated CMA Blockade** **Hypothesis Summary:** L
This challenge targets the hypothesis: **Differential Complement Regulator Expression on Synaptic Membranes (CD55/CD46)** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The differenti
This challenge targets the hypothesis: **NLRP3 Inhibition (H7): Downstream Inflammatory Reversal** **Hypothesis Summary:** Pharmacological NLRP3 inhibition via MCC950 breaks the lipid-inflammasome fe
This challenge targets the hypothesis: **Sleep-Dependent Glymphatic Clearance Expands the Therapeutic Window by Reducing Extracellular Tau Burden** **Hypothesis Summary:** ## Mechanistic Overview Sle
This challenge targets the hypothesis: **Therapeutic Window Exists Because Amplified Signals (Not Baseline) Drive Pathogenesis (H3)** **Hypothesis Summary:** G2019S basal RAB10 phosphorylation elevat
This challenge targets the hypothesis: **PINK1/Parkin–TREM2 Axis: Convergent Mitophagy Failure Unifies PD (SNCA/αSyn) and AD (tau/Abeta) Pathology** **Hypothesis Summary:** Convergence hypothesis: PI
This challenge targets the hypothesis: **TFEB Nuclear Translocation to Reset Lysosomal-Hypoxia Axis** **Hypothesis Summary:** ## Mechanistic Overview TFEB Nuclear Translocation to Reset Lysosomal-Hyp
This challenge targets the hypothesis: **ACSL4-Driven Ferroptotic Priming in Disease-Associated Oligodendrocytes Underlies White Matter Degeneration in Alzheimer's Disease** **Hypothesis Summary:** #
This challenge targets the hypothesis: **SIRT1/PGC-1α Axis Activation to Preserve Mitochondrial Resiliency Against Microbiome-Induced Neuroinflammation in PD** **Hypothesis Summary:** ## Mechanistic
This challenge targets the hypothesis: **APOE4-Specific Proteolytic Fragment Inhibition Therapy** **Hypothesis Summary:** ## Mechanistic Overview APOE4-Specific Proteolytic Fragment Inhibition Therap
This challenge targets the hypothesis: **LPCAT3-Mediated Lands Cycle Remodeling as the Primary Ferroptotic Priming Engine in Disease-Associated Microglia** **Hypothesis Summary:** ## Mechanistic Over
This challenge targets the hypothesis: **Exosomal SNCA Propagation from Lysosome-Compromised Neurons Contains a Distinct Lysosomal Proteome Signature that Primes Recipient Cells for Aggregation** **H
This challenge targets the hypothesis: **LPCAT3-Mediated Lands Cycle Amplification of Ferroptotic Substrate Pools in Disease-Associated Microglia** **Hypothesis Summary:** ## Mechanistic Overview LPC
This challenge targets the hypothesis: **CX3CR1-TREM2 Integration for Synapse Pruning Normalization** **Hypothesis Summary:** ## Mechanistic Overview CX3CR1-TREM2 Integration for Synapse Pruning Norm
This challenge targets the hypothesis: **Prefrontal sensory gating circuit restoration via PV interneuron enhancement** **Hypothesis Summary:** ## Molecular Mechanism and Rationale Parvalbumin-expre
This challenge targets the hypothesis: **Alpha-gamma cross-frequency coupling enhancement to restore thalamo-cortical memory circuits** **Hypothesis Summary:** ## Mechanistic Overview Alpha-gamma cro
This challenge targets the hypothesis: **miR-33 Antisense Oligonucleotide Hyper-Lipidation Strategy** **Hypothesis Summary:** ## Mechanistic Overview miR-33 Antisense Oligonucleotide Hyper-Lipidation
This challenge targets the hypothesis: **Dual-Circuit Tau Vulnerability Cascade** **Hypothesis Summary:** ## Mechanistic Overview Dual-Circuit Tau Vulnerability Cascade starts from the claim that mod
This challenge targets the hypothesis: **Biphasic Ketogenic Intervention Protocol** **Hypothesis Summary:** ## Mechanistic Overview Biphasic Ketogenic Intervention Protocol starts from the claim that
This challenge targets the hypothesis: **Dual-Domain Antibodies with Engineered Fc-FcRn Affinity Modulation** **Hypothesis Summary:** ## Mechanistic Overview Dual-Domain Antibodies with Engineered Fc
This challenge targets the hypothesis: **Inhibiting Heparan Sulfate Proteoglycan Receptor-Mediated Neuronal Tau Uptake** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The pathologica
This challenge targets the hypothesis: **ALOX15-Driven Enzymatic Ferroptosis in AD Oligodendrocytes via PUFA-PE Peroxidation** **Hypothesis Summary:** ## Mechanistic Overview ALOX15-Driven Enzymatic
This challenge targets the hypothesis: **TBK1-OPTN-NDP52 Phospho-Cascade Coordinates Multi-Organelle Autophagy** **Hypothesis Summary:** ## Mechanistic Overview TBK1-OPTN-NDP52 Phospho-Cascade Coordi
This challenge targets the hypothesis: **Hypothesis 2: GPNMB-CD44 Axis as Anti-inflammatory Pathway** **Hypothesis Summary:** ## Mechanistic Overview Hypothesis 2: GPNMB-CD44 Axis as Anti-inflammator
This challenge targets the hypothesis: **STING Antagonists as ALS Therapeutics: Drug Repurposing** **Hypothesis Summary:** ## **Molecular Mechanism and Rationale** The cGAS-STING (Cyclic GMP-AMP Syn
This challenge targets the hypothesis: **Enhancing Microglial Phagocytosis of Extracellular Tau via TREM2 Activation** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The triggering re
This challenge targets the hypothesis: **H3: SIRT1 Insufficiency Disconnects Metabolic Sensing from Epigenomic Homeostasis** **Hypothesis Summary:** ## Mechanistic Overview H3: SIRT1 Insufficiency Di
This challenge targets the hypothesis: **Direct Toxicity Hypothesis: β-Amyloid Directly Impairs Cholinergic Signaling** **Hypothesis Summary:** ## Mechanistic Overview Direct Toxicity Hypothesis: β-A
This challenge targets the hypothesis: **Oligodendrocyte Precursor Cell Senescence in White Matter Disease** **Hypothesis Summary:** ## Mechanistic Overview Oligodendrocyte Precursor Cell Senescence
This challenge targets the hypothesis: **Complement C1q-Mediated Synaptic Pruning Drives Early Cognitive Decline in Alzheimer's Disease** **Hypothesis Summary:** C1q (classical complement cascade ini
This challenge targets the hypothesis: **Lysosomal Cathepsin-Dependent Tau Clearance** **Hypothesis Summary:** ## Mechanistic Overview Lysosomal Cathepsin-Dependent Tau Clearance starts from the clai
This challenge targets the hypothesis: **Closed-loop transcranial focused ultrasound to restore hippocampal gamma oscillations via somatostatin interneuron disinhibition in Alzheimer's disease** **Hy
This challenge targets the hypothesis: **HDL/apoE Particle Remodeling as a Therapeutic Switch for CAA Prevention** **Hypothesis Summary:** ## Mechanistic Overview HDL/apoE Particle Remodeling as a Th
This challenge targets the hypothesis: **Kinetic Modeling Predicts Threshold-Dependent Efficacy—Early Intervention Required for Monotherapy** **Hypothesis Summary:** **Molecular Mechanism and Rationa
This challenge targets the hypothesis: **LPCAT3-Mediated Lands Cycle Amplification of Ferroptotic Vulnerability in Disease-Associated Microglia** **Hypothesis Summary:** ## Mechanistic Overview LPCAT
This challenge targets the hypothesis: **Circadian Clock-Autophagy Synchronization** **Hypothesis Summary:** ## Mechanistic Overview Circadian Clock-Autophagy Synchronization starts from the claim th
This challenge targets the hypothesis: **Hypothesis 3: HepaCAM-Containing Extracellular Vesicles** **Hypothesis Summary:** ## Mechanistic Overview Hypothesis 3: HepaCAM-Containing Extracellular Vesic
This challenge targets the hypothesis: **Cholinergic Basal Forebrain-Hippocampal Circuit Protection** **Hypothesis Summary:** ## **Molecular Mechanism and Rationale** The cholinergic basal forebrain
This challenge targets the hypothesis: **Repeat-domain exposure defines seed-competent tau conformers** **Hypothesis Summary:** Tau assemblies become seed-competent when their repeat-domain surfaces
This challenge targets the hypothesis: **PARP1-NAD+-AIF bioenergetic collapse drives a self-amplifying parthanatos loop** **Hypothesis Summary:** Oxidative DNA damage hyperactivates PARP1, rapidly co
This challenge targets the hypothesis: **N-acetylcysteine (NAC) / System Xc⁻ - Mediated GSH Support for Neurovascular Unit Protection** **Hypothesis Summary:** NAC serves as a GSH precursor and direc
This challenge targets the hypothesis: **cGAS-STING Pathway Hyperactivation Mediates Tau Propagation** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The cGAS-STING (cyclic GMP-AMP sy
This challenge targets the hypothesis: **Synaptic Vesicle Cycle Hijacking: Shared Convergent Mechanism for α-Synuclein (PD) and Tau (AD) Trans-synaptic Propagation** **Hypothesis Summary:** Convergen
This challenge targets the hypothesis: **METTL3-Mediated m6A Modification of lncRNA-0021 Regulates miR-6361 Sequestration Capacity** **Hypothesis Summary:** ## **Molecular Mechanism and Rationale**
This challenge targets the hypothesis: **INPP5D (SHIP1) Inhibition to Shift Microglial Polarization** **Hypothesis Summary:** ## Mechanistic Overview INPP5D (SHIP1) Inhibition to Shift Microglial Pol
This challenge targets the hypothesis: **Night-phase orexin receptor antagonism rescues AD by restoring sleep-dependent clearance** **Hypothesis Summary:** Timed OX1R/OX2R antagonism during the rest
This challenge targets the hypothesis: **APOE4 astrocytes exhibit impaired cholesterol efflux via ABCA1/ABCG1 transporters, driving intracellular lipid droplet accumulation and secondary neuronal chol
This challenge targets the hypothesis: **sTREM2 as Biomarker of Cystatin-C Therapeutic Efficacy** **Hypothesis Summary:** ## Mechanistic Overview sTREM2 as Biomarker of Cystatin-C Therapeutic Efficac
This challenge targets the hypothesis: **Integrated Multi-Analyte CSF Panel Combining YKL-40, sTREM2, and Neurogranin** **Hypothesis Summary:** ## Mechanistic Overview Integrated Multi-Analyte CSF Pa
This challenge targets the hypothesis: **TREM2-APOE4 Co-targeting — Simultaneous Correction of Lipid Sensing and Clearance Deficits** **Hypothesis Summary:** ## Mechanistic Overview TREM2-APOE4 Co-ta
This challenge targets the hypothesis: **p16^INK4a-CCF Axis as Senolytic Timing Biomarker** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The p16^INK4a-CCF axis represents a sophisti
This challenge targets the hypothesis: **Test: TREM2 enhances amyloid clearance** **Hypothesis Summary:** ## Mechanistic Overview Test: TREM2 enhances amyloid clearance starts from the claim that mod
This challenge targets the hypothesis: **TREM2-Dependent Switch Hypothesis: TREM2 Agonism Redirects SPP1 Signaling from Destructive to Restorative** **Hypothesis Summary:** ## Mechanistic Overview TR
This challenge targets the hypothesis: **Temporal SPP1 Inhibition During Critical Windows** **Hypothesis Summary:** ## Mechanistic Overview Temporal SPP1 Inhibition During Critical Windows starts fro
This challenge targets the hypothesis: **ω-3 Docosahexaenoic Acid (DHA) Epoxide Generation via CYP2J2 to Protect Synaptic Membranes from Aβ-Induced Rigidification** **Hypothesis Summary:** The hypoth
This challenge targets the hypothesis: **Dopaminergic Ventral Tegmental-Hippocampal Circuit Protection** **Hypothesis Summary:** ## Mechanistic Overview Dopaminergic Ventral Tegmental-Hippocampal Cir
This challenge targets the hypothesis: **GBA1 Loss Triggers a TFEB-to-TFE3 Compensatory Switch in A9 Dopaminergic Neurons that is Defective Due to LAMP2A Insufficiency** **Hypothesis Summary:** A9 do
This challenge targets the hypothesis: **Selective blockade of classical-pathway activation downstream of C1q will reduce synaptotoxic complement amplification while preserving beneficial C1q recognit
This challenge targets the hypothesis: **Tau/MAP6 ratio as a master switch for microtubule dynamics plasticity** **Hypothesis Summary:** The relative abundance of tau versus MAP6 on individual microt
This challenge targets the hypothesis: **Iron-driven lipid peroxidation and GPX4 failure create a ferroptotic amplification loop** **Hypothesis Summary:** Labile Fe2+ converts H2O2 into hydroxyl radi
This challenge targets the hypothesis: **Tau dysfunction destabilizes labile pool** **Hypothesis Summary:** Loss of tau function (as in disease states) selectively destabilizes the labile microtubule
This challenge targets the hypothesis: **VHH-Fc Fusion Constructs with Separate BBB-Targeting Moiety** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The VHH-Fc fusion construct lever
This challenge targets the hypothesis: **Astrocyte C3aR Signaling as Bifurcation Point for A1/A2 Fate** **Hypothesis Summary:** ## Mechanistic Overview Astrocyte C3aR Signaling as Bifurcation Point f
This challenge targets the hypothesis: **PDE4 Inhibition as Inflammatory Reset for PD Oligodendrocytes** **Hypothesis Summary:** ## Mechanistic Overview PDE4 Inhibition as Inflammatory Reset for PD O
This challenge targets the hypothesis: **TREM2-CSF1R Cross-Talk in Microglial Metabolic Reprogramming** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The TREM2-CSF1R metabolic cross-
This challenge targets the hypothesis: **C1QA/C1QB Subunit-Specific Inhibition to Block Aberrant PV Interneuron Input Elimination in Alzheimer's Disease** **Hypothesis Summary:** **Molecular Mechanis
This challenge targets the hypothesis: **GBA1-Deficiency Disrupts Mitochondrial- Lysosomal Contact Sites by Reducing Miro1 Degradation, Creating a Pink1-Parkin Mitophagy Blockade** **Hypothesis Summa
This challenge targets the hypothesis: **Metabolic NAD+ Salvage Pathway Enhancement Through NAMPT Overexpression** **Hypothesis Summary:** **Molecular Mechanism and Rationale** The NAD+ salvage path
RNA binding protein dysregulation across ALS FTD and AD Linked to 9 hypotheses and 9 targets.
Astrocytes adopt A1 (neurotoxic) and A2 (neuroprotective) phenotypes, but recent single-cell data reveals far greater heterogeneity. Mapping reactive subtypes to disease stages and therapeutic targets
Microglia activate astrocytes via IL-1alpha/TNF/C1q, and reactive astrocytes feed back to microglia via complement/chemokines. Linked to 5 hypotheses and 5 targets.
TDP-43 undergoes liquid-liquid phase separation that becomes pathological. Small molecules targeting phase separation properties could be therapeutic but the design principles are undefined. Linked t
Sleep disruption as cause and consequence of neurodegeneration Linked to 10 hypotheses and 10 targets.
PSP and CBD both involve 4R-tau but produce distinct neuropathological patterns (tufted astrocytes vs astrocytic plaques). Whether tau strains or regional cellular environments drive these differences
Can speech, gait, retinal imaging, sleep, and smartphone data detect neurodegeneration 5-10 years before diagnosis? Linked to 1 hypotheses and 1 targets.
Emerging evidence suggests gut microbial metabolites (SCFAs, TMAO, tryptophan metabolites) may influence amyloid-beta aggregation and neuroinflammation years before clinical symptoms, but causal mecha
Design and execute the proposed experiment to test the hypothesis: 'Closed-loop tFUS to restore hippocampal gamma oscillations via glymphatic enhancement in Alzheimer's disease'. Primary outcome: Peri
Design and execute the proposed experiment to test the hypothesis: 'Real-time gamma-guided tFUS targeting EC-II SST interneurons to restore hippocampal-prefrontal synchrony in early AD'. Primary outco
Design and execute the proposed experiment to test the hypothesis: 'TYROBP (DAP12) Conditional Antagonism for Early-Stage Neuroprotection'. Primary outcome: >=40% TYROBP knockdown in microglia; >=20%
Design and execute the proposed experiment to test the hypothesis: 'TREM2-Mediated Astrocyte-Microglia Cross-Talk in Neurodegeneration'. Primary outcome: Reduction of astrocyte A1 markers (C3, Lcn2 mR
Design and execute the proposed experiment to test the hypothesis: 'Gamma Oscillation Enhancement Synergy'. Primary outcome: Hippocampal soluble Abeta42 reduced >=40% vs sham; CA1 LFP 40 Hz power >=2x
Design and execute the proposed experiment to test the hypothesis: 'H6: Aberrant eIF2alpha Phosphorylation Creates Stalled Translation State'. Primary outcome: p-eIF2alpha/eIF2alpha ratio normalised t
Design and execute the proposed experiment to test the hypothesis: 'Neutral Sphingomyelinase-2 Inhibition for Synaptic Protection in Neurodegeneration'. Primary outcome: Synaptic density (PSD-95 punct
Design and execute the proposed experiment to test the hypothesis: 'miR-155/Interferon-gamma Feedback Loop as a Reversible Molecular Switch'. Primary outcome: miR-155 level in cortical microglia reduc
Design and execute the proposed experiment to test the hypothesis: 'TREM2-Mediated Astrocyte-Microglia Cross-Talk in Neurodegeneration'. Primary outcome: Rescue of A1 astrocyte signature (C3, LCN2, H2
Design and execute the proposed experiment to test the hypothesis: 'Sequential Iron Chelation (Deferoxamine) and GPX4 Restoration (Sulforaphane) Prevents Iron-Ferroptosis-Edema Cascade'. Primary outco
Experiment challenge for hypothesis: Plasma NfL Elevation Secondary to BBB-Associated Transport Dysfunction Enables Longitudinal Neurodegeneration Tracking ## Mechanistic Hypothesis Neurofilament lig
Experiment challenge for hypothesis: Elevated CSF/Serum Albumin Quotient Predicts Neurodegeneration Progression Independent of Age ## Mechanistic Hypothesis Serum albumin is synthesized exclusively b
Experiment challenge for hypothesis: Ketone Utilization Index as Metabolic Flexibility Biomarker ## Mechanistic Hypothesis ## Mechanistic Overview Ketone Utilization Index as Metabolic Flexibility Bi
Experiment challenge for hypothesis: LRP1-Dependent Tau Uptake Disruption ## Mechanistic Hypothesis ## Mechanistic Overview LRP1-Dependent Tau Uptake Disruption starts from the claim that modulating
Experiment challenge for hypothesis: Calcium-Dysregulated mPTP Opening as an Alternative mtDNA Release Mechanism for AIM2 Inflammasome Activation in Neurodegeneration ## Mechanistic Hypothesis ## Mec
Experiment challenge for hypothesis: TREM2-mTOR Co-Agonism for Metabolic Reprogramming ## Mechanistic Hypothesis ## Mechanistic Overview TREM2-mTOR Co-Agonism for Metabolic Reprogramming starts from
Experiment challenge for hypothesis: Dual-Receptor Antibody Shuttling ## Mechanistic Hypothesis ## Mechanistic Overview Dual-Receptor Antibody Shuttling starts from the claim that modulating not yet
Experiment challenge for hypothesis: Prime Editing Precision Correction of APOE4 to APOE3 in Microglia ## Mechanistic Hypothesis ## Mechanistic Overview Prime Editing Precision Correction of APOE4 to
Experiment challenge for hypothesis: Mitochondrial DNA-Driven AIM2 Inflammasome Activation in Neurodegeneration ## Mechanistic Hypothesis ## Mechanistic Overview Mitochondrial DNA-Driven AIM2 Inflamm
Experiment challenge for hypothesis: Targeting the Mechanistic Link Between AQP4 Dysfunction and Ferroptosis Prevents Both Cytotoxic and Vasogenic Edema After Cardiac Arrest ## Mechanistic Hypothesis
Auto-generated from hypothesis h-5b378bd3 (score=0.886). Target gene: TREM2-APOE axis. Can pharmacological dissociation of TREM2-APOE signaling selectively activate disease-associated microglia (DAM)
Auto-generated challenge from hypothesis h-013cc31a80 (score=0.886). Target: CLDN5/ZO-1 tight junction complex; KDR/VEGFR2. Question: Can targeting Focused Ultrasound with Microbubble Contrast Agents
Auto-generated from hypothesis h-d7212534 (score=0.882). Target gene: HDAC2/HDAC3. Does a ketone-body-based epigenetic priming protocol restore physiological histone acetylation balance and improve co
Auto-generated challenge from hypothesis h-ff0d545d (composite_score=0.820). Target gene: HSPB1. Source hypothesis title: HSPB1 Phosphorylation Mimetics to Promote Protective TDP-43 Liquid-Liquid Phas
Challenge generated from hypothesis h-44b1c9d415 (composite_score=0.817). Target gene/pathway: TREM2. Source hypothesis: TREM2-Deficient Microglia as Drivers of Amyloid Plaque Toxicity in Alzheimer's
Falsifiable prediction from high-scoring hypothesis (score=0.729, gene=CDKN1A). Hypothesis: Does distinct phosphorylation state of p21^Cip1 predict cellular responsiveness to autophagy-inducing therap
CyclinD1-Tagged Partial Cellular Reprogramming via Modified Yamanaka Cocktail represents a high-priority challenge in neurodegeneration therapeutics. Partial reprogramming strategies aim to restore yo
Caloric restriction mimetics represent a promising class of interventions targeting metabolic aging in neurodegeneration. The combination of Metformin, Resveratrol, and Rapamycin targets complementary
Falsifiable prediction from high-scoring hypothesis (score=0.728, gene=NR1H2 (LXRβ), ABCA1, ABCG1). Hypothesis: Can selective LXRβ agonism restore cholesterol efflux in APOE4 astrocytes by upregulatin
Falsifiable prediction from high-scoring hypothesis (score=0.728, gene=GPR43 (FFAR2)). Hypothesis: Does restoring gut-microbiome-derived SCFA (butyrate/propionate) levels rescue microglial GPR43-media
Falsifiable prediction from high-scoring hypothesis (score=0.727, gene=TFEB (TFEB), TFE3 (TFE3)). Hypothesis: Does parallel activation of TFEB and TFE3 synergistically enhance lysosomal and mitochondr
Test whether chromatin accessibility changes are upstream drivers of neurodegeneration rather than downstream effects. If true, targeting chromatin regulators should alter disease course.
Auto-generated from hypothesis h-var-e2b5a7e7db (score=0.869). Target gene: GRIN2B. Does GluN2B-mediated thalamocortical signaling control glymphatic tau clearance, and does targeted enhancement reduc
Falsifiable prediction from high-scoring hypothesis (score=0.726, gene=TREM2 and C3). Hypothesis: Can selective modulation of the TREM2-C3 axis (TREM2 agonism + C3 inhibition) simultaneously restore m
Design a causal intervention study testing whether age-related DNA methylation changes drive neurodegeneration. If causal, perturbing epigenetic machinery should alter disease trajectory.
Auto-generated from hypothesis h-e64a33a8 (score=0.867). Target gene: . Does selective inhibition of complement cascade (C1q, C3) protect synapses from complement-mediated pruning in AD without impair
Test whether UBQLN2 mutations cause ALS through disrupted ubiquitylation-dependent turnover. If true, mapping E3 ligases and perturbing UBQLN2 puncta lifetime should shift disease progression in ALS m
Design and execute experiments to test whether age-linked CpG drift is a causal driver rather than a passive correlate of neurodegeneration. If causal, locus-specific epigenome editing should shift ce
Falsifiable prediction from high-scoring hypothesis (score=0.724, gene=TARDBP). Hypothesis: Does TDP-43 liquid-liquid phase separation (LLPS) state — measured by FRAP — predict therapeutic response to
Auto-generated challenge from hypothesis h-0bcda2e0 (composite_score=0.811). Target gene: APOE, CLU. Source hypothesis title: CLU/APOE Duality in Amyloid Clearance Determines Cell-Type-Specific Vulner
Auto-generated challenge from hypothesis h-5d100034 (composite_score=0.812). Target gene: SLC7A11/GPX4. Source hypothesis title: SLC7A11 System Activation Restores Cystine Uptake and GSH Synthesis to
Auto-generated challenge from hypothesis h-var-7c976d9fb7 (composite_score=0.812). Target gene: TREM2. Source hypothesis title: TREM2-Mediated Microglial Dysfunction Disrupts Perivascular Tau Clearanc
Auto-generated challenge from hypothesis SDA-2026-04-02-gap-tau-prop-20260402003221-H003 (composite_score=0.814). Target gene: CHMP4B. Source hypothesis title: Extracellular Vesicle Biogenesis Modulat
Challenge generated from hypothesis h-var-261452bfb4 (composite_score=0.801). Target gene/pathway: ACSL4. Source hypothesis: 40 Hz Gamma Entrainment Gates ACSL4-Mediated Ferroptotic Priming to Selecti
Challenge generated from hypothesis h-0ca0f0f8f2 (composite_score=0.800). Target gene/pathway: TREM2/TYROBP. Source hypothesis: TREM2 Deficiency Drives Microglial Senescence via Lipid Metabolism Dysre
Auto-generated challenge from hypothesis h-var-76afa28dfc (score=0.852). Target: SMPD1. Question: Can targeting Senescent Cell ASM-Complement Cascade Intervention lead to therapeutic benefit in neurod
Auto-generated challenge from hypothesis h-881bc290 (score=0.858). Target: NAMPT. Question: Can targeting TREM2 R47H Variant-Driven Metabolic Dysfunction as the Primary Trigger lead to therapeutic ben
Auto-generated challenge from hypothesis h-var-6c90f2e594 (score=0.863). Target: PVALB. Question: Can targeting Optogenetic restoration of hippocampal gamma oscillations via selective PV inter lead to
Challenge generated from hypothesis h-f32ba823 (composite_score=0.798). Target gene/pathway: MANF, CDNF. Source hypothesis: Hypothesis 1: MANF/CDNF Signaling as Primary Neuroprotective Effector. ## F
Auto-generated from hypothesis h-var-862d6a66d2 (score=0.863). Target gene: PVALB. Does closed-loop focused ultrasound targeting EC-II PV interneurons restore theta-gamma coupling and prevent tau seed
Challenge generated from hypothesis h-48858e2a (composite_score=0.798). Target gene/pathway: TREM2. Source hypothesis: Microglial TREM2-SYK Pathway Enhancement. ## Falsifiable Predictions 1. SYK acti
Lysosomal acidification is critical for both chaperone-mediated autophagy (CMA via LAMP2A) and glucocerebrosidase activity (GCase/GBA1). The convergence hypothesis proposes that simultaneous dysfuncti
NAD+ depletion is a hallmark of neuronal aging and Alzheimer's disease, impairing SIRT1/SIRT3-mediated neuroprotection. NMN (nicotinamide mononucleotide) supplementation can restore NAD+ but its CNS b
Dasatinib and quercetin (D+Q) have shown senolytic activity in peripheral tissues and rodent brains. The critical question for Alzheimer's disease is whether D+Q specifically clears p16Ink4a-high sene
The mTORC1-TFEB axis controls autophagy capacity. In aging neurons, chronic mTORC1 activation keeps TFEB cytoplasmic, impairing lysosomal biogenesis and autophagic clearance. Strategies to displace mT
Mitochondrial dynamics imbalance — excessive fission (DRP1) and insufficient fusion (MFN2) — is consistently observed in Parkinson's and Alzheimer's disease neurons. The hypothesis proposes a vicious
Two major strategies target senescent cells in neurodegeneration: suppressing their inflammatory secretome (SASP) via JAK/STAT inhibitors, or eliminating them via senolytics. This tradeoff analysis ch
NG2+ oligodendrocyte progenitor cells are among the most metabolically active cell populations in the aging brain. AMPK/mTOR dysregulation in OPCs may impair their differentiation capacity, contributi
Falsifiable prediction from high-scoring hypothesis (score=0.723, gene=GRIN2B). Hypothesis: Does enhancing GluN2B-containing NMDA receptor activity at cortico-striatal synapses restore 30-40 Hz beta-b
Falsifiable prediction from high-scoring hypothesis (score=0.725, gene=S100B). Hypothesis: Can serum S100B serve as an early biomarker of BBB dysfunction in AD, preceding amyloid/tau pathology by >3 y
Auto-generated from hypothesis h-f1c67177 (score=0.879). Target gene: IFNG. Does identifying the critical temporal window for metabolic boosting therapy determine successful microglial state transitio
Auto-generated from hypothesis h-var-e0e82ff2e2 (score=0.869). Target gene: CYP46A1. Does CYP46A1-mediated cholesterol dysregulation drive TREM2-dependent microglial senescence, and does gene therapy
Auto-generated from hypothesis h-var-9da3ee8550 (score=0.867). Target gene: PVALB. Does closed-loop transcranial alternating current stimulation (tACS) targeting entorhinal cortex layer II PV interneu
Test whether the balance between K48 (degradative) and K63 (signaling) ubiquitin chains drives UBQLN2-related ALS. If true, restoring this balance should reduce aggregation and improve outcomes.
Test whether chromatin accessibility changes during aging drive neurodegeneration. If true, interventions that restore youthful chromatin states should slow disease progression.
Test whether gut microbiome dysbiosis drives neuroinflammation through TLR4 priming. If true, butyrate-restoring interventions should reduce neuroinflammation before neurodegeneration markers improve.
Test whether tight-junction remodeling drives blood-brain barrier permeability changes detectable before clinical neurodegeneration. If true, dynamic contrast MRI + CSF/serum albumin ratio should pred
Test whether plasma GFAP distinguishes harmful BBB permeability mechanisms from compensatory states. If true, GFAP-targeted studies should predict therapeutic response.
Test whether plasma LPS-binding protein mediates the gut-brain axis in neurodegeneration. If true, measuring it should predict response to gut-targeted interventions.
GBA1 mutations cause Parkinson's disease partly by creating a lipid-trafficking feedforward loop: reduced GCase activity → glucosylceramide accumulation → retromer dysfunction → further GBA1 trafficki
Challenge generated from hypothesis SDA-2026-04-02-gap-tau-prop-20260402003221-H002 (composite_score=0.780). Target gene/pathway: TREM2. Source hypothesis: TREM2-mediated microglial tau clearance enha
Challenge generated from hypothesis h-var-d98a992599 (composite_score=0.784). Target gene/pathway: SST. Source hypothesis: Closed-loop tACS targeting entorhinal cortex layer II SST interneurons to act
Challenge generated from hypothesis hyp-SDA-2026-04-12-20260411-082446-2c1c9e2d-2 (composite_score=0.785). Target gene/pathway: CHRNA7, BACE1. Source hypothesis: Vicious Cycle Hypothesis: Cholinergic
Challenge generated from hypothesis h-d4ac0303f6 (composite_score=0.790). Target gene/pathway: LRRK2. Source hypothesis: G2019S primarily raises baseline LRRK2 kinase activity rather than amplifying l
Challenge generated from hypothesis h-var-ce41f0efd7 (composite_score=0.792). Target gene/pathway: TREM2. Source hypothesis: Microglial-Mediated Tau Clearance Dysfunction via TREM2 Signaling. ## Fals
Auto-generated challenge from hypothesis h-var-6957745fea (composite_score=0.805). Target gene: AIM2/CASP1/IL1B/PYCARD. Source hypothesis title: Mitochondrial DAMPs-Driven AIM2 Inflammasome Activation
Auto-generated challenge from hypothesis h-2dbf5f1f (composite_score=0.806). Target gene: IL6R/IL6. Source hypothesis title: IL-6 Trans-Signaling Blockade at the Oligodendrocyte-Microglia Interface. S
Auto-generated challenge from hypothesis h-3b539acf (composite_score=0.806). Target gene: PADI4. Source hypothesis title: Neutrophil Extracellular Trap (NET) Inhibition. Success criteria: 1. PADI4 inh
Auto-generated challenge from hypothesis h-5b35f7a5 (composite_score=0.808). Target gene: HCAR2. Source hypothesis title: Beta-Hydroxybutyrate Receptor (HCAR2) Signaling Links Ketone Deficiency to Neu
Auto-generated challenge from hypothesis h-0cbe9bac (composite_score=0.808). Target gene: CSF1R-TREM2. Source hypothesis title: CSF1R-TREM2 Co-Agonism for Sustained Microglial Expansion. Success crite
Auto-generated challenge from hypothesis h-var-95b0f9a6bc (score=0.821). Target: MAPT. Question: Can targeting Glymphatic-Mediated Tau Clearance Dysfunction lead to therapeutic benefit in neurodegener
Auto-generated challenge from hypothesis h-var-adfecef68a (score=0.822). Target: NLRP3, CASP1, IL1B, PYCARD. Question: Can targeting Astrocyte-Intrinsic NLRP3 Inflammasome Activation by Alpha-Synuclei
Auto-generated challenge from hypothesis h-22d2cfcd (score=0.824). Target: SIRT1 and PGC1alpha (PPARGC1A) axis. Question: Can targeting SIRT1 Activation Couples Mitochondrial Biogenesis to Ferroptosis
Auto-generated challenge from hypothesis h-var-a0933e666d (score=0.824). Target: AIM2, CASP1, IL1B, PYCARD, TARDBP. Question: Can targeting Microglial AIM2 Inflammasome as the Primary Driver of TDP-43
Auto-generated challenge from hypothesis h-7b7ab657 (score=0.843). Target: PVALB, CREB1, lncRNA-9969, neuronal autophagy pathway. Question: Can targeting Gamma Oscillation Entrainment Enhances lncRNA-
Auto-generated challenge from hypothesis h-ccc05373 (score=0.848). Target: MAPK14/PRMT1. Question: Can targeting p38α Inhibitor and PRMT1 Activator Combination to Restore Physiological TDP-43 P lead t
Auto-generated from hypothesis h-d5dc9661b1 (score=5.500). Target gene: HDAC3/GPR43 (FFAR2)/IL10/TREM2/OCLN. Disease: neurodegeneration. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h
Auto-generated from hypothesis h-495e04396a (score=6.000). Target gene: SNCA/p-SNCA (Ser129)/GBA/LRRK2. Disease: neurodegeneration. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h-495e
Auto-generated from hypothesis h-8d124bccfe (score=7.000). Target gene: SNCA/GFAP/VIP/nNOS/CHAT. Disease: neurodegeneration. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h-8d124bccfe
Auto-generated from hypothesis h-f811f090ac (score=7.200). Target gene: TLR4/NFKB1/NLRP3. Disease: neurodegeneration. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h-f811f090ac
Auto-generated from hypothesis h-var-f4b4d4de63 (score=0.846). Target gene: PVALB. Does tFUS-mediated BBB opening with optogenetic PV interneuron activation restore hippocampal gamma oscillations in e
Auto-generated from hypothesis h-d5dea85f (score=0.847). Target gene: . Can TREM2/SASP axis modulation prevent microglial senescence and restore homeostatic surveillance in neurodegeneration?
Auto-generated from hypothesis h-var-de1677a080 (score=0.990). Target gene: TREM2. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-de1677a080
Auto-generated from hypothesis SDA-2026-04-16-hyp-e5bf6e0d (score=1.000). Target gene: SIRT1,PGC1A,NAMPT. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/SDA-
Falsifiable prediction from high-scoring hypothesis (score=0.721, gene=NR1H2 (LXRβ)). Hypothesis: Does APOE4-driven impairment of oligodendrocyte cholesterol efflux via reduced LXRβ signaling cause my
Falsifiable prediction from high-scoring hypothesis (score=0.720, gene=C9orf72). Hypothesis: Does antisense oligonucleotide (ASO) targeting C9orf72 repeat expansions reduce TDP-43 mislocalization and
Falsifiable prediction from high-scoring hypothesis (score=0.720, gene=NLRP3/CASP1/IL1B). Hypothesis: Does the NLRP3 inflammasome enter a locked 'hyperactive' state in senescent astrocytes that perpet
Falsifiable prediction from high-scoring hypothesis (score=0.720, gene=VCP). Hypothesis: Do VCP/p97 mutations (common in IBMPFD/ALS) impair extraction of ubiquitinated autophagy substrates, causing pr
Auto-generated from hypothesis h-0f025d94 (score=0.941). Target gene: PLCG2. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-0f025d94
Auto-generated from hypothesis h-var-e95d2d1d86 (score=0.944). Target gene: PVALB. Disease: Alzheimer's disease. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-e95d2d1d86
Auto-generated from hypothesis h-var-b7e4505525 (score=0.948). Target gene: SST. Disease: Alzheimer's disease. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-b7e4505525
Auto-generated from hypothesis h-4ed1b5a7 (score=0.919). Target gene: HK2. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-4ed1b5a7
Auto-generated from hypothesis h-var-bed9f3b7ed (score=0.907). Target gene: TREM2. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-bed9f3b7ed
Auto-generated from hypothesis h-var-18aae53fe9 (score=0.910). Target gene: SMPD1. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-18aae53fe9
Auto-generated from hypothesis h-var-a4975bdd96 (score=0.912). Target gene: CCK. Disease: Alzheimer's disease. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-a4975bdd96
Auto-generated from hypothesis h-var-a09491064e (score=0.914). Target gene: SMARCA4. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-a09491064e
Auto-generated from hypothesis h-2600483e (score=0.919). Target gene: CYP46A1. Disease: neurodegeneration. Prediction count: 5. Hypothesis: https://scidex.ai/hypothesis/h-2600483e
Auto-generated from hypothesis h-b2aeabb1 (score=0.919). Target gene: PPARA. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-b2aeabb1
Auto-generated from hypothesis SDA-2026-04-16-hyp-4a6e22aa (score=0.921). Target gene: ATG7,BCL2,BCL2L1. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/SDA-2
Auto-generated from hypothesis h-var-3fbcfc0e6c (score=0.921). Target gene: CYP46A1. Disease: neurodegeneration. Prediction count: 5. Hypothesis: https://scidex.ai/hypothesis/h-var-3fbcfc0e6c
Auto-generated from hypothesis h-var-f110ef2e0a (score=0.922). Target gene: SST. Disease: Alzheimer's disease. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-f110ef2e0a
Auto-generated from hypothesis h-var-7eaceb5a55 (score=0.927). Target gene: PVALB. Disease: Alzheimer's disease. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-7eaceb5a55
Auto-generated from hypothesis h-45d23b07 (score=0.933). Target gene: COMPOSITE_BIOMARKER. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-45d23b07
Auto-generated from hypothesis h-cef0dd34 (score=0.938). Target gene: CSF p-tau217 (biomarker), lncRNA-0021, hUC-MSC exosomes. Disease: molecular neurobiology. Prediction count: 1. Hypothesis: https:/
Auto-generated from hypothesis h-var-08a4d5c07a (score=0.888). Target gene: NLRP3, CASP1, IL1B, PYCARD. Disease: neurodegeneration. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h-var-
Auto-generated from hypothesis h-b2ebc9b2 (score=0.892). Target gene: SLC16A1, SLC16A7, LDHA, PDHA1. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-b2ebc9b
Auto-generated from hypothesis h-var-66156774e7 (score=0.892). Target gene: TREM2. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-66156774e7
Auto-generated from hypothesis h-8efcb4cf (score=0.887). Target gene: TREM2. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-8efcb4cf
Auto-generated from hypothesis h-var-b7de826706 (score=0.895). Target gene: SIRT1. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-b7de826706
Auto-generated from hypothesis h-3685e352 (score=0.898). Target gene: CSF1R. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-3685e352
Auto-generated from hypothesis hyp-SDA-2026-04-12-20260411-082446-2c1c9e2d-1 (score=0.887). Target gene: APP/PSEN1 (Aβ production), CHAT (cholinergic synthesis). Disease: neurodegeneration. Prediction
Auto-generated from hypothesis SDA-2026-04-02-gap-tau-prop-20260402003221-H004 (score=0.787). Target gene: VCP. Disease: neurodegeneration. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesi
Auto-generated from hypothesis h-da9af6a77a (score=0.790). Target gene: SIRT1/NAD+ axis. Disease: neurodegeneration. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h-da9af6a77a
Auto-generated from hypothesis h-a9f2570b (score=0.793). Target gene: C1QA, C1QB, C3, IL1B. Disease: neurodegeneration. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h-a9f2570b
Auto-generated from hypothesis h-ea85fbfb90 (score=0.790). Target gene: MAPT. Disease: neurodegeneration. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h-ea85fbfb90
Auto-generated from hypothesis h-var-ee70969116 (score=0.797). Target gene: PVALB. Disease: Alzheimer's disease. Prediction count: 1. Hypothesis: https://scidex.ai/hypothesis/h-var-ee70969116
Auto-generated from hypothesis h-ecd9ed6c (score=0.784). Target gene: CHI3L1. Disease: neurodegeneration. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h-ecd9ed6c
Auto-generated from hypothesis h-31ca9240f9fc (score=0.799). Target gene: TBK1 → NF-κB / IRF3 / p62-autophagy / cGAS-STING axis. Disease: ALS. Prediction count: 2. Hypothesis: https://scidex.ai/hypoth
Auto-generated from hypothesis h-7e9718dbda (score=0.800). Target gene: TFRC (TfR1); endosomal acidification pathway. Disease: neurodegeneration. Prediction count: 1. Hypothesis: https://scidex.ai/hyp
Auto-generated from hypothesis h-7d24e096 (score=0.801). Target gene: sTREM2/membrane-TREM2/ADAM10. Disease: neuroimmunology. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h-7d24e096
Auto-generated from hypothesis h-var-22c38d11cd (score=0.801). Target gene: ACSL4. Disease: Alzheimer's Disease. Prediction count: 2. Hypothesis: https://scidex.ai/hypothesis/h-var-22c38d11cd